GRIN2B encodes the GluN2B subunit of N-methyl-D-aspartate (NMDA) receptors, heterotetrameric ligand-gated ion channels with high calcium permeability 1. Channel activation requires L-glutamate binding to GluN2B, glycine/D-serine binding to GluN1, and membrane depolarization to relieve Mg2+ block 1. GluN2B confers differential channel kinetics, pH sensitivity, and calcium permeability 2. GRIN2B variants cause developmental and epileptic encephalopathy 27 and intellectual developmental disorder, presenting with neurodevelopmental delay, epilepsy, autism, movement disorders, and cortical visual impairment 3. De novo variants account for approximately 1% of sporadic autism spectrum disorders 4. Missense variants cluster in transmembrane segments and ligand-binding domains, producing diverse gain-of-function and loss-of-function mechanisms 3. Recent structural studies reveal ketamine binds the central vestibule through interactions with leucine 643 on GluN2B and asparagine 616 on GluN1, enabling therapeutic channel blockade for antidepressant effects 5. Functional characterization of disease variants remains incomplete but suggests altered NMDAR function correlates with clinical severity 6. Memantine, a use-dependent NMDAR blocker, shows promise but requires further clinical validation in GRIN2B encephalopathy 3.