Decoding missense variants pleiotropy in the immune GPCR P2RY8

G protein-coupled receptors (GPCRs) form the largest family of cell surface receptors and remain a central focus in pharmacology and drug discovery. Despite extensive structural and pharmacological studies, the functional impact of missense variation across GPCRs remains poorly understood, particularly for receptors involved in immune regulation. In this issue of Cell Genomics, LaFlam et al.¹ systematically map P2RY8 variant functions using deep mutational scanning (DMS) combined with structural biology approaches, revealing pleiotropy and mechanisms linking GPCR variation to B cell confinement and lymphoma.