PLEKHA1 (pleckstrin homology domain containing A1) is a phosphoinositide-binding protein that specifically recognizes phosphatidylinositol 3,4-diphosphate and recruits proteins to the plasma membrane, functioning in PI3K/AKT signaling regulation. The protein is involved in cellular responses including ruffle organization and B cell receptor signaling. Mechanistically, PLEKHA1 contains a pleckstrin homology domain enabling phospholipid binding and PDZ domain interactions for protein localization 1. Clinically, PLEKHA1 variants show cumulative association with age-related macular degeneration (AMD) risk across multiple ethnic populations 2 3. In Alzheimer's disease (AD), PLEKHA1 expression in specific immune cell types is causally associated with disease risk 4, with tandem repeat variation in PLEKHA1 linked to AD pathogenesis 5. A genomewide analysis identified PLEKHA1 in microglial and oligodendrocytic gene networks altered during aging and contributing to AD susceptibility 6. In kidney disease, PLEKHA1 is dysregulated in proximal tubule cells and functions as a disease marker; knockdown increases PT differentiation gene expression, suggesting pathogenic involvement 1. In esophageal cancer, oncogenic PLEKHA1-TACC2 fusion proteins drive tumorigenesis via EphA2/AKT/MMP2 pathway activation and vascular mimicry formation 7. PLEKHA1 also serves as a shared diagnostic biomarker in systemic lupus erythematosus and ulcerative colitis, regulating neutrophil activation and neutrophil extracellular trap formation 8.