Mutation rate heterogeneity biases variant effect prediction and reveals genuine mutational robustness.

Mutation rate heterogeneity systematically biases variant effect predictors by causing them to interpret mutation rate variation as functional importance.

• Why it matters: This bias affects the accuracy of variant effect predictions, which are crucial for understanding human genetic variation and disease, yet current methods do not account for mutation rate differences.
• What they did: The study analyzed how most VEPs and conservation metrics, like phyloP scores, correlate with mutation rate variation, and examined experimental data on protein stability to identify biological signals related to mutational robustness.
• The result: Findings show variants at low-mutation-rate sites are predicted as more damaging, and those at high-mutation-rate sites as more tolerated, emphasizing the need to explicitly model mutation probabilities in future VEPs and revealing a biological signal of mutational robustness.