A heritability-optimized method for functional prioritization of rare coding variants in complex traits.

RovHer identifies the top 1% of missense rare variants that explain 16.1% of heritability in complex traits, a tenfold improvement over existing methods.

• Why it matters: Distinguishing functional rare variants from neutral ones is crucial for understanding the genetic basis of complex diseases and improving risk prediction, yet remains challenging.
• What they did: The study developed RovHer, a heritability-optimized scoring method that integrates 75 variant- and gene-level features using multivariate adaptive regression splines across nearly 5 million RVs in large population datasets.
• The result: RovHer's predictions effectively identify high-risk carriers, generalize across ancestries, and highlight the importance of missense RVs in population risk stratification, advancing personalized medicine.