Within a homologous protein family, proteins may be grouped into subtypes that share specific functions that are not common to the entire family. Often, the amino acids present in a small number of sequence positions determine each proteins particular functional specificity. Knowledge of these specificity determining positions (SDPs) aids in protein function prediction, drug design and experimental analysis. A number of sequence-based computational methods have been introduced for identifying SDPs, however, their further development and evaluation have been hindered by the limited number of known experimentally determined SDPs.