Metadata-Version: 2.4 Name: allelix Version: 2.3.1 Summary: Open-source genotype analysis toolkit. Format-agnostic ingestion, database-agnostic annotation, offline-first. Author: Allelix Maintainer-email: dial481 License-Expression: AGPL-3.0-or-later Project-URL: Homepage, https://allelix.io Project-URL: Source, https://github.com/allelix/allelix Project-URL: Issues, https://github.com/allelix/allelix/issues Project-URL: Changelog, https://github.com/allelix/allelix/blob/main/CHANGELOG.md Keywords: genomics,genotype,snp,bioinformatics,dna Classifier: Development Status :: 5 - Production/Stable Classifier: Intended Audience :: Science/Research Classifier: Operating System :: OS Independent Classifier: Programming Language :: Python :: 3 Classifier: Programming Language :: Python :: 3.11 Classifier: Programming Language :: Python :: 3.12 Classifier: Topic :: Scientific/Engineering :: Bio-Informatics Requires-Python: >=3.11 Description-Content-Type: text/markdown License-File: LICENSE Requires-Dist: click>=8.2 Requires-Dist: mwparserfromhell>=0.6 Requires-Dist: pyyaml>=6.0 Requires-Dist: rich>=13.7 Provides-Extra: cadd Requires-Dist: pysam>=0.22; extra == "cadd" Provides-Extra: vcf-index Requires-Dist: pysam>=0.22; extra == "vcf-index" Provides-Extra: dev Requires-Dist: mypy>=1.11; extra == "dev" Requires-Dist: pre-commit>=3.7; extra == "dev" Requires-Dist: pytest>=8.0; extra == "dev" Requires-Dist: pytest-cov<8,>=7; extra == "dev" Requires-Dist: ruff>=0.6; extra == "dev" Requires-Dist: types-PyYAML>=6.0; extra == "dev" Dynamic: license-file
Allelix **Open-source genotype analysis. Format-agnostic. Offline-first.** [Website](https://allelix.io) · [Demo](https://analyze.allelix.io) · [Quickstart](#quickstart) · [Changelog](https://github.com/allelix/allelix/blob/main/CHANGELOG.md) [![python](https://img.shields.io/pypi/pyversions/allelix.svg)](https://www.python.org/downloads/) [![pypi](https://img.shields.io/pypi/v/allelix.svg)](https://pypi.org/project/allelix/) [![license](https://img.shields.io/pypi/l/allelix.svg)](LICENSE) [![CI](https://github.com/allelix/allelix/actions/workflows/ci.yml/badge.svg?branch=main)](https://github.com/allelix/allelix/actions/workflows/ci.yml) [![privacy: local-first](https://img.shields.io/badge/privacy-local--first-success)](#privacy)
# Allelix > **Status:** Production. Nine parser formats (including VCF + gVCF), four annotators (ClinVar + ClinPGx + GWAS Catalog + SNPedia), three GRCh38-only enrichment sources (gnomAD + AlphaMissense + CADD), licensable-source gating for commercial users, dual-build ClinVar caches (GRCh37 + GRCh38), HTML/JSON/terminal reports and annotated VCF output for pipeline integration (v2.3.0+), methylation + pharmacogenomics focused commands, report diffing, persistent config with commercial-mode safety switch. Modern-build position detection requires at least three concordant seed SNPs and an 80% winning ratio before it overrides a fallback or header signal; a tentative GRCh36 signal instead fails closed to GRCh36 because no modern position cache is safe for it (ADR-0025, ADR-0037). No regex on prose anywhere in production. The [Changelog](https://github.com/allelix/allelix/blob/main/CHANGELOG.md) tracks every release. ## Quickstart **Requires Python 3.11 or newer.** On Python 3.10 or older, `pip install allelix` succeeds but the first command fails with `ImportError: cannot import name 'UTC' from 'datetime'` — that's the symptom; the fix is to install on 3.11+. Check with `python --version`. ```bash pip install allelix # Download reference databases (~16 GB default install; ~22 GB if you opt into CADD). # Use --no-gnomad / --no-alphamissense to skip the large ones. # CADD is opt-in: download with `allelix db update --cadd`, then pass # `--cadd` to an analysis or set `sources.cadd = true` persistently. allelix db update # Analyze a genotype file allelix analyze your_genotype_file.txt --output report.html # VCF / gVCF input — same command, auto-detected allelix analyze your_wgs.vcf.gz --output report.html # Multi-sample VCF — pick which sample to analyze allelix analyze trio.vcf.gz --sample HG002 --output report.html # Filter to a custom