The relative mutation probabilities as a function of mutation site conservation and solvent accessibility. Relative mutation probability as a function of (a) evolutionary conservation of the mutation site (measured using relative entropy), and (b) solvent accessibility of the mutation site in the protein structure. Because the overall probability that a random mutation will cause a genetic disease or be observed as a polymorphism is not known, the probabilities have only relative meaning within each mutation class (disease, synonymous, nonsynonymous). To show different trends clearly, the relative probabilities were normalized to 1 within each class. Conservation of mutation sites in evolution was characterized by the relative entropy using close sequence homologs (see Materials and methods). The solvent accessibility of mutation sites was calculated using the program NACESS . An increase in the degree of evolutionary conservation increases the probability of deleterious mutations and decreases the probability of nonsynonymous benign SNPs (a). An increase in the degree of solvent accessibility decreases the probability of deleterious mutations and increases the probability of nonsynonymous benign SNPs (b). Synonymous mutations do not change amino-acid sequences and are predominantly neutral. Consequently, the probability that a synonymous mutation will be deleterious is relatively constant across sites.