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Peer-reviewedCC BYNature Communications

Allostery is a widespread cause of loss-of-function variant pathogenicity

  • Xiaotian Liao1,2,3
  • Ben Lehner4,5,6,7,8,9,10,2
10 affiliations
  1. 1University of Cambridge, Cambridge, UK
  2. 2Wellcome Sanger Institute, Cambridge, UK
  3. 3University of Cambridge, UK
  4. 4Centre for Genomic Regulation (CRG), Barcelona Institute for Science and Technology (BIST), Barcelona, Spain. [email protected]
  5. 5Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. [email protected]
  6. 6Universitat Pompeu Fabra (UPF), Barcelona, Spain. [email protected]
  7. 7Wellcome Sanger Institute, Cambridge, UK. [email protected]
  8. 8Centre for Genomic Regulation (CRG), Barcelona Institute for Science and Technology (BIST), Barcelona, Spain
  9. 9Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
  10. 10Universitat Pompeu Fabra (UPF), Barcelona, Spain
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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.

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Cite

BibTeXRIS
BibTeX
@article{liao2026allostery,
  title = {{Allostery is a widespread cause of loss-of-function variant pathogenicity}},
  author = {Xiaotian Liao and Ben Lehner},
  journal = {Nature Communications},
  year = {2026},
  month = jun,
  doi = {10.1038/s41467-026-74517-8},
  url = {https://doi.org/10.1038/s41467-026-74517-8},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Allostery is a widespread cause of loss-of-function variant pathogenicity
AU  - Xiaotian Liao
AU  - Ben Lehner
PY  - 2026
DA  - 2026/06/22
JO  - Nature Communications
DO  - 10.1038/s41467-026-74517-8
UR  - https://doi.org/10.1038/s41467-026-74517-8
AB  - 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.
SN  - 2041-1723
ER  -