ArticleProceedings of the National Academy of Sciences of the United States of America2020
Comprehensive characterization of amino acid positions in protein structures reveals molecular effect of missense variants.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 74 papers, 1 of them a synthesis that pooled it.
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Who cites it
74 citing papers in PubMed, 1 synthesis or guideline pooled it, 122 citations in OpenAlex.
- Genome-wide association meta-analysis of age at onset of walking in over 70,000 infants of European ancestry.Nature human behaviour · 2025Pooled it
- From Pathogenicity to Mechanism: A Variant Interpretation Framework for Monogenic Epilepsy.Clinical genetics · 2026Article
- Electrostatics and disease: Large-scale assessment of human missense variants causing protein charge alterations and their implications for disease.Biophysical journal · 2026Article
- AAVC: An automated framework for high-accuracy ACMG-based variant classification.Genetics in medicine : official journal of the American College of Medical Genetics · 2026Article
- Comparative Transcriptomic Analysis Reveals Divergent Stress Adaptation Strategies in Gamma-Induced Soybean Mutants.Plants (Basel, Switzerland) · 2026Article
- Computational identification of rare pathogenic genomic variants in esophageal cancer markers: Transcript-level analysis, sequence-based insights, and structural-functional impacts of non-synonymous SNPs.Biochemistry and biophysics reports · 2026Article
- An interpretable molecular framework for predicting cancer driver missense mutations.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Interpretable machine-learning prediction of PSEN1 missense variant pathogenicity based on multi-omics enrichment in six core Alzheimer's disease genes.Alzheimer's research & therapy · 2026Article
- Exploratory identification of coding and splicing-related SNV variants in A1A1 and A2A2 β-casein Holstein dairy cows.Journal of animal science · 2026Article
- The Performance ofHuman mutation · 2026Article
- A multimodal framework for comprehensive driver variant prediction in cancer.Communications medicine · 2025Article
- Calibrated Variant Effect Prediction at the Residue Level Using Conditional Score Distributions.bioRxiv : the preprint server for biology · 2025Article
- Mutational landscapes of HNF MODY gene products display a wide distribution with functional implications.Endocrine connections · 2025Review
- PreMode predicts mode-of-action of missense variants by deep graph representation learning of protein sequence and structural context.Nature communications · 2025Article
- VarMeter: a prediction method for the impact of glycogene variants.Journal of human genetics · 2025Review
- Report of a missense TJP2 variant associated to PFIC4 with a pronounced phenotypic variability: Focus on the structural effects on the protein level.Journal of human genetics · 2025Article
- Proteome-wide assessment of differential missense variant clustering in neurodevelopmental disorders and cancer.Cell genomics · 2025Article
- Functional profiling of serine, threonine and tyrosine sites.Nature chemical biology · 2025Article
- Integrative structural analysis of NF45-NF90 heterodimers reveals architectural rearrangements and oligomerization on binding dsRNA.Nucleic acids research · 2025Article
- Exploring Evolution to Uncover Insights Into Protein Mutational Stability.Molecular biology and evolution · 2025Article
14 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
16 authors at 5 institutions in 7 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Interpretation of the colossal number of genetic variants identified from sequencing applications is one of the major bottlenecks in clinical genetics, with the inference of the effect of amino acid-substituting missense variations on protein structure and function being especially challenging. Here we characterize the three-dimensional (3D) amino acid positions affected in pathogenic and population variants from 1,330 disease-associated genes using over 14,000 experimentally solved human protein structures. By measuring the statistical burden of variations (i.e., point mutations) from all genes on 40 3D protein features, accounting for the structural, chemical, and functional context of the variations' positions, we identify features that are generally associated with pathogenic and population missense variants. We then perform the same amino acid-level analysis individually for 24 protein functional classes, which reveals unique characteristics of the positions of the altered amino acids: We observe up to 46% divergence of the class-specific features from the general characteristics obtained by the analysis on all genes, which is consistent with the structural diversity of essential regions across different protein classes. We demonstrate that the function-specific 3D features of the variants match the readouts of mutagenesis experiments for BRCA1 and PTEN, and positively correlate with an independent set of clinically interpreted pathogenic and benign missense variants. Finally, we make our results available through a web server to foster accessibility and downstream research. Our findings represent a crucial step toward translational genetics, from highlighting the impact of mutations on protein structure to rationalizing the variants' pathogenicity in terms of the perturbed molecular mechanisms.
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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.