ALPK3 encodes alpha-protein kinase 3, a non-sarcomeric protein involved in cardiomyocyte differentiation and cardiac muscle development 1. Functionally, ALPK3 appears critical for normal myocardial development, as loss-of-function variants disrupt cardiomyocyte organization and contractile function. Biallelic damaging ALPK3 variants cause pediatric-onset cardiomyopathy with distinctive pathophysiology: most patients initially present with neonatal dilated cardiomyopathy (44.4%) that transitions to ventricular hypertrophy during disease progression 1. Histopathologically, affected myocardium shows focal cardiomyocyte hypertrophy, subendocardial fibroelastosis, myofibrillar disarray, extensive myocardial fibrosis, and myocyte vacuolation 12. Most biallelic cases exhibit extracardiac manifestations including musculoskeletal abnormalities (contractures, scoliosis), craniofacial features (cleft palate, facial dysmorphisms), and webbed neck 13. Heterozygous ALPK3 truncating variants are pathogenic causes of autosomal dominant hypertrophic cardiomyopathy, occurring in 1.56% of HCM patients with significantly elevated odds ratios 2. ALPK3 truncating variants associate with apical/concentric hypertrophy patterns and short PR intervals, with myocardial outcomes comparable to sarcomere gene-positive patients 24. Recent ClinGen curation classified ALPK3 as having strong evidence for autosomal dominant and definitive evidence for autosomal recessive HCM 5. Intermediate-effect missense variants in ALPK3 contribute to approximately 4.8% of HCM genetic burden and modify disease severity 6.