Predicting deleterious amino acid substitutions

Many missense substitutions are identified in single nucleotide polymorphis m (SNP) data and large-scale random mutagenesis projects. Each amino acid s ubstitution potentially affects protein Function. We have constructed a too l that uses sequence homology to predict whether a substitution affects pro tein function. SIFT, which sorts intolerant from tolerant substitutions, cl assifies substitutions as tolerated or deleterious. A higher proportion of substitutions predicted to be deleterious by SIFT gives an affected phenoty pe than substitutions predicted to be deleterious by substitution scoring m atrices in three test cases, Using SIFT before mutagenesis studies could re duce the number of functional assays required and yield a higher proportion of affected phenotypes. SIFT may be used to identify plausible disease can didates among the SNPs that cause missense substitutions.