PLXNA3 is an X-linked transmembrane receptor that serves as a coreceptor for semaphorin-3A and -3F ligands in complex with neuropilins 1. Its primary function involves axon guidance and neurodevelopment through semaphorin-plexin signaling pathways. In the developing nervous system, PLXNA3 cooperates with PLXNA1 to pattern olfactory and vomeronasal axons that guide gonadotropin-releasing hormone (GnRH) neuron migration 2. The receptor's cytosolic juxtamembrane domain modulates oligomerization and signal transduction, with a heptad repeat interface controlling homomeric interactions necessary for proper signaling 3. Patogenic variants in PLXNA3 cause X-linked intellectual disability syndrome characterized by autism, developmental delays, fine motor dyspraxia, and seizures, with more severe phenotypes associated with cytoplasmic domain mutations 1. Loss-of-function variants cause idiopathic hypogonadotropic hypogonadism through impaired GnRH and olfactory neuron development 4. In cancer contexts, elevated PLXNA3 expression correlates with poor prognosis in breast and colorectal cancers 5 6. PLXNA3 overexpression promotes cancer cell proliferation, invasion, and migration while suppressing immune activation and reducing CD8+ T cell infiltration, conferring resistance to anti-PD1 immunotherapy 5 6. In ovarian cancer, PLXNA3 shows discordant estrogen regulation compared to normal epithelium and inhibits cell invasiveness 7.