PLCL2 (phospholipase C like 2) is a phospholipase enzyme located on chromosome 3.3 that regulates inositol 1,4,5-trisphosphate signaling around the endoplasmic reticulum and modulates calcium release and phosphatidylinositol-mediated signaling pathways 1. The gene exhibits GABA receptor binding activity and influences GABAergic synaptic transmission and cold-induced thermogenesis [GO annotations]. PLCL2 genetic variants are associated with multiple disease susceptibilities. SNPs rs1372072 and rs11117432 confer increased systemic sclerosis risk, particularly the limited cutaneous subtype 2. PLCL2 variants rs4685423 and rs4618210 significantly associate with large artery atherosclerotic stroke risk in Han Chinese populations 3, with rs4685423 also predicting early neurological deterioration in stroke patients 4. The gene represents a novel psoriasis susceptibility locus identified through meta-analysis 5. Additionally, PLCL2 polymorphisms associate with severe obesity phenotypes 6. Functionally, PLCL2 overexpression attenuates uterine muscle contraction and is regulated by progesterone receptor signaling in myometrial tissue, influencing labor and pregnancy outcomes 17. PLCL2 expression also correlates with triple-negative breast cancer prognosis and immunotherapy response 8.