CAPN1 encodes calpain 1, a calcium-regulated cysteine protease that mediates limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction. The enzyme is activated by calcium influx, which triggers dissociation into active subunits 1. CAPN1 cleaves key regulatory proteins including CTBP1 and caspase-7, modulating both structural dynamics and apoptotic signaling pathways. CAPN1 mutations cause spastic paraplegia type 76 (SPG76), an inherited neurological disorder characterized by lower-limb spasticity and hyperreflexia, often accompanied by ataxia, dysarthria, and emotional dysfunction 2. Pathogenic variants impair protein localization and cytoskeletal interaction; mutant calpain 1 forms abnormal intracellular aggregates rather than normal cytoplasmic distribution 2. Both homozygous and compound heterozygous mutations cause disease 3. Recently, loss-of-function variants in CD99L2, an activating interactor of CAPN1, were identified as a cause of X-linked spastic ataxia, with impaired CAPN1 activation disrupting synaptic function and neuronal pathways 4. At the population level, gnomAD v4.1 classifies CAPN1 as loss-of-function tolerant (LOEUF=0.98); however, this is distinct from clinical pathogenicity, as the gene harbors 50 ClinVar pathogenic or likely pathogenic variants. No approved targeted therapeutics specifically address CAPN1 dysfunction.