ArticleHuman mutation2011
Prediction of missense mutation functionality depends on both the algorithm and sequence alignment employed.
Article in Human mutation, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 116 papers, 1 of them a synthesis that pooled it.
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Who cites it
116 citing papers in PubMed, 1 synthesis or guideline pooled it, 227 citations in OpenAlex.
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- Investigating the Structural and Functional Consequences of Pathogenic SNPs on Human VEGFA Dimer: Insights from Molecular Dynamics Study.ACS omega · 2025Article
- Meta-EA: a gene-specific combination of available computational tools for predicting missense variant effects.Nature communications · 2025Article
- Evaluating the Performance ofCombinatorial chemistry & high throughput screening · 2025Article
- Exploring the Structural and Functional Consequences of Deleterious Missense Nonsynonymous SNPs in theJournal of personalized medicine · 2024Article
- Elucidating the functional impact of G137V and G144R variants in Maroteaux Lamy's Syndrome by Molecular Dynamics Simulation.Molecular diversity · 2024Article
- A computational approach to analyzing the functional and structural impacts of Tripeptidyl-Peptidase 1 missense mutations in neuronal ceroid lipofuscinosis.Metabolic brain disease · 2024Article
- Exploring the Role of Non-synonymous and Deleterious Variants Identified in Colorectal Cancer: A Multi-dimensional Computational Scrutiny of Exomes.Current genomics · 2024Article
- Spectrum of variants associated with inherited retinal dystrophies in Northeast Mexico.BMC ophthalmology · 2024Article
- Infer global, predict local: Quantity-relevance trade-off in protein fitness predictions from sequence data.PLoS computational biology · 2023Article
- Perturbations in fatty acid metabolism and collagen production infer pathogenicity of a novelFrontiers in endocrinology · 2023Article
- Comprehensive In Silico Functional Prediction Analysis of CDKL5 by Single Amino Acid Substitution in the Catalytic Domain.International journal of molecular sciences · 2022Article
- Genome interpretation using in silico predictors of variant impact.Human genetics · 2022Review
- Clinical characteristics and proteome modifications in two Charcot-Marie-Tooth families with the AARS1 Arg326Trp mutation.BMC neurology · 2022Article
- Theranostic Interpolation of Genomic Instability in Breast Cancer.International journal of molecular sciences · 2022Review
- Variant predictions in congenital adrenal hyperplasia caused by mutations in CYP21A2.Frontiers in pharmacology · 2022Article
56 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Multiple algorithms are used to predict the impact of missense mutations on protein structure and function using algorithm-generated sequence alignments or manually curated alignments. We compared the accuracy with native alignment of SIFT, Align-GVGD, PolyPhen-2, and Xvar when generating functionality predictions of well-characterized missense mutations (n = 267) within the BRCA1, MSH2, MLH1, and TP53 genes. We also evaluated the impact of the alignment employed on predictions from these algorithms (except Xvar) when supplied the same four alignments including alignments automatically generated by (1) SIFT, (2) Polyphen-2, (3) Uniprot, and (4) a manually curated alignment tuned for Align-GVGD. Alignments differ in sequence composition and evolutionary depth. Data-based receiver operating characteristic curves employing the native alignment for each algorithm result in area under the curve of 78-79% for all four algorithms. Predictions from the PolyPhen-2 algorithm were least dependent on the alignment employed. In contrast, Align-GVGD predicts all variants neutral when provided alignments with a large number of sequences. Of note, algorithms make different predictions of variants even when provided the same alignment and do not necessarily perform best using their own alignment. Thus, researchers should consider optimizing both the algorithm and sequence alignment employed in missense prediction.
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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.