VANGL2 (VANGL planar cell polarity protein 2) is a core component of the planar cell polarity (PCP) pathway that regulates cellular polarization and morphogenetic movements during embryonic development 1. The protein functions primarily through Wnt/PCP signaling to control convergent extension movements, cell intercalation, and oriented cell division during gastrulation and neural tube closure 1. VANGL2 requires proper subcellular localization regulated by reversible S-stearoylation cycles involving acyltransferase ZDHHC9 and deacylase APT1 for effective PCP signaling 2. Beyond developmental roles, VANGL2 exhibits diverse regulatory functions including suppression of NF-κB inflammatory signaling through p65 degradation 3 and control of mesenchymal stem cell differentiation by targeting LAMP-2A for degradation to limit chaperone-mediated autophagy 4. Disease relevance is significant, as mutations in VANGL2 cause neural tube defects through disrupted interactions with Scribble PDZ domains 5 and contribute to congenital vertebral malformations in congenital scoliosis 6. Additionally, aberrant VANGL2 promoter methylation and decreased expression are associated with tetralogy of Fallot 7, while dysregulation may promote cancer progression through enhanced cellular motility and invasiveness 8.