Pharmacogenomics

What the source does

• FilesystemNone observedNo reads or writes in the source
• NetworkNone observedNo outbound calls in the source
• ShellNone observedNo commands run in the source
• DependenciesPinnedNothing floats
• SecretsNone foundNo keys in source

Five audit layers

Gates applied: no behavioural pass.

Audit 0.4.1 · source sha c8c1fc3a2b13 · 19 Oct 2026Report an issue or request a re-scan

• PublisherGPTomics GitHub organizationOwner of the repository this skill is read from
• Source folderGPTomics/bioSkills/clinical-databases/pharmacogenomicsThe exact folder we audited
• LicenceMITAs the repository states it
• Commit pinned for this verdictc8c1fc3a2b13A new audit runs when the source changes
• Repository statusArchivedLast push 65 days ago
• Sandboxed runNot runSkills are read, not executed; layer L4 is skipped

Its description: Queries PharmGKB / CPIC / DPWG for drug-gene interactions; calls CYP2D6/CYP2C9/CYP2C19/DPYD/TPMT/NUDT15/UGT1A1/SLCO1B1 star alleles and phenotype with PharmCAT, Cyrius (CYP2D6 structural variants), Aldy, Stargazer;…

---
name: bio-clinical-databases-pharmacogenomics
description: Queries PharmGKB / CPIC / DPWG for drug-gene interactions; calls CYP2D6/CYP2C9/CYP2C19/DPYD/TPMT/NUDT15/UGT1A1/SLCO1B1 star alleles and phenotype with PharmCAT, Cyrius (CYP2D6 structural variants), Aldy, Stargazer; applies Caudle 2020 activity-score translation. Use when implementing pharmacogenomic-guided prescribing, applying CPIC vs DPWG guidance, screening HLA risk alleles for ICI / antiepileptics / abacavir, or interpreting compound TPMT+NUDT15 thiopurine risk.
tool_type: mixed
primary_tool: PharmCAT
---

## Version Compatibility

Reference examples tested with: PharmCAT 2.13+, Cyrius 1.1+ (Chen 2021), Aldy 4.0+, Stargazer 2.0+, StarPhase 1.0+ (PacBio HiFi), HIBAG 1.40+, requests 2.31+, pandas 2.2+. CPIC guideline versions are gene-specific; PharmVar releases are quarterly. DPYD dosing uses the CPIC gene activity-score system (Amstutz 2018 *Clin Pharmacol Ther* 103:210, the 2017-update guideline); the 2025 TPMT/NUDT15 update (Maillard 2026) refines compound-IM dosing.

Before using code patterns, verify installed versions match. If versions differ:
- Python: `pip show <package>` then `help(module.function)` to check signatures
- CLI: `<tool> --version` then `<tool> --help` to confirm flags

If code throws ImportError, AttributeError, or TypeError, introspect the installed package and adapt the example to match the actual API rather than retrying. PharmVar is the authoritative star-allele source (`https://www.pharmvar.org`); the older Human CYP Allele Nomenclature Database was deprecated in 2017.

# Pharmacogenomics; Star Alleles, Activity Scores, and CPIC/DPWG Guidance

**'What is my patient's CYP2D6 metabolizer status and should I adjust their tamoxifen dose?'** -> Call star alleles (haplotype-level), translate diplotype -> activity score -> phenotype, apply CPIC + DPWG dosing.

- CLI (recommended): `pharmcat -vcf input.vcf.gz -o pharmcat_out`; CPIC-recommended, single-tool reporting
- CLI (CYP2D6 SV-aware): `cyrius -m sample.bam -o cyrius_out`; mandatory addition for CYP2D6
- CLI (multi-gene CN-aware): `aldy genotype -p illumina sample.bam`; alternative
- CLI (long-read 8-field): PacBio HiFi `starphase`; transplant-grade including HLA
- R (SNP-array): HIBAG for HLA-B*57:01/B*15:02/B*58:01/A*31:01 imputation
- API: `requests.get('https://api.pharmgkb.org/v1/data/clinicalAnnotation', ...)`

