CALM1

CALM1 encodes calmodulin, a highly conserved EF-hand calcium-binding protein that functions as a central intracellular calcium sensor and transducer of Ca²⁺-dependent signaling events^[1]. Upon Ca²⁺ binding, calmodulin undergoes conformational changes that enable interactions with diverse target proteins, thereby regulating calcium-dependent signaling pathways involved in cellular homeostasis, ion channel control, and signal transduction^[1][2]. Mechanistically, proper calmodulin activity is required for coordinated Ca²⁺ signaling, and disease-associated variants can disrupt calcium binding or downstream protein interactions, resulting in altered cellular responses^[1][3]. In disease contexts, pathogenic CALM1 variants are strongly associated with calmodulinopathy, a disorder characterized by ventricular arrhythmias, long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, and sudden cardiac death^[4][5]. Experimental and clinical evidence indicates that impaired calmodulin function affects membrane ion channel regulation and cardiac electrophysiology, providing a mechanistic basis for severe arrhythmic phenotypes^[1][4]. Compared with the related isoforms CALM2 and CALM3, CALM1 encodes an identical calmodulin protein sequence but exhibits distinct expression, translational contribution, and variant-associated clinical outcomes, highlighting gene-specific biological relevance despite protein identity^[4]. Notably, carriers of pathogenic CALM1 missense variants display a higher frequency of cardiac events than carriers of corresponding CALM3 variants, emphasizing the importance of isoform-specific interpretation in disease research and experimental design^[4].