PLEKHG6 is a guanine nucleotide exchange factor that activates the small GTPases RHOA and RHOG, playing crucial roles in cytoskeletal organization and cellular processes 1. The protein localizes to the apical pole of epithelial cells where it promotes the formation of microvilli and membrane ruffles through RhoG activation 1. PLEKHG6 functions as part of a complex with ezrin and is essential for macropinocytosis, as demonstrated by reduced dextran uptake when either PLEKHG6 or ezrin expression is downregulated 1. In neuronal development, a primate-specific isoform of PLEKHG6 regulates neuroprogenitor differentiation and neuronal migration via RhoA signaling, with variants associated with periventricular nodular heterotopia 2. The gene shows clinical relevance across multiple diseases, functioning as a putative tumor suppressor in colorectal cancer where it is co-activated by super-enhancer polymorphisms 3. PLEKHG6 expression correlates with favorable prognosis in bladder cancer and serves as a biomarker in ulcerative colitis with strong correlations to immune cell infiltration 45. Additionally, PLEKHG6 methylation patterns are affected by maternal circadian disruption, potentially impacting fetal development 6.