panel (rsIDs + gene names, one per line; '#' comments and blank lines ignored) allelix analyze your_genotype_file.txt --filter-file my_panel.txt --output report.html # Annotated VCF output — VCF-in / VCF-out for pipeline integration # Writes a valid VCF with annotations as INFO fields + full provenance in the header. # Missing ##contig declarations are synthesized; raw CHROM names are preserved. # Refuses to overwrite; requires VCF or gVCF input. allelix analyze your_wgs.vcf.gz --vcf-out annotated.vcf ``` See [Development](#development) for source installs and running tests, [Managing your data](#managing-your-data) for cache locations and cleanup, and [Troubleshooting](#troubleshooting) for common failure states. ## Supported Formats | Format | Status | Notes | |---|---|---| | MyHappyGenes (Tempus) | ✓ | Tab-delimited, 5 columns. **Build is auto-detected** — real-world MHG exports mislabel the header as "build 37.1" while shipping GRCh38 coordinates. Allelix detects from position data and warns on header/data disagreement (ADR-0021). | | 23andMe | ✓ | Tab-delimited, 4 columns, concatenated genotype. Supports build 36/37/38 from header. I-prefixed probe IDs passed through. | | AncestryDNA | ✓ | Tab-delimited, 5 columns. Chromosome mapping: 23→X, 24→Y, 25→X (PAR), 26→MT. V1 and V2 chip layouts. | | Family Tree DNA | ✓ | CSV, double-quoted fields, concatenated genotype. Build 37 default. | | MyHeritage DNA | ✓ | CSV, same structure as FTDNA. Detected by "MyHeritage" in comment header. Handles double-double-quoted field variant. | | Living DNA | ✓ | Tab-delimited despite `.csv` extension. Handles AX-, AFFX-prefixed and CHR:POS positional SNP IDs. | | FTDNA Illumina raw | ✓ | Tab-delimited variant of the FTDNA export (distinct from the CSV format above). `RSID/CHROMOSOME/POSITION/RESULT` columns. Build 37 default. | | FTDNA FamFinder | ✓ | Third FTDNA file shape: tab-delimited with **separate `ALLELE1` / `ALLELE2` columns** instead of a concatenated `RESULT`. Detected by the `famfinder` substring in the file header plus the 5-column canonical header. Build 37 default. | | VCF / gVCF | ✓ | REF/ALT encoding, `0/1` genotype notation. Plain VCF: absence at a position means reference. gVCF: explicit reference blocks (lines with `` ALT and `END=` INFO) are skipped — they match nothing in any annotation database. Multi-sample files require `--sample `. Streams via stdlib; `.vcf.gz` handled transparently. Optional `pip install allelix[vcf-index]` enables pysam-backed tabix random access for fast `extract --snps` on huge VCFs. | Adding a new format means adding one file to `allelix/parsers/` and registering an instance in the `PARSERS` list in `allelix/parsers/__init__.py`. ### Roadmap | Release | Theme | |---|---| | **v2.2** | Annotation model expansion (cross-source conflict surfacing, risk-allele display, structured MTAG flag), custom-panel UX improvements, methylation panel retune + citations, ClinVar source switch (VCF → `variant_summary.txt`), CLI cleanups (`db clean` / `db path`). | | **v2.3** | Annotated VCF output plus v2.3.1 correctness hardening: cross-build enrichment guards, GWAS effect-type disambiguation, conservative build confidence, SNPedia orientation handling, and strict slow-suite drift verification. | | **v2.4** | Forward-strand normalization for GWAS risk alleles, broader and chromosome-aware build sampling with explicit provenance, test isolation, and deferred cache-loader hardening. | | **Later** | Variant consequences, CNVs and repeat expansions, gnomAD genomes, supplemental genotype-file merging, ancestry estimation, and PRS support. These are directional themes rather than release commitments. | Issues and milestones are tracked at [github.com/allelix/allelix/issues](https://github.com/allelix/allelix/issues). Annotator-level strand-aware carrier matching (R-1) shipped in v2.1.0's ADR-0035 cluster. ## Supported Databases | Database | Status | Notes | |---|---|---| | ClinVar (GRCh37 + GRCh38) | ✓ | Public domain (NCBI). SNVs + indels + multi-allelic sites. **Both builds cached**; `analyze` dispatches by detected build (ADR-0021). Carrier rule (ADR-0007) requires the user to carry