ATP8B4 is a putative P4-ATPase flippase that catalyzes ATP hydrolysis coupled to aminophospholipid transport from the outer to inner leaflet of cellular membranes, maintaining asymmetric phospholipid distribution and facilitating vesicle formation. Recent genetic studies have identified ATP8B4 as a significant disease risk factor across multiple conditions. Rare damaging variants in ATP8B4 are associated with increased Alzheimer's disease risk, particularly in early-onset cases 1. A missense variant (F436L) significantly increases systemic sclerosis risk, with differential ATP8B4 expression observed in affected patients 2. The gene also shows mechanosensitive upregulation in cardiac fibroblasts under varying matrix stiffness conditions, suggesting roles in cardiac fibrosis pathogenesis 3. Additionally, ATP8B4 variants appear enriched among deleterious mutations in populations and may contribute to HIV-1 susceptibility through glycolysis/gluconeogenesis pathway modulation 4. ATP8B4 variants are now included in clinical genetic screening panels for Alzheimer's disease, representing one of the rare risk factors with moderate-to-strong effects 5. These findings collectively highlight ATP8B4's emerging importance in multiple disease contexts beyond its fundamental role in membrane phospholipid homeostasis.