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Pathogenic missense protein variants affect different functional pathways and proteomic features than healthy population variants

Research output: Contribution to journalArticlepeer-review

Original languageEnglish
Article numbere3001207
JournalPLoS Biology
Issue number4
Accepted/In press26 Mar 2021
Published28 Apr 2021

Bibliographical note

Publisher Copyright: © 2021 Laddach et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors


Missense variants are present amongst the healthy population, but some of them are causative of human diseases. A classification of variants associated with “healthy” or “diseased” states is therefore not always straightforward. AAU deeper: Pleaseconfirmthattheedittothese understanding of the nature of missense variants in health and disease, the cellular processes they may affect, and the general molecular principles which underlie these differences is essential to offer mechanistic explanations of the true impact of pathogenic variants. Here, we have formalised a statistical framework which enables robust probabilistic quantification of variant enrichment across full-length proteins, their domains, and 3D structure-defined regions. Using this framework, we validate and extend previously reported trends of variant enrichment in different protein structural regions (surface/core/interface). ByAU examining: Pleaseconfirmth the association of variant enrichment with available functional pathways and transcriptomic and proteomic (protein half-life, thermal stability, abundance) data, we have mined a rich set of molecular features which distinguish between pathogenic and population variants: Pathogenic variants mainly affect proteins involved in cell proliferation and nucleotide processing and are enriched in more abundant proteins. Additionally, rare population variants display features closer to common than pathogenic variants. We validate the association between these molecular features and variant pathogenicity by comparing against existing in silico variant impact annotations. This study provides molecular details into how different proteins exhibit resilience and/or sensitivity towards missense variants and provides the rationale to prioritise variant-enriched proteins and protein domains for therapeutic targeting and development. The ZoomVar database, which we created for this study, is available at It allows users to programmatically annotate missense variants with protein structural information and to calculate variant enrichment in different protein structural regions.

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