ACTG1 (actin gamma 1) encodes γ-actin, a highly conserved cytoskeletal protein ubiquitously expressed in eukaryotic cells with critical roles in cell motility and structural integrity. 1 As a major intracellular protein, ACTG1 regulates diverse cellular processes including focal adhesion assembly, stress fiber formation, and cell migration. 2 γ-actin knockout studies demonstrate that ACTG1 plays a more prominent role in melanoma cell migration and invasion compared to β-actin, with particular importance for lamellipodia formation and focal adhesion-dependent signaling. 2 ACTG1 has emerged as clinically significant in cancer biology. Exosomal PGAM1 interacts with ACTG1 to promote podosome formation and angiogenesis in endothelial cells, facilitating prostate cancer metastasis. 3 ACTG1 amplification and overexpression occur in 5-20% of uterine cancers across all four subtypes, correlating with poor prognosis and activation of oncogenic pathways. 4 In non-small cell lung cancer, ACTG1 overexpression mediates cisplatin resistance through mitochondrial dysfunction and suppression of ferroptosis. 5 ACTG1 mutations cause developmental disorders: Baraitser-Winter cerebrofrontofacial syndrome, characterized by intellectual disability and distinctive facial features, 6 and autosomal dominant non-syndromic hearing loss (DFNA20). 7 Clinical phenotypic variability is extreme, ranging from isolated hearing loss to complex syndromic presentations. 8 Pathogenic variants cause dysregulated actin dynamics and neuronal migration defects, while loss-of-function variants produce milder phenotypes. 1