## Governance: CPIC vs DPWG vs PharmGKB vs FDA

These four authorities are routinely conflated. They differ in scope, scale, and recommendations:

| Authority | Scope | Output | Anchors |
|-----------|-------|--------|---------|
| **CPIC** (US Clinical Pharmacogenetics Implementation Consortium) | Once a result is available, what to prescribe | Level A/B/C/D gene-drug pair + strength of recommendation per phenotype + evidence quality | ~26 guidelines, ~25 genes, 100+ drugs as of 2026 |
| **DPWG** (Dutch Pharmacogenetics Working Group) | Whether to test AND what to prescribe | 5-pt (0-4) evidence + 7-pt (AA-F) clinical-relevance scale | G-Standaard (Dutch EHR-integrated); RCT-validated via PREPARE |
| **PharmGKB clinical annotation levels** | Evidence cataloguing | 1A/1B/2A/2B/3/4 | 1A = guideline OR medical-society OR PGRN/eMERGE implementation; NOT pure evidence |
| **FDA Table of Pharmacogenomic Biomarkers** | Drug label info | ~300 drugs (informational) | NOT an actionability list; many entries are dosing-suggestion-only |
| **FDA Table of Pharmacogenetic Associations** | Actionable subset | Closer to CPIC | Compare head-to-head with CPIC |

**Bank et al 2018** *Clin Pharmacol Ther* 103:599 (DOI 10.1002/cpt.762) is the canonical CPIC-vs-DPWG comparison. Notable disagreements:
- CYP2D6 IM + multiple antidepressants: DPWG actionable; CPIC says insufficient evidence.
- HLA-B*15:11 carbamazepine: DPWG actionable; CPIC silent.
- CYP2C19 IM + voriconazole: dosing magnitudes differ 25-50%.

**Common PGx-evidence critiques:** (1) EUR over-representation in discovery cohorts; (2) most PGx RCTs are open-label / prescriber-unblinded; (3) publication bias in antiseizure PGx may overstate effects ~2x; (4) subjective composite endpoints.

## PharmGKB Clinical Annotation Levels: What 1A Actually Means

| Level | Requirement |
|-------|-------------|
| **1A** | Variant-drug pair appears in CPIC guideline OR medical-society guideline OR is implemented at a PGRN/eMERGE site |
| **1B** | Replication in multiple cohorts; preponderance of evidence; no formal guideline yet |
| **2A** | Replicated association in a VIP (Very Important Pharmacogene) |
| **2B** | Replicated association in non-VIP gene |
| **3** | Single significant association OR mixed-evidence variant-drug pair |
| **4** | In vitro / case report / molecular evidence only |

1A does NOT require RCT evidence; mechanism + guideline status suffices.

## Star Allele Nomenclature (PharmVar)

PharmVar (`https://www.pharmvar.org`) is authoritative for: CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP2F1, CYP2J2, CYP2R1, CYP2S1, CYP2W1, CYP3A4, CYP3A5, CYP3A7, CYP3A43, CYP4A11, CYP4F2, CYP19A1, CYP26A1, DPYD, NUDT15, SLCO1B1, TPMT.

**A star allele is a haplotype, not a single variant.** *Suballeles* (*1.001, *1.002, etc.) encode the exact SNV+indel pattern within a defined functional haplotype.

**The *1 reference is the PharmVar consensus reference, NOT biological wild type.** Defined as the absence of all known functional variants at the locus.

### CYP2D6 Activity Scores (Caudle 2020 *Clin Transl Sci*; DOI 10.1111/cts.12692)

| Phenotype | Activity score (AS) range |
|-----------|--------------------------|
| **PM (Poor Metabolizer)** | 0 |
| **IM (Intermediate Metabolizer)** | 0 < AS < 1.25 |
| **NM (Normal Metabolizer)** | 1.25 <= AS <= 2.25 |
| **UM (Ultra-rapid)** | AS > 2.25 |

Key per-allele activity values (selected):

| Allele | Activity | Notes |
|--------|----------|-------|
| \*1, \*2, \*35 | 1.0 | Normal |
| \*3, \*4, \*5 (gene deletion),

Excerpt, first 6,000 characters of SKILL.md, verbatim from the audited commit. It is text from someone else’s repository, quoted so you can judge it before your agent reads it.

pip install cyrius
pip install aldy
pip install requests pandas

git clone https://github.com/GPTomics/bioSkills
git -C bioSkills checkout c8c1fc3a2b13

Works in

1. 2026-10-19
   ✓SAFE B 89 / 100

   first audit · source c8c1fc3a2b13

Questions about Pharmacogenomics

• github.com/GPTomics/bioSkills/tree/main/clinical-databases/pharm — the audited source at commit c8c1fc3a2b13 and every finding aboveObserved · 19 Oct 2026

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