C10orf71 is a cardiomyocyte-specific intrinsically disordered protein that functions as a critical regulator of cardiac contractile function 1. The gene activates calcineurin/NFAT signaling and contributes to myocardium morphogenesis and cardiac mass regulation through mechanisms involving altered expression and splicing of contractile cardiac genes 1. Loss-of-function variants in C10orf71 cause dilated cardiomyopathy (DCM), with frameshift mutations identified in families and 492 sporadic DCM patients across independent cohorts 1. C10orf71-deficient cardiomyocytes exhibit impaired contractile function with structurally normal sarcomeres, and cardiac contractile defects are recapitulated in human induced pluripotent stem cell-derived cardiomyocytes and organoids 1. Rare loss-of-function variants in C10orf71 are also associated with increased atrial fibrillation and cardiomyopathy risk, particularly when combined with high polygenic risk scores 2. Notably, therapeutic intervention with cardiac myosin activators restores contractile function in C10orf71-deficient models, suggesting mutation-specific therapeutic targets 1. C10orf71 involvement extends beyond cardiac disease; rare splicing mutations have been associated with congenital cataract and developmental abnormalities 3. Additionally, C10orf71-related loci are associated with heart rate variation 4.