CALM2 encodes calmodulin, a calcium-binding protein that functions as a critical regulator of cardiac electrophysiology and muscle contraction. As one of three identical calmodulin-encoding genes (CALM1, CALM2, CALM3), CALM2 activates protein kinases and phosphatases while regulating calcium channels and release from cardiac sarcoplasmic reticulum stores 1. The protein mediates calcium-dependent signaling through interactions with multiple cardiac proteins, including calcineurin and ryanodine receptors 2. CALM2 variants cause calmodulinopathies, a distinct class of inherited long QT syndrome with atypical features including congenital atrioventricular block 1. Pathogenic CALM2 mutations (e.g., D130G) prolong cardiac action potential duration, promoting life-threatening ventricular arrhythmias 3. CALM2 also functions in glycogen storage disease type IX as the regulatory delta subunit of phosphorylase kinase 4. Clinically, CALM2-mediated arrhythmias are refractory to conventional pharmacotherapy. Emerging therapeutic approaches show promise: antisense oligonucleotide-mediated CALM1 depletion alleviates bidirectional ventricular tachycardia in mouse models without compromising cardiac function 5, and suppression-replacement gene therapy normalizes prolonged action potentials in patient-derived cardiomyocytes carrying CALM2 variants 3. In myocardial infarction, dysregulated CALM2 promotes cardiomyocyte apoptosis through miR-525-5p pathway modulation 6.