{
  "abstract": "The interpretation of missense variants remains a major challenge in clinical genetics. \"Meta-domains\" aggregate population and pathogenic variation across homologous Pfam domain instances in the human proteome, providing per-residue context for interpreting variants of uncertain significance (VUS). Our 2019 implementation, MetaDome, is widely used and named in clinical variant-classification guidelines. Here we present the MetaDome 2027 update, featuring a comprehensively updated dataset and GRCh38 support. The redesigned pipeline enables incremental updates of GENCODE, UniProtKB/Swiss-Prot, Pfam, gnomAD, and ClinVar while maintaining 100% sequence-identity gene-to-protein mapping. Annotated Pfam domain instances grew 14.9% from 71,419 to 82,069 and meta-domain-eligible Pfam families ([≥]2 human occurrences) by 73.3% from 3,334 to 5,778; Pfam domains are annotated to 92% of human proteins. Approximately 43% of mapped protein-coding nucleotides (14.3 million in GRCh38, 13.8 million in GRCh37) are in a meta-domain; in GRCh38 67.9% (37,692 of 55,548) of pathogenic or likely pathogenic ClinVar missense variants fall at such a position. We show how MetaDome helped reclassify a de novo missense VUS in RALA and identify 52,463 ClinVar missense VUS for which meta-domains supply otherwise unavailable pathogenic evidence. MetaDome is freely available at www.metadome.app.",
  "abstract_shown": true,
  "affiliations": [
    "Stanford University"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 22,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "L. Wiel"
    },
    {
      "name": "F. Ferraro"
    },
    {
      "name": "J. Yu"
    },
    {
      "name": "J. Zhen"
    },
    {
      "name": "D. Nachun"
    },
    {
      "name": "R. Mendez"
    },
    {
      "name": "C. M. Reuter"
    },
    {
      "name": "J. L. Cui"
    },
    {
      "name": "D. E. Bonner"
    },
    {
      "name": "J. N. Carter"
    },
    {
      "name": "S. Marwaha"
    },
    {
      "name": "M. van de Vorst"
    },
    {
      "name": "S. Emami"
    },
    {
      "name": "E. Kravets"
    },
    {
      "name": "M. B. Neu"
    },
    {
      "name": "T. W. van Ham"
    },
    {
      "name": "T. Kleefstra"
    },
    {
      "name": "E. A. Ashley"
    },
    {
      "name": "J. A. Bernstein"
    },
    {
      "name": "S. B. Montgomery"
    },
    {
      "name": "C. Gilissen"
    },
    {
      "name": "M. T. Wheeler"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/aqrkes2zyvax3.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.08.26.747388",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.08.26.747388v1.full",
  "id": "aqrkes2zyvax3",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.08.26.747388v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "bioinformatics"
    ],
    [
      "openalex",
      "1311|Genomics and Rare Diseases"
    ]
  ],
  "openalex": "W7202266581",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.08.26.747388v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-08-26",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/aqrkes2zyvax3.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:42Z",
      "native_id": "10.64898/2026.08.26.747388",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.08.26.747388v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:bioinformatics",
      "subfield": "bioinformatics"
    }
  ],
  "title": "MetaDome 2027: a comprehensively updated resource for aggregating missense variant evidence across homologous human protein domains",
  "title_text": "MetaDome 2027: a comprehensively updated resource for aggregating missense variant evidence across homologous human protein domains",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:42Z",
  "url": "https://research.draconitic.com/paper/aqrkes2zyvax3",
  "venue": "bioRxiv",
  "versions": []
}