ACTG2 encodes gamma-2 smooth muscle actin, a highly conserved cytoskeletal protein essential for smooth muscle contraction in the gastrointestinal tract and bladder 1. The protein functions as a structural component critical for peristalsis and proper muscle contractility 2. ACTG2 mutations predominantly cause visceral myopathy, a severe disorder characterized by impaired intestinal and bladder motility 1. Pathogenic variants, typically heterozygous missense mutations affecting conserved arginine residues, account for approximately 44% of chr2 intestinal pseudo-obstruction cases and present with diverse phenotypes including megacystis-microcolon-intestinal hypoperistalsis syndrome 3. Mechanistically, different mutations cause distinct defects: some impair filament polymerization, others disrupt actin-binding protein interactions or destabilize filaments 4. Disease severity correlates with specific arginine substitutions, with mutations at p.Arg257, p.Arg178, and p.Arg40 conferring increasing severity, including poor outcomes requiring parenteral nutrition, transplantation, or resulting in mortality 5. Clinical presentation typically occurs perinatally, though later-onset cases occur 1. Females show worse outcomes than males, with higher rates of parenteral nutrition dependence and mortality 1. Beyond visceral myopathy, ACTG2 overexpression promotes hepatocellular carcinoma metastasis through Notch1-dependent mechanisms 6. Additionally, an ACTG2-ALK fusion has been identified in uterine leiomyosarcomas as a potentially targetable event 7.