CAPNS2 encodes a novel small regulatory subunit of calpains, calcium-dependent cysteine proteases involved in limited proteolysis of cytoskeletal and signaling proteins 1. As a tissue-specific rather than ubiquitous protein, CAPNS2 functions analogously to the conventional small subunit by facilitating proper folding of the large catalytic subunit into its active conformation, though it binds more weakly and lacks autolytic conversion typical of classical small subunits 1. CAPNS2 is implicated in extracellular matrix organization, with expression most significantly upregulated in studies of collagen biosynthesis regulation 2. Genetically, rare coding variants in CAPNS2 were identified as novel associations with neuroticism in large-scale exome sequencing of 394,005 individuals, contributing to the estimated 7.3% heritability of rare coding variants in this neuropsychiatric trait 3. Common variants near CAPNS2 (LPCAT2/CAPNS2 locus) show gender-specific associations with thyroid function markers FT4 and TSH, suggesting a role in hypothalamic-pituitary-thyroid axis regulation and potential involvement in thyroid dysfunction 4. These findings position CAPNS2 at the intersection of neuropsychiatric, endocrine, and fibrotic disease pathways, though functional mechanisms require further investigation.