PLEKHA3 (pleckstrin homology domain containing A3) is a phosphatidylinositol 4-phosphate (PtdIns(4)P)-binding protein that regulates vesicular transport and membrane homeostasis. The protein plays a critical role in vesicular cargo transport from the trans-Golgi network to the plasma membrane and regulates Golgi PtdIns(4)P levels by activating the phosphatase activity of SACM1L when bound to PtdIns(4)P [UniProt]. PLEKHA3 negatively regulates APOB secretion from hepatocytes, suggesting involvement in lipid metabolism [UniProt]. The protein's pleckstrin homology domain enables specific binding to PtdIns(4)P, which is essential for membrane recruitment and coincidence detection mechanisms at cellular membranes. Recent genome-wide association studies have identified PLEKHA3 as a significant genetic locus associated with atrioventricular block, indicating potential roles in cardiac conduction 1. Additionally, PLEKHA3 expression changes have been observed in microglial cells during neuroinflammatory responses, with increased expression noted when TGR5-mediated anti-inflammatory pathways are inhibited in multiple sclerosis models 2. Copy number variants affecting PLEKHA3 have been identified in children with short stature, suggesting possible involvement in growth regulation 3. These findings collectively indicate PLEKHA3's importance in membrane trafficking, metabolic regulation, and potential disease pathogenesis.