TNNI3K is a cardiac-restricted kinase that regulates cardiac contractility, conduction, and myocyte function through its serine autophosphorylation activity 1. The protein interacts with cardiac troponin I and modulates cardiomyocyte calcium dynamics and protein kinase A signaling in response to β-adrenergic stimulation 2. Loss-of-function or hypomorphic TNNI3K variants impair contractile reserve and promote concentric remodeling with ventricular wall thickening 2. TNNI3K variants are associated with multiple cardiac pathologies including dilated cardiomyopathy, supraventricular arrhythmias, conduction disease, and cardiomyopathy 1. Increased autophosphorylation of TNNI3K appears to drive pathogenicity in DCM and arrhythmia phenotypes 3. In both dominant and recessive inheritance patterns, TNNI3K mutations contribute to early-onset heart failure and sudden cardiac death risk 4. The common I686T variant, present in the general population, is hypomorphic and may confer elevated hypertrophy risk 2. Clinically, TNNI3K represents a novel therapeutic target for ischemic heart disease, with overexpression promoting cardiac myogenesis and attenuating ischemia-induced remodeling in preclinical models 5. Gene-gene interactions between TNNI3K and other cardiac modifier genes modulate disease severity 6.