Background <p>Alpha-actinin-2, a protein with high expression in cardiac and skeletal muscle, is located in the Z-disc and plays a key role in sarcomere stability. Mutations in <i>ACTN2</i> have been associated with both hypertrophic and dilated cardiomyopathy and, more recently, with skeletal myopathy.</p> Methods <p>Genetic, clinical, and muscle imaging data were collected from 37 patients with an autosomal dominant <i>ACTN2</i> myopathy belonging to 11 families from Spain and Belgium. Haplotypes were studied to confirm a common ancestry for the two most common recurrent variants identified in this study. A trained machine learning model was used to compare muscle MRI scans in <i>ACTN2</i> myopathy with other neuromuscular diseases to identify a specific pattern of muscle involvement.</p> Results <p>The clinical phenotype ranged from asymptomatic to limb-girdle weakness and facial involvement and was depending on genotype. Cardiac and respiratory involvement were not common. Belgian families carrying the p.Ile134Asn variant and Basque-Spanish families carrying the p.Cys487Arg variant each showed unique haplotypes supporting respective common ancestry. Available muscle biopsies showed non-specific changes. In muscle imaging, the most affected muscles were the glutei minor, glutei medius, hamstrings, tibialis anterior, and soleus. A machine learning model showed that the most differentiating features in dominant <i>ACTN2</i> myopathy were the involvement of the tibialis anterior and gluteus medius muscles and preservation of the quadratus femoris, gastrocnemius lateralis, and tensor fasciae latae muscles.</p> Conclusion <p>We provide new insights into genetic, clinical, and muscle imaging characteristics of non-congenital dominant <i>ACTN2</i> myopathy, broadening the phenotypic spectrum of muscle disorders caused by <i>ACTN2</i> variants.</p>