Here, we use the largest currently available sample of human standing variation to illustrate the landscape of missense intolerance within the GluN1, GluN2A and GluN2B subunits, and provide the first evaluation of the molecular mechanisms of mutations in NMDAR pre-M1 helix that links the agonist binding domain to the channel pore in patients with epilepsy and/or intellectual disability. Here, GRIN2B is linked to epilepsy.