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J Mol Biol. 2013 Nov 1;425(21):4023-33. doi: 10.1016/j.jmb.2013.07.037. Epub 2013 Aug 3.

A gene-specific method for predicting hemophilia-causing point mutations.

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Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.


A fundamental goal of medical genetics is the accurate prediction of genotype-phenotype correlations. As an approach to develop more accurate in silico tools for prediction of disease-causing mutations of structural proteins, we present a gene- and disease-specific prediction tool based on a large systematic analysis of missense mutations from hemophilia A (HA) patients. Our HA-specific prediction tool, HApredictor, showed disease prediction accuracy comparable to other publicly available prediction software. In contrast to those methods, its performance is not limited to non-synonymous mutations. Given the role of synonymous mutations in disease and drug codon optimization, we propose that utilizing a gene- and disease-specific method can be highly useful to make functional predictions possible even for synonymous mutations. Incorporating computational metrics at both nucleotide and amino acid levels along with multiple protein sequence/structure alignment significantly improved the predictive performance of our tool. HApredictor is freely available for download at


HA; HB; NCBI; National Center for Biotechnology Information; RSCU; UniProt Knowledgebase; UniProtKB; coagulation factor IX; coagulation factor VIII; gene/disease-specific prediction tool; hemophilia A; hemophilia A/B; hemophilia B; relative synonymous codon usage; synonymous mutation

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