Gene and regional collapsing. (A) A standard gene-based approach for collapsing analysis of nonsynonymous and canonical splice rare variants in cases (green) and controls (black) on example Gene A. (B) A domain-unit–based regional approach in which only the domains that are intolerant to functional variation are considered as units for collapsing. (C) Intolerance-informed gene collapsing: a regional approach to gene collapsing in which the unit for collapsing is the entire gene, yet missense variants only qualify for the analysis if they reside in domains that are intolerant to variation (domain 1 and 3). Loss-of-function variants (big circles) continue to qualify regardless of whether they reside in a tolerant or intolerant domain of the gene. Bright blue background marks qualifying region.
