GRIN1

Chr 9ARAD

glutamate ionotropic receptor NMDA type subunit 1

Also known as: DEE101, GluN1, MRD8, NDHMSD, NDHMSR, NMD-R1, NMDA1, NMDAR1

NCBI Gene: 2902ENSG00000176884UniProt: Q05586

The protein encoded by this gene is a critical subunit of N-methyl-D-aspartate receptors, members of the glutamate receptor channel superfamily which are heteromeric protein complexes with multiple subunits arranged to form a ligand-gated ion channel. These subunits play a key role in the plasticity of synapses, which is believed to underlie memory and learning. Cell-specific factors are thought to control expression of different isoforms, possibly contributing to the functional diversity of the subunits. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 101MIM #619814
AR
Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominantMIM #614254
AD
Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessiveMIM #617820
AR
497
ClinVar variants
83
Pathogenic / LP
0.98
pLI score· haploinsufficient
1
Active trials
Clinical Summary— GRIN1
🧬
Gene-Disease Validity (ClinGen)
complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
83 Pathogenic / Likely Pathogenic· 209 VUS of 497 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.31LOEUF
pLI 0.976
Z-score 5.25
OE 0.17 (0.10–0.31)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
6.22Z-score
OE missense 0.28 (0.24–0.32)
163 obs / 586.7 exp
Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.17 (0.10–0.31)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.28 (0.24–0.32)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.95
0≤1.21.6
LoF obs/exp: 8 / 46.8Missense obs/exp: 163 / 586.7Syn Z: 0.67

ClinVar Variant Classifications

497 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic55
Likely Pathogenic28
VUS209
Likely Benign187
Benign5
Conflicting13
55
Pathogenic
28
Likely Pathogenic
209
VUS
187
Likely Benign
5
Benign
13
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
4
7
44
0
55
Likely Pathogenic
3
20
5
0
28
VUS
6
170
29
4
209
Likely Benign
0
10
77
100
187
Benign
0
0
3
2
5
Conflicting
—13
Total13207158106497

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

GRIN1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

GRIN1-related epileptic encephalopathy

definitive
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

GRIN1-related neurodevelopmental disorder with or without hyperkinetic movements and seizures

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Developmental and epileptic encephalopathy 101

MIM #619814

Molecular basis of disorder known

Autosomal recessive

Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant

MIM #614254

Molecular basis of disorder known

Autosomal dominant

Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive

MIM #617820

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — GRIN1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
L-serine treatment in patients with GRIN-related encephalopathy: a phase 2A, non-randomized study.
Juliá-Palacios N et al.·Brain
2024Clinical trial
Solving the Etiology of Developmental and Epileptic Encephalopathy with Spike-Wave Activation in Sleep (D/EE-SWAS).
Viswanathan S et al.·Ann Neurol
2024
A homozygous GRIN1 null variant causes a more severe phenotype of early infantile epileptic encephalopathy.
Blakes AJM et al.·Am J Med Genet A
2022Review
Spectrum of NMDA Receptor Variants in Neurodevelopmental Disorders and Epilepsy.
Gjerulfsen CE et al.·Methods Mol Biol
2024Review
Progress report on new medications for seizures and epilepsy: A summary of the 17th Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVII). II. Drugs in more advanced clinical development.
Bialer M et al.·Epilepsia
2024
Overlapping cortical malformations in patients with pathogenic variants in GRIN1 and GRIN2B.
Brock S et al.·J Med Genet
2023Cohort
Genetic Predisposition to Schizophrenia and Depressive Disorder Comorbidity.
Shnayder NA et al.·Genes (Basel)
2022Review
Recurrent seizure-related GRIN1 variant: Molecular mechanism and targeted therapy.
Xu Y et al.·Ann Clin Transl Neurol
2021Case report
GRIN1 variants associated with neurodevelopmental disorders reveal channel gating pathomechanisms.
Ragnarsson L et al.·Epilepsia
2023Functional
Inhibition of GluN2B-containing N-methyl-D-aspartate receptors by radiprodil.
Banke TG et al.·Brain
2026
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Neurodevelopmental disorder-causing GRIN1 Y647S variant alters red blood cell physiology in mice.
Okafor SC et al.·Physiol Rep
2026🔓 Open Access
APOE-mediated associations of promoter variants of GRIN1 and GRIN2B with behavioral symptoms and age at onset of Alzheimer's disease dementia.
de Oliveira FF et al.·Neurol Res
2025
Prenatal Exposure to Bonito Broth Attenuates the Induction of Drd1 and Grin1 upon Corn Oil Ingestion in Offspring.
Fushimi S et al.·J Nutr Sci Vitaminol (Tokyo)
2025
Foxg1 regulates translation of neocortical neuronal genes, including the main NMDA receptor subunit gene, Grin1.
Artimagnella O et al.·BMC Biol
2024🔓 Open Access
TFAP2A is involved in neuropathic pain by regulating Grin1 expression in glial cells of the dorsal root ganglion.
Yuan BT et al.·Biochem Pharmacol
2024
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10

External Resources

Links to major genomics databases and tools