ArticleProceedings of the National Academy of Sciences of the United States of America2015
Comparison of predicted and actual consequences of missense mutations.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 147 papers, 1 of them a synthesis that pooled it.
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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
147 citing papers in PubMed, 1 synthesis or guideline pooled it, 231 citations in OpenAlex.
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- Trial
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- <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
- eSIG-Net: Accurate prediction of single-mutation induced perturbations on protein interactions using a language model.bioRxiv : the preprint server for biology · 2026Article
- Investigating the Structural and Functional Consequences of Pathogenic SNPs on Human VEGFA Dimer: Insights from Molecular Dynamics Study.ACS omega · 2025Article
- A novel missense variant at the site of interaction between RLIM and E2 ubiquitin-conjugating enzymes causes Tønne-Kalscheuer syndrome.BMC pediatrics · 2025Article
- Modular inflammation network discovery from large-scale phenotypic screening in genetically heterogeneous mouse brains.Journal of neuroinflammation · 2025Article
- Off-target effects in CRISPR-Cas genome editing for human therapeutics: Progress and challenges.Molecular therapy. Nucleic acids · 2025Review
- Increasing pathogenic germline variant diagnosis rates in precision medicine: current best practices and future opportunities.Human genomics · 2025Review
- 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
- Functionally constrained human proteins are less prone to mutational instability from single amino acid substitutions.Nature communications · 2025Article
- Exome Sequencing of a Type 1 Diabetes Mellitus Family Exposes Both Common and Individualized Rare Variants Contributing to Pathogenesis.Journal of diabetes research · 2025Article
- Fine-tuning protein language models to understand the functional impact of missense variants.Computational and structural biotechnology journal · 2025Article
- Identification ofAnimal biotechnology · 2024Article
- Understanding the heterogeneous performance of variant effect predictors across human protein-coding genes.Scientific reports · 2024Article
- A fitness distribution law for amino-acid replacements.bioRxiv : the preprint server for biology · 2024Article
- Functional validation of EIF2AK4 (GCN2) missense variants associated with pulmonary arterial hypertension.Human molecular genetics · 2024Article
- Prediction of Deleterious Single Amino Acid Polymorphisms with a Consensus Holdout Sampler.Current genomics · 2024Article
87 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 2 institutions in 2 countries.
Funding
Abstract
Each person's genome sequence has thousands of missense variants. Practical interpretation of their functional significance must rely on computational inferences in the absence of exhaustive experimental measurements. Here we analyzed the efficacy of these inferences in 33 de novo missense mutations revealed by sequencing in first-generation progeny of N-ethyl-N-nitrosourea-treated mice, involving 23 essential immune system genes. PolyPhen2, SIFT, MutationAssessor, Panther, CADD, and Condel were used to predict each mutation's functional importance, whereas the actual effect was measured by breeding and testing homozygotes for the expected in vivo loss-of-function phenotype. Only 20% of mutations predicted to be deleterious by PolyPhen2 (and 15% by CADD) showed a discernible phenotype in individual homozygotes. Half of all possible missense mutations in the same 23 immune genes were predicted to be deleterious, and most of these appear to become subject to purifying selection because few persist between separate mouse substrains, rodents, or primates. Because defects in immune genes could be phenotypically masked in vivo by compensation and environment, we compared inferences by the same tools with the in vitro phenotype of all 2,314 possible missense variants in TP53; 42% of mutations predicted by PolyPhen2 to be deleterious (and 45% by CADD) had little measurable consequence for TP53-promoted transcription. We conclude that for de novo or low-frequency missense mutations found by genome sequencing, half those inferred as deleterious correspond to nearly neutral mutations that have little impact on the clinical phenotype of individual cases but will nevertheless become subject to purifying selection.
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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.