CAPN3 (calpain 3) is a calcium-regulated cysteine protease with unique characteristics among human calpains, including rapid autodegradation and dependence on sodium for activation 1. The protein possesses both proteolytic and non-proteolytic functions, with the distinctive ability to regain protease activity after autolytic dissociation through intermolecular complementation 1. CAPN3 mediates proteasome-independent degradation of p53 and cleaves CTBP1, contributing to protein quality control and transcriptional regulation. CAPN3 mutations cause limb-girdle muscular dystrophy type 2A (LGMD2A), an autosomal recessive disorder characterized by progressive proximal muscle weakness. Among large diagnostic cohorts, CAPN3 mutations represent a major genetic cause of LGMD, accounting for approximately 17-19% of molecularly diagnosed cases 23. Patients typically present between ages 6-18 years, with wheelchair dependence by age 32 years 4. Over 100 distinct mutations have been identified throughout the CAPN3 gene, with the 2362AG→TCATCT mutation being most frequent 4. Two null mutations correlate with more severe phenotypes, though mutation type alone does not predict disease progression 4. CAPN3 dysfunction impairs satellite cell function, affecting muscle regeneration capacity 5. Combined clinical and biochemical assessment provides ~91% diagnostic accuracy for calpainopathy 4.