U2AF2 is an essential RNA-binding protein that plays critical roles in pre-mRNA splicing and transcriptional regulation. The protein functions as part of the U2AF heterodimer complex, binding to polypyrimidine tracts at 3' splice sites during spliceosome assembly 1. U2AF2 exhibits chr19-binding properties throughout gene bodies, requiring histone H3-lysine36 trimethylation, and preferentially occupies exons of highly expressed genes to enhance exon selection accuracy 2. The protein facilitates recursive splicing of large introns by supporting splicing at ratchet points 3. Beyond splicing, U2AF2 regulates mRNA stability through interactions with other RNA-binding proteins and influences alternative splicing of genes like EIF2AK2 4. Disease relevance is significant, as de novo missense variants in U2AF2 cause neurodevelopmental disorders characterized by intellectual disability, epilepsy, and brain anomalies 5. These pathogenic variants can disrupt normal splicing function, with some causing exon skipping and protein truncation 6. Clinically, U2AF2 dysfunction leads to reduced neuritogenesis and cellular proliferation defects 56. The protein also serves as a tumor antigen recognized by T cells in colorectal cancer 7, highlighting its broader clinical significance in both neurodevelopmental and oncological contexts.