the ALT allele. Indel-anchor protection (ADR-0011) prevents single-base array readouts from matching anchor-base indels. | | ClinPGx (formerly PharmGKB) | ✓ | CC BY-SA 4.0. Clinical annotations only — single-rsid SNVs; star alleles and haplotypes deferred (ADR-0009). **Primary non-finding filter is the ClinVar REF carrier rule (ADR-0023):** if ClinVar publishes a single-base REF for the rsid and the user is homozygous for it, the row is suppressed. CPIC's `(rsid, base) → function_class` join (ADR-0020) survives as a secondary tier for rsids ClinVar doesn't catalog. Earlier prose tiers (ADR-0013, ADR-0017, ADR-0018) are superseded. | | CPIC (per-allele function table) | ✓ | Internal data source for the ClinPGx filter. Fetched from `api.cpicpgx.org` at `db update` time. Used to populate the `pharmgkb_allele_function` table — not surfaced to end users as its own annotator. | | SNPedia | ✓ | CC BY-NC-SA 3.0 US. Pre-built cache downloaded via `db update` (~216K wiki pages, ~105K genotype rows). The cache carries SNPedia's orientation metadata: minus-strand alleles are complemented before matching, while unknown-orientation palindromic genotypes abstain rather than risk a false match. If the database is absent, analysis runs without it. For commercial use, pass `--exclude-snpedia`. The cache can also be rebuilt from source via `scripts/scrape_snpedia.py` + `scripts/parse_snpedia.py`. | | GWAS Catalog | ✓ | Public domain (EBI/NHGRI). Trait–SNP associations with p-values and effect sizes. Carrier rule (ADR-0007) requires the user to carry the risk allele. P-value magnitude scoring maps continuous p-values to the 0–10 scale; only a confidence-interval field that positively identifies a bare odds ratio receives the odds-ratio modifier. Beta coefficients and ambiguous or unit-bearing effects receive no modifier (ADR-0038). Unknown-risk-allele entries fire on rsID match alone but are capped at 3.0. GWAS risk-allele strand normalization remains deferred to v2.4. | | gnomAD | ✓ | ODbL v1.0. **GRCh38-only enrichment annotator** — adds population allele frequency context to existing annotations. Shows how common each variant is in the general population (~16M exome variants from 730K individuals). A pathogenic variant that 35% of people carry reads very differently from one seen in 0.001%. Pre-built cache downloaded via `db update` (~6GB on disk). It is deliberately disabled, including for rsID resolution, on GRCh37 and GRCh36 inputs. Use `--no-gnomad` to skip. | | AlphaMissense | ✓ | CC BY 4.0. **GRCh38-only enrichment annotator** — adds DeepMind's protein-structure-based pathogenicity predictions to existing annotations. Scores 71M missense variants on a 0–1 scale: <0.34 = likely benign, >0.564 = likely pathogenic. Complements ClinVar's expert classifications with computational predictions — especially valuable for variants ClinVar hasn't reviewed yet. Pre-built cache downloaded via `db update` (~8GB on disk). It is deliberately disabled on GRCh37 and GRCh36 inputs. Use `--no-alphamissense` to skip. | | CADD | ✓ | LicenseRef-CADD (non-commercial). **GRCh38-only enrichment annotator** — adds PHRED-scaled deleteriousness scores from CADD v1.7. **Opt-in**, disabled by default and always disabled on GRCh37 and GRCh36 inputs; see [CADD modes](#cadd-modes) below for details. | ### CADD modes CADD ranks how deleterious any single-nucleotide variant is using 100+ annotation tracks (coding, non-coding, regulatory). PHRED 10 = top 10% most deleterious, 20 = top 1%, 30 = top 0.1%. **Opt-in**: download the cache with `allelix db update --cadd`. Then pass `--cadd` to an analysis for a one-run override, or enable it persistently with `allelix config set sources.cadd true`. Downloading the cache alone does not change persistent configuration. Use `--no-cadd` to skip enrichment for a single run when it is enabled in config. Two modes: - **Cache mode** (default): pre-built ~5.8 GB SQLite cache (~120M GRCh38 variant keys). Covers nearly every GRCh38 position allelix can annotate from its other databases (gnomAD, AlphaMissense, ClinVar). It is deliberately disabled for GRCh37 and GRCh36 input, even when an rsID happens to