CALM1 encodes calmodulin, a ubiquitous calcium-binding protein essential for cellular calcium signaling and protein quality control. The gene is expressed across all human tissues with tissue-specific mRNA isoforms, featuring a six-exon structure conserved across species 1. CALM1 functions as a critical regulator of cardiac electrophysiology through calcium channel modulation and calcineurin-mediated signaling pathways. The protein participates in diverse cellular processes including autophagosome membrane docking, mitochondrial-ER tethering, and serves as a component of the UBR4 E4 ubiquitin ligase complex for protein quality control 2. Pathogenic variants in CALM1 cause calmodulinopathies, rare inherited arrhythmia syndromes with strong evidence for disease causation 3. These variants produce congenital long QT syndrome with atypical features including neonatal atrioventricular block and life-threatening ventricular arrhythmias 4. CALM1 mutations also serve as a calmodulin subunit (δ-subunit) in phosphorylase kinase, contributing to glycogen storage disease type IX pathology 5. Clinically, CALM1 polymorphisms (rs12885713, rs2300496) are associated with increased osteoarthritis risk, particularly in Asian populations and knee OA 6. Emerging therapeutic approaches include antisense oligonucleotide depletion and suppression-replacement gene therapy, which normalize cardiac repolarization in CALM1-mutant cardiomyocytes without affecting overall calmodulin protein levels 7, 8.