GRIN2B

Chr 12AD

glutamate ionotropic receptor NMDA type subunit 2B

Also known as: DEE27, EIEE27, GluN2B, MRD6, NMDAR2B, NR2B, NR3, hNR3

NCBI Gene: 2904 ENSG00000273079 UniProt: Q13224 OMIM: 138252

The protein functions as the GluN2B subunit of NMDA receptors, forming heterotetrameric calcium-permeable ion channels that bind glutamate and mediate excitatory synaptic transmission critical for synaptic plasticity, learning, and memory. Autosomal dominant mutations cause developmental and epileptic encephalopathy 27 and intellectual developmental disorder with or without seizures, predominantly through loss-of-function mechanisms. The gene shows extreme intolerance to loss-of-function variants, consistent with haploinsufficiency as a primary disease mechanism.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the N-methyl-D-aspartate (NMDA) receptor family within the ionotropic glutamate receptor superfamily. The encoded protein is a subunit of the NMDA receptor ion channel which acts as an agonist binding site for glutamate. The NMDA receptors mediate a slow calcium-permeable component of excitatory synaptic transmission in the central nervous system. The NMDA receptors are heterotetramers of seven genetically encoded, differentially expressed subunits including NR1 (GRIN1), NR2 (GRIN2A, GRIN2B, GRIN2C, or GRIN2D) and NR3 (GRIN3A or GRIN3B). The early expression of this gene in development suggests a role in brain development, circuit formation, synaptic plasticity, and cellular migration and differentiation. Naturally occurring mutations within this gene are associated with neurodevelopmental disorders including autism spectrum disorder, attention deficit hyperactivity disorder, epilepsy, and schizophrenia. [provided by RefSeq, Aug 2017]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 27MIM #616139

Intellectual developmental disorder, autosomal dominant 6, with or without seizuresMIM #613970

Clinical highlights

Management implications

Functional class guides an NMDA-antagonist vs agonist strategy — largely investigational.Direction of therapy depends on GOF vs LOF; evidence is preliminary.

GRIN2B: treatment depends on gain/loss of function

Gene–disease validity (ClinGen · GenCC)

Definitive · complex neurodevelopmental disorder · AD · ClinGen 2019
Definitive · intellectual disability, autosomal dominant 6 · AD · G2P
Definitive · developmental and epileptic encephalopathy, 27 · AD · G2P
Strong · GRIN2B-related complex neurodevelopmental disorder · AD · PanelApp Australia

Interpreting a novel variant

Both gain of function and loss of function mechanisms are described for this gene and which one applies is variant-dependent. Do not assume a null variant is — or isn't — the pathogenic class without checking the specific variant against curated evidence.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

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Pubs (1 yr)

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P/LP submissions

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P/LP missense

0.06

LOEUF· LoF intol.

GOF/LOF*

Mechanism· annotated

📖

GeneReview available — GRIN2B

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Treatment implicationsDepends on gain/loss of function

GRIN2B-related neurodevelopmental disorder

Direction of therapy depends on GOF vs LOF; evidence is preliminary.

Functional class guides an NMDA-antagonist vs agonist strategy — largely investigational.

Gain-of-function

Gain-of-function → NMDA-receptor antagonists (memantine) — investigational.

Loss-of-function

Loss-of-function → l-serine supplementation reported (investigational).

Platzer & Lemke 2019 (GeneReviews). Confirm with a neurologist and current guidelines. Functional class (GOF/LOF) is from published functional/segregation data, never inferred from the variant. As of 2026-10. Curated from the clinical genetics/neurology literature (cited per gene). Decision-support, not prescribing.

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.06LOEUF

pLI 1.000

Z-score 6.48

OE 0.00 (0.00–0.06)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

5.42Z-score

OE missense 0.48 (0.44–0.52)

415 obs / 862.7 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.06)

0≤0.351.4

Missense OE?0.48 (0.44–0.52)

0≤0.61.4

Synonymous OE?1.14

0≤1.21.6

LoF obs/exp: 0 / 48.9Missense obs/exp: 415 / 862.7Syn Z: -2.00

Background carrier burden — how many people carry a rare variant somewhere in GRIN2B?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 89

1,189 rare PASS variants

Rare truncating (LoF)

1 in 11,000

24 rare PASS variants

Rare synonymous (reference)

1 in 54

842 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GRIN2B. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 95	1 in 18,000
South Asian	~43k	1 in 93	≈ 1 in 22,000
Remaining (unassigned)	~30k	1 in 91	≈ 1 in 30,000
European (Finnish)	~27k	1 in 240	1 in 3,000
Admixed American	~22k	1 in 79	1 in 3,800
African / African American	~21k	1 in 100	none seen
East Asian	~20k	1 in 72	1 in 2,600
Ashkenazi Jewish	~13k	1 in 1,100	none seen
Middle Eastern	~2,884	1 in 130	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 10 of 12 coding exons well covered in gnomAD exomes; exons 5, 12 marginal. Genomes: all 12.? see exons ↓