Abstract The major histocompatibility complex (MHC) is highly polymorphic and more than 1500 human MHC alleles are known to date. These alleles do not bind to a given peptide with identical affinity. Although MHC alleles are functionally related, it is difficult to quantify the functional variation between them. Three-dimensional structures of known MHC-peptide (MHCp) complexes suggest that specific peptide residues bind selectively to functional pockets in the binding groove. From a set of known MHCp structures we identified 21 critical polymorphic functional residue positions (CPFRP) that significantly reduced functional pocket variability to just 189 among 212 HLA-A alleles. Interestingly 101 HLA-A alleles clustered into 29 clusters such that the six functional pockets formed by the CPFRPs are identical within the cluster.