NOTCH2NLA is a human-specific protein that emerged 2.1-3.7 million years ago through segmental duplication on chromosome 1 12. As a highly conserved paralog present in every human haplotype, NOTCH2NLA plays a critical role in cerebral cortex expansion by promoting neural progenitor proliferation and self-renewal 13. Mechanistically, NOTCH2NLA enhances Notch signaling through dual pathways: non-cell-autonomous interaction with NOTCH2 and cell-autonomous inhibition of cis DLL1-NOTCH2 interactions that promote neuronal differentiation, thereby delaying progenitor differentiation and increasing overall neuronal output. NOTCH2NLA harbors paralog-specific regulatory elements that distinguish it from other NOTCH2NL variants, suggesting specialized transcriptional control 12. Clinically, mutations or structural variations affecting NOTCH2NLA are implicated in microcephaly, reflecting its essential contribution to normal human brain size determination 3. The gene's human-specific origin and neurodevelopmental function underscore its significance in the evolutionary expansion of human cortical capacity.