exist in the cache. - **Full mode** (`options.cadd_full = true`): tabix queries against the complete CADD v1.7 file via pysam (GRCh38 only). Adds coverage for novel or private variants that appear only in WGS/WES data and are not in any pre-computed database. Requires `pip install allelix[cadd]` for the pysam dependency. If your input is a GRCh38 genotyping chip file, cache mode is normally all you need. CADD enrichment is unavailable for GRCh37 and GRCh36 chip files. ### Build coverage asymmetry (GRCh37 vs GRCh38) ClinVar dispatches per build and ships with both GRCh37 and GRCh38 caches. gnomAD v4.1 exomes, AlphaMissense, and CADD v1.7 are GRCh38 datasets in Allelix's current data model. Their enrichment and provenance are therefore emitted only for GRCh38 analyses; GRCh37 and GRCh36 analyses intentionally receive none of those values. This guard prevents an rsID or coordinate collision from attaching a valid GRCh38 score to the wrong allele on another assembly. The same rule applies to position-based rsID recovery: ClinVar can resolve against the selected GRCh37 or GRCh38 cache, while the broader gnomAD resolver participates only on GRCh38. GRCh37 files with rsIDs still use ClinPGx, GWAS Catalog, and SNPedia normally, but an rsID-less GRCh37 VCF has narrower recovery coverage. If you convert between assemblies, re-normalize REF/ALT as part of the conversion and pass `--build` explicitly when the file does not carry a trustworthy build signal. ### Known ClinPGx limitation: reference-genotype rows where ClinVar and CPIC both lack data ADR-0022 + ADR-0023: a tiny residual of ClinPGx rows may appear in reports even when the user is homozygous reference. ClinPGx publishes one annotation per genotype including the reference homozygote, and for the reference-homozygote row to be suppressed Allelix needs structured data on the variant from either: - **ClinVar's REF allele** (the primary filter — see ADR-0023). Covers any rsID ClinVar catalogs. - **CPIC's per-allele function table** (the secondary fallback — see ADR-0020). Covers rsIDs CPIC has classified. For the rare rsID where ClinPGx has an annotation but *neither* ClinVar nor CPIC has data, the row emits. These are identifiable by a homozygous-reference genotype combined with "decreased risk," "may have a typical response," or similar comparative language. They are an upstream data gap, not an Allelix bug — we surface them honestly rather than hide them behind a curated exclusion list (which would recreate the maintenance trap the v0.5–v0.7 prose filters were trying to escape). The CFTR × ivacaftor leak (~30+ rows on real data, pre-v0.7.3) is fixed by the ADR-0023 ClinVar REF check: CPIC's CFTR vocabulary (`"ivacaftor responsive"`) doesn't match the four-class enum the secondary tier expects, but ClinVar publishes REF for every CFTR rsID, so the primary tier catches them universally. ### Known ClinVar upstream data quality issues Two ClinVar rows in real-world reports are known upstream artifacts, not Allelix bugs: - **PKD1 rs199476100 GG (Pathogenic/Likely pathogenic, magnitude 8.5).** This is a stop-gained variant with a gnomAD frequency of 0.0005% (7 observations in 1.38 million chromosomes). Homozygosity for this variant is biologically implausible — PKD1 is autosomal dominant and the nonsense variant would be embryonic-lethal or devastating in homozygous state. The chip genotyping call is almost certainly a probe artifact. The code correctly reports what ClinVar says and what the chip reads; the error is upstream of Allelix. Future work: population-frequency filtering could flag ultra-rare variants where the chip call is likely unreliable. - **IL10 rs1800896 CT (Pathogenic, magnitude 9.0).