GRIN2D encodes the GluN2D subunit of N-methyl-D-aspartate receptors (NMDARs), heterotetrameric ligand-gated cation channels with high calcium permeability and voltage-dependent magnesium block 1. Channel activation requires L-glutamate binding to GluN2D, glycine or D-serine binding to GluN1, plus membrane depolarization to relieve magnesium inhibition 1. GluN2D confers distinctive electrophysiological properties including unique activation/deactivation kinetics and pH sensitivity, contributing to learning, memory, and neuronal development 1. Pathogenic GRIN2D variants cause developmental and epileptic encephalopathy (DEE), a severe early-onset neurological disorder characterized by spontaneous seizures, motor deficits, and cognitive impairment 2. Notably, patients with GRIN2D-related DEE show refractoriness to conventional antiepileptic drugs, including ketamine, necessitating alternative approaches such as perampanel and memantine 123. Gain-of-function mutations, particularly the recurrent de novo p.Val667Ile variant, represent potential precision medicine targets 4. Beyond neurology, GRIN2D expression in pancreatic cancer and gastric cancer cells mediates glutamate-driven proliferation and metabolic reprogramming through calcium signaling, suggesting broader disease relevance 56.