ArticleNature communications2022
The 3D mutational constraint on amino acid sites in the human proteome.
Article in Nature communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed.
- Probabilistic mapping of sub-genic intolerance reveals functional and disease-critical protein regions.bioRxiv : the preprint server for biology · 2026Article
- InstructPLM-mu: protein fitness prediction from structure instructions.Briefings in bioinformatics · 2026Article
- VUStruct: A compute pipeline for high throughput and personalized structural biology.PLoS computational biology · 2026Article
- <italic>MKRN3</italic> Variants in Central Precocious Puberty as an Example of the Complexity to Classify Missense Variants in Imprinted Genes as Pathogenic.Hormone research in paediatrics · 2026Article
- Mechanisms of mTORC1 and GCN2 amino acid sensing pathways in tumorigenesis and metastatic progression (Review).International journal of molecular medicine · 2026Review
- Phenotypic Variability and Paternal Inheritance of a CHD8 Variant Causing Intellectual Developmental Disorder With Autism and Macrocephaly Confirmed by Epigenetic and Structural Analyses.Molecular genetics & genomic medicine · 2025Article
- Functionally constrained human proteins are less prone to mutational instability from single amino acid substitutions.Nature communications · 2025Article
- Decoding the functional impact of the cancer genome through protein-protein interactions.Nature reviews. Cancer · 2025Review
- Missense variant analysis in the TRPV1 ARD reveals the unexpected functional significance of a methionine.PloS one · 2025Article
- Graph masked self-distillation learning for prediction of mutation impact on protein-protein interactions.Communications biology · 2024Article
- MTR3D-AF2: Expanding the coverage of spatially derived missense tolerance scores across the human proteome using AlphaFold2.Protein science : a publication of the Protein Society · 2024Article
- A unified analysis of evolutionary and population constraint in protein domains highlights structural features and pathogenic sites.Communications biology · 2024Article
- Article
- GTExome: Modeling commonly expressed missense mutations in the human genome.bioRxiv : the preprint server for biology · 2023Article
- Unbiased curriculum learning enhanced global-local graph neural network for protein thermodynamic stability prediction.Bioinformatics (Oxford, England) · 2023Article
- AQcalc: A web server that identifies weak molecular interactions in protein structures.Protein science : a publication of the Protein Society · 2023Article
- Estimating clinical risk in gene regions from population sequencing cohort data.American journal of human genetics · 2023Article
- Predicting the pathogenicity of missense variants using features derived from AlphaFold2.Bioinformatics (Oxford, England) · 2023Article
- Unified access to up-to-date residue-level annotations from UniProtKB and other biological databases for PDB data.Scientific data · 2023Article
- Conserved patterns across ion channels correlate with variant pathogenicity and clinical phenotypes.Brain : a journal of neurology · 2023Article
Corrections and comments
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Authors and funding
3 authors.
Funding
Abstract
Quantification of the tolerance of protein sites to genetic variation has become a cornerstone of variant interpretation. We hypothesize that the constraint on missense variation at individual amino acid sites is largely shaped by direct interactions with 3D neighboring sites. To quantify this constraint, we introduce a framework called COntact Set MISsense tolerance (or COSMIS) and comprehensively map the landscape of 3D mutational constraint on 6.1 million amino acid sites covering 16,533 human proteins. We show that 3D mutational constraint is pervasive and that the level of constraint is strongly associated with disease relevance both at the site and the protein level. We demonstrate that COSMIS performs significantly better at variant interpretation tasks than other population-based constraint metrics while also providing structural insight into the functional roles of constrained sites. We anticipate that COSMIS will facilitate the interpretation of protein-coding variation in evolution and prioritization of sites for mechanistic investigation.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.