NMDA receptors are ligand-gated cation-selective ion channels that mediate a slow, Ca2+-permeable component of transmission at excitatory synapses in the central nervous system. The glutamate receptors are tetrameric assemblies comprised of two GluN1 and two GluN2 subunits. GluN1 subunits are encoded by a single gene (GRIN1), which undergoes alternative splicing. The GluN2 subunits are encoded by a family of four genes (GRIN2A, GRIN2B, GRIN2C, GRIN2D) that are differentially expressed both anatomically and developmentally. Over the past decades, rare variants in a number of genes encoding various ion channels have been linked to neurological disease, sometimes referred to as channelopathies. More recently, a large number of de novo and inherited GRIN mutations have been identified in patients with neurological conditions (Yuan et al., 2015). These variants are absent from the healthy population, and are most commonly associated with seizure disorders. Among the GRIN genes, GRIN2A harbors the most rare variants (<1%) and de novo mutations that are associated with neurological disease, with the most common phenotype being patients suffering from seizure disorders. For this reason, GRIN2A has been proposed to be a locus for childhood epilepsy (Carvill et al., 2013; Lemke et al., 2013; Lesca et al., 2013). Despite the identification of hundreds of missense NMDA receptor mutations and rare variants, there are still less than a dozen de novo mutations for which functional data are available describing the effects of the amino acid exchange on receptor response properties. However, without understanding how these variants impact receptor function, it is difficult if not impossible to assess their role in terms of the neurological conditions they are associated with. We have sought to advance our understanding of the role of these mutations in neurological disease by obtaining functional data on all known variants as well as new cases identified by our collaborators. These studies have revealed some patient populations with de novo mutations in the ion channel pore and associated linkers that show similar enhancement of function, raising the possibility that these patients may be amenable to therapeutic treatment. Functional data will be presented showing the effects of different mutations in the ion channel pore and the adjacent linkers on NMDA receptor response time course and channel properties. In addition, the idea that mutations that enhance NMDA receptor function could be neurotoxic will also be discussed. A better understanding of the functional properties of these rare variants and mutations will help to elucidate the role these mutations play in the neurological conditions they are associated with, as well as advance our understanding of how the NMDA receptor works.