PLCG2 (phospholipase C gamma 2) is a crucial transmembrane signaling enzyme that catalyzes the production of second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3), mediating calcium-dependent intracellular signal transduction. The enzyme functions as a critical downstream substrate of Bruton's tyrosine kinase (BTK) in B cell receptor signaling 1, regulating B cell activation and immune responses. Pathogenic PLCG2 variants cause autosomal-dominant immune dysregulation disorders. Gain-of-function (GOF) mutations and a newly identified class of monoallelic loss-of-function (LOF) variants produce distinct disease phenotypes 2. GOF and LOF variants both associate with infection susceptibility and autoinflammation, while LOF variants specifically correlate with a novel cluster featuring humoral immune deficiency, autoinflammation, herpesvirus susceptibility, and natural killer cell dysfunction 2. Beyond immune dysfunction, PLCG2 dysregulation associates with cancer progression. A PLCG2-high phenotype in small cell lung cancer correlates with stem-like, pro-metastatic features and worse overall survival 3. In ovarian cancer, PLCG2 transcriptional upregulation via the PARP1-DOT1L axis contributes to PARP inhibitor resistance 4. PLCG2 variants have also been identified as disease-associated loci in inflammatory bowel disease 5, establishing PLCG2 as a multifunctional signaling hub relevant to both immune regulation and malignant transformation.