To identify residues responsible for allostery, cooperativity, and other subtle but functionally important interactions, SIPRIS employs statistical inference based on the assumption that residues distinguishing a protein subgroup from evolutionarily divergent subgroups often constitute an interacting functional network. SIPRIS identifies such networks with the aid of two measures of statistical significance. One measure aids identification of divergent subgroups based on distinguishing residue patterns. For each subgroup, a second measure identifies structural interactions involving pattern residues.