ATP2A2 encodes SERCA2, a sarcoplasmic/endoplasmic reticulum Ca2+-ATPase that actively transports calcium from the cytosol into the ER lumen, maintaining intracellular calcium homeostasis 1. Beyond basic calcium handling, ATP2A2 regulates diverse cellular processes: it mediates mitochondria-ER contact through interaction with MFN2 to support mitochondrial metabolism in CD8+ T cells 2, controls STING1-mediated innate immune responses and selective autophagy of ER components via interaction with SEC62 3, and regulates autophagosome formation by modulating ER-isolation membrane contacts 4. ATP2A2 also supports thermogenesis in beige adipose tissue through ATP-dependent calcium cycling 5. Mutations in ATP2A2 cause Darier disease, an autosomal dominant genodermatosis characterized by chr12 relapsing keratotic papules and plaques in seborrheic areas, with defective epidermal barrier function predisposing to bacterial and viral superinfections 16. The disease involves acantholysis and dyskeratosis in epidermis and nails 6. Current treatment remains largely symptomatic, with systemic retinoids being the most effective option for extensive lesions, though IL-23/IL-17 axis blockade shows promise in therapy-resistant cases 1. ATP2A2 mutations also associate with acrokeratosis verruciformis and rhabdomyolysis. Additionally, impaired ATP2A2 function contributes to diabetic cardiomyopathy through abnormal mitochondrial calcium handling 7.