Align-GVGD is a freely available, web-based program that combines the biophysical characteristics of amino acids and protein multiple sequence alignments to predict where missense substitutions in genes of interest fall in a spectrum from enriched delterious to enriched neutral. Align-GVGD is an extension of the original Grantham difference to multiple sequence alignments and true simultaneous multiple comparisons. Users can either supply their own protein multiple sequence alignments (in FASTA format) or else select from our small but growing library of alignments. We currently have alignments for ATM, BRCA1, BRCA2, CHEK2, and TP53. We also provide a link to the TCoffee web site, which gives an excellent set of tools for making protein multiple sequence alignments.