** This is a common polymorphism (MAF ~20–40%) in the IL-10 promoter. ClinVar's Pathogenic classification comes from a single submitter for hepatitis C susceptibility; another submission classifies the allele as "Uncertain risk allele" for leprosy susceptibility. Allelix's per-SCV loader keeps each submitter's significance paired with its own condition, so it does not create cross-submission combinations. The remaining concern is the upstream strength of a single-submitter classification on a common variant. Future work: review-status weighting could down-weight that evidence. Neither issue affects Allelix's filter logic. Both are inherent to ClinVar's aggregation model and the limitations of array-based genotyping chips. ## Regulatory Posture Allelix is an informational research tool. It reports classifications made by external databases. It does not independently classify variants, diagnose conditions, or make health recommendations. All variant significance is attributed to its source — Allelix says "ClinVar classifies this variant as pathogenic," never "this variant is pathogenic." This is not a disclaimer afterthought. It is a design constraint that affects model naming, report wording, and category labeling throughout the codebase. ## Privacy - No data leaves your machine. No telemetry. No uploads. No analytics. - Reference databases are downloaded via `allelix db update` and cached locally. - Analysis runs offline against local database caches. A brief freshness check runs before analysis by default (skipped with `--no-update`). ### Output files contain real annotations of your genome The JSON / HTML / terminal output of `allelix analyze` and its focused subcommands contains real annotations against your specific variants — drug-response calls, carrier-status flags, hereditary- disease findings. Wherever you write them via `--output `, that's where they sit until you delete them. Allelix doesn't auto-clean and won't warn you when you write to `/tmp/` or any other shared location. Treat the files as personal data: read them, move them somewhere you control, or delete when you're done. `allelix db clean` (shipped in v2.2.0) handles the cache side of the lifecycle; output reports are still the user's responsibility to manage. ## Configuration Allelix stores persistent configuration in `config.toml` (in the data directory, default `~/.local/share/allelix/`). A default config is created on first run. ```bash # View current config (annotated with license notes) allelix config show # Read a single key allelix config get sources.cadd allelix config get license.commercial # Disable a source permanently allelix config set sources.gnomad false # Enable commercial mode (auto-disables non-commercial sources) allelix config set license.commercial true # Assert that you hold a commercial CADD license allelix config set license.cadd true ``` CLI flags (`--no-gnomad`, `--no-alphamissense`, `--no-cadd`, `--exclude-snpedia`, `--cadd`) override the config for a single run. The config sets the baseline; flags override per-invocation. ### Database sizes and download times Not all databases are equal in size. `allelix db update` downloads them all by default, but you can skip the large ones if disk space or bandwidth is a concern: | Database | On disk | Download time | What it adds | |---|---|---|---| | ClinVar (GRCh37 + GRCh38) | ~900MB | 1–2 min | Core clinical variant classifications. Required. | | ClinPGx + CPIC | ~6MB | seconds | Drug-gene interactions. | | GWAS Catalog | ~200MB | 1–2 min | Trait-SNP associations from genome-wide studies. | | gnomAD | ~6GB | 5–15 min | Population allele frequencies (how common is this variant?). | | AlphaMissense | ~8GB | 5–15 min | Missense pathogenicity predictions (how likely to break protein function?). | | CADD (opt-in) | ~5GB | 5–15 min | Variant deleteriousness scores (how damaging is this variant?). Download with `db update --cadd`; enable per analysis or in config. | gnomAD and AlphaMissense are the largest but add the most interpretive context. gnomAD answers "is this variant rare or common?" — a pathogenic variant carried by 35% of the population reads very differently from one seen in 3 people. AlphaMissense answers "does this missense change likely damage the protein?" — especially valuable for the thousands of variants ClinVar hasn't reviewed yet. To skip either during download: `allelix db update --no-gnomad --no-alphamissense`. To disable permanently: `allelix config set sources.gnomad false`. ### Managing your data Allelix stores reference database caches at `~/.local/share/allelix/` (Linux/macOS) or the XDG-equivalent on other platforms. Default install (no CADD) is ~16 GB on disk; with the CADD opt-in it's ~22 GB. ``` ~/.local/share/allelix/ ├── alphamissense.sqlite ~7.8 GB ├── gnomad.sqlite ~6.1 GB ├── cadd.sqlite ~5.8 GB (only if you opted into --cadd) ├── clinvar.GRCh37.sqlite ~470 MB ├── clinvar.GRCh38.sqlite ~480 MB ├── gwas_catalog_associations.tsv ~700 MB ├── snpedia.sqlite ~390 MB ├── gwas.sqlite ~190 MB └── pharmgkb.sqlite ~14 MB ``` **The caches are disposable and re-downloadable.