PLXNA1 (plexin A1) is a transmembrane coreceptor for class 3 semaphorins (SEMA3A, SEMA3C, SEMA3F, SEMA3G, and SEMA6D) that functions in axon guidance and cell migration by modulating neuropilin-semaphorin complex affinity and activating cytoplasmic signaling cascades 1. PLXNA1 works cooperatively with neuropilins and other plexins to pattern developing neural circuits, particularly in GnRH neuron migration and hypothalamic melanocortin circuit formation, where semaphorin-plexin signaling controls energy homeostasis 12. Disease-relevant variants in PLXNA1 are associated with idiopathic hypogonadotropic hypogonadism (both normosmic and anosmic forms) with 3.9% prevalence in IHH cohorts, often co-occurring with mutations in other developmental genes 3. Clinically, PLXNA1 dysregulation contributes to multiple cancers: elevated expression in hepatocellular carcinoma and esophageal cancer correlates with poor prognosis and enhanced proliferation/migration 45; in prostate cancer, PLXNA1 amplification drives enzalutamide resistance through AKT signaling activation 6. Conversely, endothelial cell-derived SEMA3G-PLXNA1 signaling suppresses glioblastoma stem cells via c-Myc degradation, suggesting therapeutic potential 7. Rare PLXNA1 variants show enrichment in Parkinson's disease cohorts, implicating neurodegeneration pathways 8.