Why try to find subgenic regions that are specifically missense constrained? Splitting up genes reveals patterns of negative and neutral selection that are obscured when looking gene-wide, including highlighting regions that have a large number of known pathogenic variants. 3/10

Missense depleted regions show an enrichment of (1) de novo missense variants in neurodevelopmental disorder cases compared to controls, (2) partitioned common variant heritability for >260 independent traits from the UK Biobank, and (3) ClinVar pathogenic (P/LP) variants. 4/10