MAPP (Multivariate Analysis of Protein Polymorphism) considers the physicochemical variation present in a column of a protein sequence alignment and, on the basis of this variation, predicts the impact of all possible amino acid substitutions on the function of the protein.
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Stone EA, Sidow A.
Physicochemical constraint violation by missense substitutions mediates impairment of protein function and disease severity
Genome Res. 2005 Jul;15(7):978-86.