NOVA2 is a neuron-specific RNA-binding protein that functions as a critical regulator of alternative splicing during brain development and neurodevelopment 1. The protein binds specifically to YCAY sequences on pre-mRNA transcripts to control exon inclusion or exclusion, with binding to exonic YCAY clusters promoting exon skipping while intronic binding enhances exon inclusion 2. NOVA2 exhibits distinct spatiotemporal expression patterns, being predominantly expressed in cortical regions, and regulates alternative splicing of axon guidance genes essential for neural network wiring and cortical development 1. Beyond linear splicing, NOVA2 globally promotes circular RNA biogenesis in the developing brain by binding to YCAY clusters in flanking introns 3. In vascular biology, NOVA2 regulates angiogenesis by controlling alternative splicing of genes like UNC5B in endothelial cells, generating pro-apoptotic isoforms required for proper blood vessel development 4. De novo truncating variants in NOVA2 cause a severe neurodevelopmental disorder characterized by intellectual disability, motor delays, autistic features, and structural brain abnormalities including corpus callosum hypoplasia 21. These mutations disrupt alternative splicing regulation, demonstrating the critical importance of RNA processing in normal neurodevelopment 5.