{
  "abstract": "Allosteric communication between non-contacting sites in proteins plays a fundamental role in biological regulation and drug action. While allosteric gain-of-function variants are known drivers of oncogene activation, the broader importance of allostery in genetic disease and protein evolution is less clear. Here, we introduce a comparative framework that disentangles functional disruption by mutations from protein destabilization. Applying this framework across diverse datasets-ranging from paired experimental measurements of abundance and activity to proteome-wide comparisons of evolutionary fitness and biophysical stability predictions-we provide evidence that allostery is a widespread cause of loss-of-function variant pathogenicity in human genetic diseases. In addition, our analyses reveal a conserved distance-dependent decay of allosteric mutational effects outside of protein active sites. As an important mechanism of pathogenicity, allostery needs to be better mapped, understood, and predicted across the human proteome.",
  "abstract_shown": true,
  "affiliations": [
    "University of Cambridge, Cambridge, UK",
    "Wellcome Sanger Institute, Cambridge, UK",
    "University of Cambridge, UK",
    "Centre for Genomic Regulation (CRG), Barcelona Institute for Science and Technology (BIST), Barcelona, Spain. bl11@sanger.ac.uk",
    "Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. bl11@sanger.ac.uk",
    "Universitat Pompeu Fabra (UPF), Barcelona, Spain. bl11@sanger.ac.uk",
    "Wellcome Sanger Institute, Cambridge, UK. bl11@sanger.ac.uk",
    "Centre for Genomic Regulation (CRG), Barcelona Institute for Science and Technology (BIST), Barcelona, Spain",
    "Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain",
    "Universitat Pompeu Fabra (UPF), Barcelona, Spain"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 2,
  "authors": [
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Xiaotian Liao",
      "orcid": "0000-0002-9715-270X"
    },
    {
      "affs": [
        3,
        4,
        5,
        6,
        7,
        8,
        9,
        1
      ],
      "name": "Ben Lehner",
      "orcid": "0000-0002-8817-1124"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/7hbpqwd7w4a6t.bib",
  "cited_by": 13,
  "doi": "10.1038/s41467-026-74517-8",
  "fulltext_url": null,
  "id": "7hbpqwd7w4a6t",
  "issns": [
    "2041-1723"
  ],
  "landing_url": "https://doi.org/10.1038/s41467-026-74517-8",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1311|Genomics and Rare Diseases"
    ]
  ],
  "openalex": "W4411645736",
  "pdf_url": null,
  "pmcid": "PMC13439481",
  "pmid": "42331831",
  "published": "2026-06-22",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/7hbpqwd7w4a6t.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T13:26:46Z",
      "native_id": "W4411645736",
      "source": "openalex",
      "url": "https://doi.org/10.1038/s41467-026-74517-8"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:1311|Genomics and Rare Diseases",
      "subfield": "genetics-genomics"
    }
  ],
  "title": "Allostery is a widespread cause of loss-of-function variant pathogenicity",
  "title_text": "Allostery is a widespread cause of loss-of-function variant pathogenicity",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T13:21:05Z",
  "url": "https://research.draconitic.com/paper/7hbpqwd7w4a6t",
  "venue": "Nature Communications",
  "versions": []
}