Allostery is a widespread cause of loss-of-function variant pathogenicity (opens in new tab)

Allosteric communication between non-contacting sites in proteins plays a fundamental role in biological regulation and drug action. While allosteric gain-of-function variants are known drivers of oncogene activation, the broader importance of allostery in genetic disease and protein evolution is less clear. Here, we introduce a comparative framework that disentangles functional disruption by mutations from protein destabilization. Applying this framework across diverse datasets—ranging from ...