PLCG2 across human disease: genetic variants, signaling mechanisms, and clinical implications

BACKGROUND: Phospholipase Cγ2 (PLCG2) serves as a central signal transducer within immune and neural lineages, catalyzing the conversion of membrane phosphoinositides into second messengers to regulate intracellular Ca2+ dynamics. By integrating inputs from B-cell receptor (BCR) signaling, TREM2-mediated microglial activation, and the NF-κB and Akt-mTOR pathways, PLCG2 coordinately regulates essential programs of cell survival, proliferation, and inflammatory response. MAIN BODY: Recent human genetic and functional studies have established PLCG2 as a pleiotropic driver of disease. Dysregulated expression and specific genetic variants-including gain-of-function, loss-of-function, and protective alleles-are now linked to a broad spectrum of pathologies, ranging from neurodegenerative diseases and hematologic malignancies to autoimmune syndromes, immunodeficiencies, and solid tumors. This review synthesizes current mechanistic and clinical evidence linking PLCG2 biology to these diverse conditions and evaluates the protein's growing potential as both a diagnostic biomarker and a therapeutic target. CONCLUSIONS: While PLCG2 represents a promising nexus for intervention, urgent mechanistic gaps and translational priorities remain. We argue that future efforts must prioritize the development of precise, variant-directed targeting strategies and systematic phenotype-genotype mapping to successfully translate PLCG2 research into tangible patient benefits. CLINICAL TRIAL NUMBER: Not applicable.