KCNJ12 encodes Kir2.2, an inward rectifying potassium channel that controls resting membrane potential in electrically excitable tissues 1. The channel allows preferential potassium influx, with inward rectification primarily mediated by internal magnesium blockade of outward current 2. KCNJ12 is located on chromosome 17.1 as a single-exon gene in humans 1, though canine ortholog analysis revealed conserved three-exon structure across vertebrates 3. The arginine residue at position 285 in the C-terminal domain is critical for functional expression in mammalian cells 2. Pathologically, KCNJ12 mutations cause dilated cardiomyopathy (DCM), with a KCNJ12 p.Glu334del mutation identified in a family presenting with heart failure, arrhythmia, and sudden death 4. Additionally, rare germline KCNJ12/KCNJ18 mutations associate with familial esophageal squamous cell carcinoma risk 5. Beyond Mendelian disorders, KCNJ12 expression is regulated in cancer: circRNA hsa_circ_0014130 acts as a miR-132-3p sponge to upregulate KCNJ12 in bladder cancer, promoting epithelial-mesenchymal transition and GSK3β/AKT signaling 6. KCNJ12 DNA methylation status serves as a novel biomarker for colorectal cancer detection in blood with high diagnostic sensitivity 7.