** Everything here was fetched by `allelix db update` and can be re-fetched at any time. There's no per-user state in the cache — your genotype files never enter this directory. Safe to delete to reclaim space (or to force a full refresh if you suspect a cache went stale): ```bash # Reclaim all ~16-22 GB, with size report and confirmation prompt allelix db clean # Preserve the CADD cache (avoids re-downloading the slowest one, ~5.8 GB) allelix db clean --keep-cadd # Show what would be deleted without acting allelix db clean --dry-run # Scripted use — skip the confirmation prompt allelix db clean --yes # Re-populate from scratch next time you analyze a file allelix db update ``` `db clean` refuses to act on a directory that doesn't contain any recognized allelix cache files — a typo'd `--data-dir ~/Documents` won't result in `rm -rf` against an unrelated tree, even with `--yes`. Pass `--force` if you've staged caches under a non-standard name and want to delete them anyway. For scripting and backup integration, `allelix db path` prints the resolved data directory: ```bash ALLELIX_DATA=$(allelix db path) du -sh "$ALLELIX_DATA" # --check additionally verifies the path is writable; exit non-zero if not allelix db path --check ``` **The one thing worth backing up: `config.toml`.** It lives inside the resolved data directory (typically `~/.local/share/allelix/config.toml`) and stores your license assertions (commercial-mode toggle, CADD opt-in confirmation) and per-source enable/disable settings. It's the only non-reproducible state in the install. The caches will rebuild on the next `db update`; `config.toml` won't. `allelix db clean` always preserves it. To fully uninstall allelix and reclaim everything: ```bash ALLELIX_DATA=$(allelix db path) allelix db clean --yes # reference database caches rm -f "$ALLELIX_DATA/config.toml" # license + source-toggle config pip uninstall allelix ``` ## Data Sources & Licensing Allelix source code is licensed under the **GNU Affero General Public License v3.0 or later** (AGPL-3.0-or-later). Allelix ships with **zero third-party data**. All reference databases are downloaded by the user at runtime via `allelix db update`. Each database retains its original license on the user's machine: | Database | Source | License | Usage | |---|---|---|---| | ClinVar | NCBI | Public domain | No restrictions | | GWAS Catalog | EBI/NHGRI | Public domain | No restrictions | | ClinPGx (formerly PharmGKB) | clinpgx.org | CC BY-SA 4.0 | Attribution required | | CPIC | cpicpgx.org | CC BY-SA 4.0 | Attribution required. Per-allele function data fetched from `api.cpicpgx.org` at `db update` time; used internally for the ClinPGx non-finding filter (ADR-0020), not surfaced as its own annotator. | | SNPedia | snpedia.com | CC BY-NC-SA 3.0 US | Attribution required, **non-commercial only**. Use `--exclude-snpedia` to omit. | | gnomAD | gnomad.broadinstitute.org | ODbL v1.0 | Attribution required. GRCh38-only population allele frequencies for context; not a clinical annotator. Use `--no-gnomad` to omit. | | AlphaMissense | zenodo.org/records/10813168 | CC BY 4.0 | Attribution required. Cheng et al., Science 2023. GRCh38-only missense variant pathogenicity predictions. Use `--no-alphamissense` to omit. | | CADD | cadd.gs.washington.edu | LicenseRef-CADD | Attribution required, **non-commercial by default**. Commercial licenses available from UW CoMotion. GRCh38-only enrichment; download with `allelix db update --cadd`, then enable per analysis with `--cadd` or persistently in config. Use `--no-cadd` to omit. | **Commercial users:** When `license.commercial = true`, non-commercial sources are gated by a