GRIN1

Chr 9ARAD

glutamate ionotropic receptor NMDA type subunit 1

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

NCBI Gene: 2902 ENSG00000176884 UniProt: Q05586 OMIM: 138249

The protein is the GluN1 subunit of NMDA receptors, which form heterotetrameric ligand-gated calcium channels essential for synaptic plasticity, learning, and memory formation. Mutations cause developmental and epileptic encephalopathy and neurodevelopmental disorders with or without hyperkinetic movements and seizures through both autosomal dominant and autosomal recessive inheritance patterns. The gene is highly constrained against loss-of-function variants, and mutations can cause disease through multiple mechanisms depending on the specific variant type and location.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 101MIM #619814

Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominantMIM #614254

Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessiveMIM #617820

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · complex neurodevelopmental disorder · AD · ClinGen 2018
Definitive · neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive · AR · G2P
Definitive · neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant · AD · G2P
Strong · developmental and epileptic encephalopathy 101 · AR · Labcorp Genetics (formerly Invitae)

+2 more curated pairs

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.31

LOEUF· LoF intol.

LOF

Mechanism· G2P

📖

GeneReview available — GRIN1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

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?

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?

LoF OE?0.17 (0.10–0.31)

0≤0.351.4

Missense OE?0.28 (0.24–0.32)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 8 / 46.8Missense obs/exp: 163 / 586.7Syn Z: 0.67

Background carrier burden — how many people carry a rare variant somewhere in GRIN1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 280

654 rare PASS variants

Rare truncating (LoF)

1 in 2,600

94 rare PASS variants

Rare synonymous (reference)

1 in 70

590 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GRIN1. 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 280	1 in 1,900
South Asian	~43k	1 in 250	1 in 7,100
Remaining (unassigned)	~30k	1 in 180	≈ 1 in 28,000
European (Finnish)	~27k	1 in 480	1 in 2,100
Admixed American	~22k	1 in 200	≈ 1 in 5,200
African / African American	~21k	1 in 220	1 in 3,400
East Asian	~20k	1 in 230	1 in 3,900
Ashkenazi Jewish	~13k	1 in 690	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 220	≈ 1 in 1,100

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): All 20 coding exons well covered in gnomAD exomes and genomes.? see exons ↓