PHYSEAN predicts protein classes with highly variable sequences on the basis of their physical, chemical and biological characteristics such as diverse hydrophobicity, structural propensity and steric properties. These characteristics, calculated from multiple positions in a sequence, may be conserved even between sequences that fail to produce alignments at any acceptable level of statistical significance. PHYSEAN complements methods that require sequence alignments (BLAST, FASTA, dynamic programming) by adding less residue- and position-specific physicochemical information on the protein or the domain.