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

RovHer prioritizes rare missense variants, explaining 16.1% of total RV heritability in UK Biobank traits, a tenfold increase over alternative methods.

• Why it matters: Distinguishing functional from neutral rare variants is crucial for understanding the genetic basis of complex diseases and improving risk prediction.
• 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 21 traits from 357,086 individuals.
• The result: RovHer's predictions are independent of allele frequency, generalize across ancestries, and effectively identify high-risk carriers, highlighting the importance of missense RVs in population risk stratification.