three-state permission model. SNPedia is permanently blocked (no commercial license is available). CADD is blocked by default but can be unlocked — the University of Washington offers commercial licenses at `https://els2.comotion.uw.edu/product/cadd-scores`; after purchasing, assert your license with `allelix config set license.cadd true` to re-enable CADD in commercial mode. All other databases (ClinVar, ClinPGx, GWAS Catalog, gnomAD, AlphaMissense) are compatible with commercial use. `allelix config show` displays the permission state for each source. ### SNPedia data download SNPedia data is downloaded automatically by `allelix db update` from a pre-built cache. If the SNPedia database is not present, `allelix analyze` runs normally using all other databases and prints a note that SNPedia data is not available. To rebuild the cache from source (not normally needed): ```bash python scripts/scrape_snpedia.py # scrape 216K pages from bots.snpedia.com (1-4 hours) python scripts/parse_snpedia.py # parse raw wiki markup into structured genotype rows ``` ### Known SNPedia source data quality notes SNPedia appears frozen — no edits have been observed since mid-2023. The data below reflects the state of the wiki at scrape time (May 2026) and is unlikely to change. Of the 104,806 genotype pages in the archive: - **103 pages have empty or missing allele fields.** These are incomplete entries on the source wiki — the `{{Genotype}}` template was created but the `allele1`/`allele2` fields were never filled in (e.g., `Rs1131692198(;)` with `|allele1=\n|allele2=\n`). All 103 were verified against the live site on 2026-05-21; every one matches the source exactly. The annotator silently skips these — they cannot match any user genotype. - **1 page has no `{{Genotype}}` template at all.** `Rs1799853(T)` is a malformed single-allele page (`{{is a|genotype}}` instead of a proper genotype template). Skipped by the parser. - **2 pages have a space before the parenthesis in the title** (`Rs52820871 (G;G)` and `Rs52820871 (G;T)` instead of the standard `Rs52820871(G;G)` format). The annotator handles both title styles. None of these are scraping errors. They are editorial inconsistencies on the source wiki. The annotator handles all of them correctly: incomplete entries are skipped, variant title formats are matched, and no false annotations are produced. The v2.3.1 cache format also preserves each page's SNPedia orientation. Known minus-strand rows are complemented to forward orientation before genotype matching. For palindromic A/T or C/G genotypes whose orientation is unknown, Allelix abstains because the source data cannot distinguish the strands safely. Re-run `allelix db update` after upgrading so a pre-v2.3.1 SNPedia cache is rebuilt. ## Troubleshooting ### `ImportError: cannot import name 'UTC' from 'datetime'` You're on Python 3.10 or older. Allelix requires 3.11+. `python --version` to check; upgrade and reinstall. ### `allelix db update` failed partway through Run it again. The update is idempotent — completed downloads are skipped (signal-matched against the upstream freshness probe), so re-running picks up where it left off. If a specific optional source keeps failing, use its `--no-*` flag to finish the other sources, then remove the skip flag and re-run the full update later. `--only clinvar` exists for the ClinVar-only CI and recovery path; other sources do not currently have standalone `--only` selectors. If the failure is a network timeout on the same source repeatedly, the issue is likely on the source's end (HuggingFace / NCBI / EBI / etc. transient outage). Wait an hour and retry. ### `db status` shows an annotator as "not ready" but the cache files exist on disk Almost always a schema or interpreter version bump in a recent allelix release that invalidates the pre-bump cache. The fix is `allelix db update` — it'll re-ingest only the affected annotators (everything else signal-skips). See the relevant `CHANGELOG.md` entry for "Cache invalidation" notes per release. ### Build mismatch warning when analyzing a known-good file Either: (a) the file's header claims one build and the position data confidently