{
  "abstract": "Pharmacogene missense variants can disrupt protein stability, catalytic competence, or substrate handling through distinct mechanisms. General-purpose predictors estimate clinical pathogenicity as a single scalar, whereas pharmacogene interpretation requires knowing which biochemical dimension a variant perturbs, since that determines whether reduced function is substrate-dependent. Five deep mutational scanning datasets comprising 26,198 missense variants across CYP2C9, CYP2C19, and NUDT15 were assembled from MaveDB. Paired assays showed that this dimensionality dominates the data: 28% of CYP2C9 variants (1,236 of 4,421) decoupled catalytic activity from abundance, and 48% of NUDT15 variants (1,364 of 2,844) decoupled thiopurine sensitivity from stability, with CYP2C9 discordance concentrating at substrate-channel residues. AlphaMissense, a representative general-purpose pathogenicity predictor, scored these classes in line with its clinical training objective rather than the assayed biochemistry, assigning likely-benign scores to 38 of 195 stable-but-dead CYP2C9 variants and likely-pathogenic scores to 140 of 222 destabilized but thiopurine-resistant NUDT15 variants. To test whether this dimensionality is recoverable, a supervised ESM-2 sequence baseline was benchmarked against the ESM1v zero-shot ensemble and AlphaMissense under position-based 5-fold cross-validation, together with 3 architectural extensions: AlphaFold structural features, multitask learning across paired assays, and contact-graph neural networks. The baseline reached Pearson r of 0.54–0.72, matching or marginally exceeding both comparators, and no extension improved upon it. Trained directly on each assay, it nonetheless recovered the paired-assay difference at r = 0.28 for CYP2C9 and 0.43 for NUDT15, separating discordant variants at AUROC 0.60 and 0.51. Pharmacogene interpretation therefore requires assay-specific, substrate-aware functional measurements rather than a single generic score.",
  "abstract_shown": true,
  "affiliations": [
    "Faculty of Engineering, Department of Bioengineering, Bilecik Şeyh Edebali University, TR, Bilecik 11100, Türkiye"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 1,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Kevser Kübra Kırboğa",
      "orcid": "0000-0002-2917-8860"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/9y38beaswwcd2.bib",
  "cited_by": 0,
  "doi": "10.1093/g3journal/jkag248",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13732479/",
  "id": "9y38beaswwcd2",
  "issns": [
    "2160-1836"
  ],
  "landing_url": "https://doi.org/10.1093/g3journal/jkag248",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "AcademicSubjects/SCI01140"
    ],
    [
      "heading",
      "AcademicSubjects/SCI01180"
    ],
    [
      "heading",
      "Investigation"
    ],
    [
      "openalex",
      "3004|Pharmacogenetics and Drug Metabolism"
    ]
  ],
  "openalex": "W7204647752",
  "pdf_url": "https://academic.oup.com/g3journal/advance-article-pdf/doi/10.1093/g3journal/jkag248/70870342/jkag248.pdf",
  "pmcid": "PMC13732479",
  "pmid": "42667690",
  "published": "2026-08-29",
  "publisher": "Oxford University Press",
  "ris": "https://research.draconitic.com/paper/9y38beaswwcd2.ris",
  "sources": [
    {
      "first_seen": "2026-11-08T12:22:27Z",
      "native_id": "PMC13732479",
      "source": "pmc",
      "url": "https://doi.org/10.1093/g3journal/jkag248"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:3004|Pharmacogenetics and Drug Metabolism",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "Deep mutational scanning of CYP2C9, CYP2C19, and NUDT15 shows that pharmacogene variant interpretation requires assay-specific functional data",
  "title_text": "Deep mutational scanning of CYP2C9, CYP2C19, and NUDT15 shows that pharmacogene variant interpretation requires assay-specific functional data",
  "type": "peer-reviewed",
  "updated_at": "2026-11-08T12:22:27Z",
  "url": "https://research.draconitic.com/paper/9y38beaswwcd2",
  "venue": "G3: Genes | Genomes | Genetics",
  "versions": []
}