CALM3 encodes calmodulin 3, one of three identical calmodulin proteins produced by CALM1, CALM2, and CALM3 genes 1. CALM3 is the most actively transcribed of the three calmodulin genes in certain cell types 1. Calmodulin functions as a calcium-binding protein critical for regulating calcium-dependent signaling pathways, including calcineurin-mediated signaling and calcium channel regulation. CALM3 variants cause calmodulinopathies, a group of inherited arrhythmia syndromes characterized by prolonged QT intervals and life-threatening ventricular arrhythmias 23. CALM3 pathogenic variants are associated with Long QT syndromes 14-16 and catecholaminergic polymorphic ventricular tachycardia types 4 and 6 4. Notably, CALM1, CALM2, and CALM3 mutations cause LQTS with atypical features, including neonatal atrioventricular block, and were classified as having strong or definitive evidence for causality 2. CALM3 also functions as the regulatory δ subunit of phosphorylase kinase in glycogen storage diseases type IX 5. Beyond cardiac disease, CALM3 polymorphisms associate with bone mineral density variations in postmenopausal women 6 and may modify hypertrophic and dilated cardiomyopathy phenotypes 7. Emerging therapeutic approaches include antisense oligonucleotides and suppression-replacement gene therapy targeting individual CALM genes 34.