1. We allow a mixture of alignable and unalignable sequence data. Specifically, sequences that can be reliably multiply aligned should be grouped and aligned. These clades of multiply-aligned sequences, including each "degenerate clade" of one sequence that cannot be reliably aligned with any other sequence, are used by PhyloScan. A phylogenetic tree relating the sequences within a clade, a user-specified nucleotide substitution model, and an extension to Staden's precise p-value calculation that is phylogenetically aware are all employed by PhyloScan to increase the statistical power of Staden's original method. (See Methods.)