KIR2DL5A is an inhibitory killer cell immunoglobulin-like receptor expressed on natural killer (NK) cells that functions as a ligand-binding protein for HLA recognition. Located on chromosome 19.4, KIR2DL5A is one of two paralogous genes (with KIR2DL5B) arising from gene duplication, displaying significant allelic polymorphism and copy number variation 1. The receptor contains a distinctive D0-D2 immunoglobulin domain configuration, unlike most KIR family members 2. Functionally, KIR2DL5A inhibits NK cell cytotoxic activity, preventing inappropriate cell lysis—a role critical for immune homeostasis. Allelic variants substantially affect KIR2DL5A surface expression; the common KIR2DL5A*001 allele localizes to the cell surface efficiently, while the second most common KIR2DL5A*005 variant undergoes intracellular retention due to a glycine-174 serine substitution, reducing functional NK cell expression 2. Clinically, KIR2DL5A genotype correlates with disease outcomes: the absence of KIR2DL5A (KIR2DL5A-/2DL5B+) associates with hepatitis C virus spontaneous clearance 3, while KIR2DL5A presence correlates with minimal residual disease positivity in acute lymphoblastic leukemia, suggesting reduced NK cell anti-leukemic efficacy 4. Additionally, KIR2DL5A upregulation in blood associates with faster cognitive decline in early Alzheimer's disease, indicating potential biomarker utility 5.