ArticleNature genetics2019
A map of constrained coding regions in the human genome.
Article in Nature genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 153 papers.
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Who cites it
153 citing papers in PubMed.
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- NEDAMSS syndrome-related truncating and missense mutations are associated with aberrant liquid-liquid phase separation of IRF2BPL.Nature communications · 2026Article
- Regional nonsense constraint offers biological and clinical insights into genetic disease.Nature communications · 2026Article
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- GDIv2: improving variant selection from human exomes.Bioinformatics advances · 2026Article
- A practical framework for predicting splicing single nucleotide variants in exome sequencing.NAR genomics and bioinformatics · 2025Article
- Haplotype analysis and molecular marker development for the cold tolerance gene OsCTS11 at the seedling stage of rice.TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik · 2025Article
- Proteome-wide model for human disease genetics.Nature genetics · 2025Article
- Federated learning for the pathogenicity annotation of genetic variants in multi-site clinical settings.Bioinformatics (Oxford, England) · 2025Article
- Dominant rhabdomyolysis linked to a recurrent ATP2A2 variant reducing SERCA2 function in muscle.Brain : a journal of neurology · 2025Article
- A probabilistic graphical model for estimating selection coefficients of nonsynonymous variants from human population sequence data.Nature communications · 2025Article
- PRESCOTT: a population aware, epistatic, and structural model accurately predicts missense effects.Genome biology · 2025Article
- Analysis of canine gene constraint identifies new variants for orofacial clefts and stature.Genome research · 2025Article
- Identifying deleterious noncoding variation through gain and loss of CTCF binding activity.American journal of human genetics · 2025Article
- Diverse ancestral representation improves genetic intolerance metrics.Nature communications · 2025Article
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- Detailed tandem repeat allele profiling in 1,027 long-read genomes reveals genome-wide patterns of pathogenicity.bioRxiv : the preprint server for biology · 2025Article
93 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors.
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Abstract
Deep catalogs of genetic variation from thousands of humans enable the detection of intraspecies constraint by identifying coding regions with a scarcity of variation. While existing techniques summarize constraint for entire genes, single gene-wide metrics conceal regional constraint variability within each gene. Therefore, we have created a detailed map of constrained coding regions (CCRs) by leveraging variation observed among 123,136 humans from the Genome Aggregation Database. The most constrained CCRs are enriched for pathogenic variants in ClinVar and mutations underlying developmental disorders. CCRs highlight protein domain families under high constraint and suggest unannotated or incomplete protein domains. The highest-percentile CCRs complement existing variant prioritization methods when evaluating de novo mutations in studies of autosomal dominant disease. Finally, we identify highly constrained CCRs within genes lacking known disease associations. This observation suggests that CCRs may identify regions under strong purifying selection that, when mutated, cause severe developmental phenotypes or embryonic lethality.
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