PLEKHG3 is a guanine nucleotide exchange factor (RhoGEF) that regulates cell polarity and directed migration by coordinating Rac1 and Cdc42 activation with actin polymerization 1. The protein selectively binds newly polymerized actin filaments at the leading edge of migrating cells and activates Rac1/Cdc42 to promote local actin polymerization, creating an autocatalytic positive feedback loop essential for maintaining cell polarity 1. PLEKHG3 functions as a PI3K-regulated effector in this process 1. Beyond cell migration, PLEKHG3 participates in interferon signaling; phosphorylation at serine-1081 creates a binding motif for 14-3-3 proteins, coordinating interferon-stimulated gene expression independently of JAK/STAT pathways 2. PLEKHG3 also acts as a promoter of Rac-mediated membrane ruffling downstream of RHOG 3. Clinically, PLEKHG3 haploinsufficiency has been associated with intellectual disability and developmental disorders; deletions of the 14q23.2-23.3 region containing PLEKHG3 have been identified in patients with autism, intellectual disability, and hereditary spherocytosis 456. Genome-wide association studies identified PLEKHG3 variants associated with optic disc parameters relevant to glaucoma pathogenesis 7.