SRGAP2B is a human-specific gene duplication of the ancestral synaptic regulator SRGAP2A that emerged approximately 3.4 million years ago 1. Primary Function: SRGAP2B regulates synaptic development through inhibition of SRGAP2A function via heterodimerization, reducing SRGAP2A protein levels in a proteasome-dependent manner 2. Unlike SRGAP2C, SRGAP2B does not induce long-lasting changes in synaptic density throughout adulthood 2. Mechanism: SRGAP2B promotes synaptic neoteny—the prolonged developmental immaturity of human synapses—by reducing SRGAP2A levels, thereby increasing postsynaptic SYNGAP1 accumulation 3. SRGAP2B also induces neotenic features in microglia structural and functional maturation, non-cell autonomously impacting neuronal synaptic development 4. Disease Relevance: SRGAP2B downregulation accelerates synaptic development and can modify phenotypic expression of genetic mutations causing intellectual disability and autism spectrum disorder through regulation of human synaptic neoteny 3. A CREBBP-SRGAP2B fusion gene has been identified in pediatric acute lymphoblastic leukemia cases, with potential implications for disease prognosis 5. SRGAP2B variants have been detected in proliferative verrucous leukoplakia 6. Clinical Significance: SRGAP2B's role in human brain evolution and its involvement in developmental disorders suggest potential therapeutic targets for neurodevelopmental conditions and cancer prognosis stratification.