# Kernel Allelic Series Model

Rare missense contributions to complex traits have been underestimated because collapsing variants within a gene into one burden score averages away effect differences. The Kernel Allelic Series Model (KASM) builds within-gene effect covariance kernels from protein-structure and variant-effect annotations; across 786,871 exomes and 26 continuous traits it raises the lower bound on rare missense heritability from 0.54±0.04% to at least 1.27±0.09%, and to 1.83±0.11% under the most flexible model, above the 0.87±0.05% for loss-of-function variants.

Rare missense contributions to complex traits have been underestimated because collapsing variants within a gene into one burden score averages away effect differences. The Kernel Allelic Series Model (KASM) builds within-gene effect covariance kernels from protein-structure and variant-effect annotations; across 786,871 exomes and 26 continuous traits it raises the lower bound on rare missense heritability from 0.54±0.04% to at least 1.27±0.09%, and to 1.83±0.11% under the most flexible model, above the 0.87±0.05% for loss-of-function variants.