Alpha-actinin-2 is a protein which in humans is encoded by the ACTN2 gene. This gene encodes an alpha-actinin isoform that is expressed in both skeletal and cardiac muscles and functions to anchor myofibrillar actin thin filaments and titin to Z-discs. The primary function of alpha-actinin-2 is to crosslink filamentous actin molecules and titin molecules from adjoining sarcomeres at Z-discs, a function that is modulated by phospholipids. Mutations in ACTN2 are associated with hypertrophic cardiomyopathy, as well as dilated cardiomyopathy and endocardial fibroelastosis. The diverse functions of alpha-actinin-2 are reflected in the diverse clinical presentation of patients carrying ACTN2 mutations.