indicates another (real-world MHG / Tempus exports do this — header says 37, positions are 38), or (b) the position signal is too small or mixed to be authoritative. Allelix requires at least three concordant seed SNPs and an 80% winning ratio; weaker GRCh37/38 evidence is reported as tentative and the header or fallback remains effective. A tentative GRCh36 winner is the safety exception: Allelix uses GRCh36 so it cannot accidentally query a modern position cache. Modern position-keyed caches are unavailable for that build (see [`docs/grch36-liftover.md`](https://github.com/allelix/allelix/blob/main/docs/grch36-liftover.md)). If you trust the file's header more than allelix's detection, force the build: `--build grch37` or `--build grch38`. The build banner in the analyze output will reflect what was actually used. ### Is my database stale? How fresh is the data? `allelix db status` shows the ingestion date of each cache. The freshness model is signal-driven: `allelix db update` queries an upstream freshness signal (md5 / etag) per source and re-ingests only when the signal changed. There's no time-based staleness — a 6-month-old cache against an unchanged source IS current. If you want to force a refresh: `allelix db update --force` re-downloads every cache regardless of freshness signal. ### Output reports contain real genome annotations Anything `allelix analyze` writes to disk contains real annotations of your genome. Treat the output files (HTML, JSON, terminal redirects) as sensitive — they're as private as the input genotype file. Allelix does not transmit them; the lifecycle is local. ### Where does allelix store its data? See [Managing your data](#managing-your-data) above for cache locations, the disposability rule, what to back up, and the uninstall procedure. ## Architecture & Design Decisions The "why" behind major design choices lives in [`docs/adr/`](https://github.com/allelix/allelix/blob/main/docs/adr/README.md) as Architecture Decision Records. Read these before proposing changes that touch the parser/annotator interfaces, the regulatory posture, or the data-handling model. Notable load-bearing ADRs: - **ADR-0016 — Data Classification Principle.** Classification reads structured fields only. Regex on prose is forbidden in production code. - **ADR-0020 — CPIC API as the per-allele function source.** The ClinPGx non-finding filter is a table join keyed on `(rsid, base) → clinicalfunctionalstatus`, sourced from CPIC's structured API. Supersedes the prose-extraction tiers from earlier versions (ADR-0017, ADR-0018). - **ADR-0007 — Genotype matching requires the user to carry the ALT allele.** Applies to ClinVar. - **ADR-0009 — ClinPGx matches the user's exact normalized diploid call.** - **ADR-0015 — Mock data generators are the contract.** Fixture shape must mirror real data shape; invariants tested. - **ADR-0036 — Annotated VCF output contract.** JSON and annotated VCF schemas evolve independently. - **ADR-0037 — Conservative position-based build confidence.** A winning build needs at least three matches and an 80% ratio; weaker signals remain diagnostic only. - **ADR-0038 — GWAS effect-modifier disambiguation.** Only positively identified odds ratios receive an effect-size modifier; beta and ambiguous effects abstain. Release history: see [`CHANGELOG.md`](https://github.com/allelix/allelix/blob/main/CHANGELOG.md). ## Development ```bash source .venv/bin/activate pip install -e ".[dev]" # One-time: install pre-commit hooks pre-commit install --hook-type pre-commit ruff check . ruff format --check . pytest ``` The pre-commit hook enforces `ruff check` + `ruff format --check`. If a commit is blocked, fix the underlying problem rather than skipping the hook. For the full real-data release-validation battery — every parser format, VCF/gVCF, PLINK round-trip, edge cases, the GIAB/1000G corpus — see [`test_data/FULL_TEST_PROTOCOL.md`](test_data/FULL_TEST_PROTOCOL.md). That document is the project's real-data testing story; running `pytest` covers the fast suite that gates every commit. ## License GNU Affero General Public License v3.0 or later (AGPL-3.0-or-later). See `LICENSE`.