TPM2 (tropomyosin 2) encodes a protein that binds to actin filaments and plays a central role in regulating muscle contraction. In striated muscle, TPM2 functions with the troponin complex to enable calcium-dependent regulation of contraction 1, while in smooth muscle it interacts with caldesmon 2. In non-muscle cells, TPM2 stabilizes cytoskeletal actin filaments and may participate in receptor internalization 3. TPM2 mutations cause multiple congenital myopathies affecting actin-myosin interaction and myofibril force production 2. Disease-causing variants have been identified in nemaline myopathy, distal arthrogryposis (types 1A and 2B4), and congenital myopathy 23 14. Phenotypic heterogeneity exists, with the same mutations sometimes producing different diseases in family members 1. Beyond muscle disease, TPM2 serves as a fibroblast-specific biomarker associated with poor prognosis in colorectal cancer 56. Additionally, TPM2 is regulated by the CRL3GIG ubiquitin ligase complex, which targets it for proteasomal degradation to maintain actin filament homeostasis; mutations disrupting this pathway contribute to giant axonal neuropathy 3. Regulatory variants in TPM2 have also been implicated in clubfoot development 7.