This report described the largest actinopathy pedigree to date, comprising six generations and 33 affected individuals with scapuloperoneal myopathy caused by a c.591C>A (p.Glu197Asp) variant in ACTA1. Affected individuals showed clinical and morphological features distinctive from other actinopathies, including scapulo-humeral-peroneal distribution with striking upper extremity predilection in some individuals, progressive but variable disease course, and sparing of respiratory muscles until advanced stages of the disease. This evidence concerns the gene ACTA1 and alpha-actinopathy.