ArticlePLoS genetics2013
Genic intolerance to functional variation and the interpretation of personal genomes.
Article in PLoS genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 603 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
603 citing papers in PubMed, 988 citations in OpenAlex.
- Whole Exome Sequencing IdentifiesInternational journal of molecular sciences · 2021Trial
- Understanding Symptoms in RYR1-Related Myopathies: A Mixed-Methods Analysis Based on Participants' Experience.The patient · 2020Trial
- Probabilistic mapping of sub-genic intolerance reveals functional and disease-critical protein regions.bioRxiv : the preprint server for biology · 2026Article
- End-to-end deep learning methods for genetic risk prediction of schizophrenia.Nature communications · 2026Article
- From conservation scores to language models: a feature engineering perspective on machine learning for genetic variant interpretation.Briefings in bioinformatics · 2026Review
- Prediction of human missense variant effects from functional evidence.Nature genetics · 2026Article
- Review
- Prdm15 Deficiency Results in Impaired Hippocampal Neurogenesis and Autism-Like Behaviors.Cellular and molecular neurobiology · 2026Article
- In silico Genotype-Phenotype Correlation Analysis of Inherited Variations in Autism Spectrum Disorder Families Identify an Interplay between Sensory Function and Repetitive-behaviour Genes.Journal of molecular neuroscience : MN · 2026Article
- A Genetic Landscape of Euploid Miscarriages From Couples With Recurrent Pregnancy Loss Through Whole Exome Sequencing.Molecular genetics & genomic medicine · 2026Article
- The genetic landscape of human functional brain connectivity.Nature communications · 2026Article
- Multi-omics Differential Inference for Functional Interpretation (MoDIFI): A Statistical Framework to Prioritize Cell Lines for Neurodevelopmental Variants.bioRxiv : the preprint server for biology · 2026Article
- MIRAGE: A Bayesian statistical method for gene-level rare-variant analysis incorporating functional annotations.American journal of human genetics · 2026Article
- Benchmarking knowledge graph embedding models for the prediction of oligogenic combinations.Briefings in bioinformatics · 2026Article
- FAVOR 2.0: A reengineered functional annotation of variants online resource for interpreting genomic variation.Nucleic acids research · 2026Article
- GDIv2: improving variant selection from human exomes.Bioinformatics advances · 2026Article
- Rare Variants of Immune-Related Genes Increase Susceptibility to Autoimmune Encephalitis: An Association Study.Neurology international · 2025Article
- Proteome-wide model for human disease genetics.Nature genetics · 2025Article
- Genomic Insights Into the Origin, Decline and Recovery of the Once Critically Endangered Iberian Lynx.Molecular ecology · 2025Review
- Expanding the utility of variant effect predictions with phenotype-specific models.Nature communications · 2025Article
543 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
5 authors at 1 institution in 2 countries.
Funding
Abstract
A central challenge in interpreting personal genomes is determining which mutations most likely influence disease. Although progress has been made in scoring the functional impact of individual mutations, the characteristics of the genes in which those mutations are found remain largely unexplored. For example, genes known to carry few common functional variants in healthy individuals may be judged more likely to cause certain kinds of disease than genes known to carry many such variants. Until now, however, it has not been possible to develop a quantitative assessment of how well genes tolerate functional genetic variation on a genome-wide scale. Here we describe an effort that uses sequence data from 6503 whole exome sequences made available by the NHLBI Exome Sequencing Project (ESP). Specifically, we develop an intolerance scoring system that assesses whether genes have relatively more or less functional genetic variation than expected based on the apparently neutral variation found in the gene. To illustrate the utility of this intolerance score, we show that genes responsible for Mendelian diseases are significantly more intolerant to functional genetic variation than genes that do not cause any known disease, but with striking variation in intolerance among genes causing different classes of genetic disease. We conclude by showing that use of an intolerance ranking system can aid in interpreting personal genomes and identifying pathogenic mutations.
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What OpenQuestion holds
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.