Distribution of amino acid scores (aaPEC) for different missense SNP alleles in HGMD and dbSNP. (A) The distribution from HGMD shows that >40% of the disease-associated mutant alleles (hatched bars) are rare (aaPEC < –3) in alignments of related sequences, whereas >70% of the wild-type alleles (blackbars) are the most common allele across evolutionarily related sequences (aaPEC = 0). (B) The distribution from dbSNP (presumably randomly sampled SNPs) is very different from A, containing four times fewer evolutionarily rare alleles (aaPEC < –3) and more than one-third fewer evolutionarily most common alleles (aaPEC = 0).