PhyloP and GERP Conservation Score Interpretation

What Conservation Can Tell You

Conservation identifies positions that have changed less often than expected across species. It does not determine whether a particular substitution is damaging. A conserved position can tolerate one amino acid change and reject another.

PhyloP measures deviation from a neutral substitution rate. GERP reports rejected substitutions. The two metrics use different calculations and should be read independently.

PhyloP (100-Way Vertebrate)

PhyloP measures evolutionary conservation across 100 vertebrate species using phylogenetic models. It compares the observed substitution rate at each position against the neutral expectation derived from the phylogenetic tree.

GERP++ (Genomic Evolutionary Rate Profiling)

GERP++ measures evolutionary constraint by comparing observed substitutions against the expected number at each position across a multi-species alignment. The difference between expected and observed substitutions is the "rejected substitution" score -- higher values indicate that more mutations have been eliminated by natural selection.

Why Conservation Scores Are Context, Not Evidence

Conservation tells you that a position is important, but it does not tell you whether a specific change at that position is damaging. A highly conserved position could tolerate certain amino acid substitutions (for example, leucine to isoleucine at a hydrophobic core position) while being completely intolerant of others (for example, leucine to proline, which would break the helix). This is why conservation scores are displayed as additional context rather than used as direct ACMG evidence.