Applications of rapidly advancing sequencing technology exacerbate the need to interpret individual sequence variants. Sequencing of phenotyped clinical subjects will soon become a method of choice in studies of the genetic causes of Mendelian and complex diseases. New exon-capture techniques will direct sequencing efforts to the most informative and easily interpretable protein-coding fraction of the genome. Thus, the demand for computational predictions of the impact of protein sequence variants will continue to grow. Here we present a new method and the corresponding soft- ware tool, PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/, Supplementary Software), for predicting damaging effects of missense mutations.