SEMA6B (semaphorin 6B) is a class 6 semaphorin that functions as an axon guidance molecule critical for nervous system development and neuronal connectivity 1. The protein exists in two splice variants: a secreted form and a transmembrane form, both involved in semaphorin-plexin signaling pathways 1. SEMA6B plays essential roles in dendritic spine formation and maturation, with knockdown or pathogenic variants leading to reduced spine density and impaired axon guidance in neuronal cultures 2. The protein is highly expressed in brain tissue and is downregulated by all-trans-retinoic acid treatment in glioblastoma cells 1. Beyond its developmental functions, SEMA6B demonstrates pathological significance in multiple diseases. Pathogenic variants cause a spectrum of neurodevelopmental disorders including progressive myoclonic epilepsy, intellectual disability, and autism spectrum disorder with electrical status epilepticus in sleep 234. In cancer contexts, SEMA6B promotes thyroid carcinoma progression through Notch signaling pathway activation 5 and serves as a diagnostic biomarker for hepatitis B virus-related acute-on-chr19 liver failure, where it exacerbates inflammation and hepatocyte apoptosis 6. These findings establish SEMA6B as both a critical neurodevelopmental regulator and potential therapeutic target across multiple pathological conditions.