Most tools I know (SIFT, PolyPhen, CADD) rely on conservation or structural features but does anyone use the raw informational constraint of the genetic code itself?
1 answer
Yes, though it usually goes by other names. The direct version is site degeneracy classes - 0-fold degenerate sites are positions where every possible change is nonsynonymous, 4-fold are where none are. That partition is exactly the constraint you're describing, and it's already the denominator of every dN/dS calculation via Nei-Gojobori site counting.
For a per-codon "how bad could one mutation be" value, the usual construction is Grantham distance over the amino acids reachable by a single nucleotide change from that codon.
Why it isn't a standalone predictor: degeneracy is a property of the codon, not of the position. Every Met codon scores the same whether it's a catalytic residue or sitting in a disordered loop, so once you have conservation it adds almost nothing discriminative. It ends up as a feature inside CADD rather than a tool of its own.
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