The myopathy-causing Tpm3.12-R91C variant increases the ability of Tpm3.12 to inhibit cofilin-2 activity, supporting the hypothesis that the phenotype typical of congenital myopathies, such as muscle weakness and disarray of the thin filaments, may result from both impaired Ca2+-dependent regulation of actin–myosin interactions and disturbances in regulation of cofilin-2-dependent maintenance of thin filament length. This evidence concerns the gene TPM3 and congenital myopathy with cores.