ArticleGenome research2020
Identification of pathogenic variant enriched regions across genes and gene families.
Article in Genome research, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers, 2 of them syntheses that pooled it.
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Who cites it
48 citing papers in PubMed, 2 syntheses or guidelines pooled it, 81 citations in OpenAlex.
- Gene variant effects across sodium channelopathies predict function and guide precision therapy.Brain : a journal of neurology · 2022Pooled it
- Genomic Landscape and Mutational Spectrum of ADAMTS Family Genes in Mendelian Disorders Based on Gene Evidence Review for Variant Interpretation.Biomolecules · 2020Pooled it
- Probabilistic mapping of sub-genic intolerance reveals functional and disease-critical protein regions.bioRxiv : the preprint server for biology · 2026Article
- Review
- ACMG/AMP variant classification specifications from the ClinGen Epilepsy Sodium Channel Variant Curation Expert Panel.Genetics in medicine : official journal of the American College of Medical Genetics · 2026Article
- Elicited Repetitive Daily Blindness Associated With Gain-of-FunctionNeurology. Genetics · 2026Article
- Gene Portals: A Framework for Integrating Clinical, Functional, and Structural Evidence into Rare Disease Variant Classification.medRxiv : the preprint server for health sciences · 2026Article
- Article
- Calibrated Variant Effect Prediction at the Residue Level Using Conditional Score Distributions.bioRxiv : the preprint server for biology · 2025Article
- Molecular Screening of SCN1A-Related Seizures in Children With Febrile Seizures: Diagnostic Yield and Variant Distribution.Annals of clinical and translational neurology · 2025Article
- Conserved missense variant pathogenicity and correlated phenotypes across paralogous genes.Genome biology · 2025Article
- A series of reviews in familial cancer: genetic cancer risk in context variants of uncertain significance in MMR genes: which procedures should be followed?Familial cancer · 2025Review
- Genetic variants and phenotypic data curated for the CAGI6 intellectual disability panel challenge.Human genetics · 2025Article
- Ligand distances as key predictors of pathogenicity and function in NMDA receptors.Human molecular genetics · 2025Article
- Optimizing gene prioritization for clinical diagnosis of metabolic genetic disorders.PloS one · 2025Article
- Fine-tuning protein language models to understand the functional impact of missense variants.Computational and structural biotechnology journal · 2025Article
- Genetic variant profiling of neonatal diabetes mellitus in Iranian patients: Unveiling 58 distinct variants in 14 genes.Journal of diabetes investigation · 2024Article
- Boolean Modeling of Biological Network Applied to Protein-Protein Interaction Network of Autism Patients.Biology · 2024Article
- Genetic constraint at single amino acid resolution in protein domains improves missense variant prioritisation and gene discovery.Genome medicine · 2024Article
- A unified analysis of evolutionary and population constraint in protein domains highlights structural features and pathogenic sites.Communications biology · 2024Article
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Missense variant interpretation is challenging. Essential regions for protein function are conserved among gene-family members, and genetic variants within these regions are potentially more likely to confer risk to disease. Here, we generated 2871 gene-family protein sequence alignments involving 9990 genes and performed missense variant burden analyses to identify novel essential protein regions. We mapped 2,219,811 variants from the general population into these alignments and compared their distribution with 76,153 missense variants from patients. With this gene-family approach, we identified 465 regions enriched for patient variants spanning 41,463 amino acids in 1252 genes. As a comparison, by testing the same genes individually, we identified fewer patient variant enriched regions, involving only 2639 amino acids and 215 genes. Next, we selected de novo variants from 6753 patients with neurodevelopmental disorders and 1911 unaffected siblings and observed an 8.33-fold enrichment of patient variants in our identified regions (95% C.I. = 3.90-Inf,
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Registered trials
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.