GRIA1

Chr 5

glutamate ionotropic receptor AMPA type subunit 1

Also known as: GLUH1, GLUR1, GLURA, GluA1, HBGR1, MRD67, MRT76

NCBI Gene: 2890 ENSG00000155511 UniProt: P42261

This gene encodes a subunit of AMPA glutamate receptors, which form ligand-gated ion channels that mediate excitatory neurotransmission in the brain. Mutations cause intellectual developmental disorder through both autosomal dominant and autosomal recessive inheritance patterns. The high pLI score (0.999) and low LOEUF score (0.259) indicate the protein is highly intolerant to loss-of-function mutations, suggesting haploinsufficiency as a likely mechanism for the dominant form.

ResearchSummary from RefSeq, OMIM, UniProt

Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes. These receptors are heteromeric protein complexes with multiple subunits, each possessing transmembrane regions, and all arranged to form a ligand-gated ion channel. The classification of glutamate receptors is based on their activation by different pharmacologic agonists. This gene belongs to a family of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.26

Clinical Summary— GRIA1

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADModerate

Moderate evidence — consider for supplementary testing

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

8 unique Pathogenic / Likely Pathogenic· 162 VUS of 238 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.26LOEUF

pLI 0.999

Z-score 5.45

OE 0.13 (0.07–0.26)

Highly constrained

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

Missense Constraint?

3.60Z-score

OE missense 0.56 (0.51–0.62)

302 obs / 536.6 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.13 (0.07–0.26)

0≤0.351.4

Missense OE?0.56 (0.51–0.62)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 6 / 45.7Missense obs/exp: 302 / 536.6Syn Z: -0.49

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateGRIA1-related neurodevelopmental disorderOTHERAD

This gene — mechanism propensity

0.5576th %ile

GOF

0.6637th %ile

LOF

0.58top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF25% of P/LP variants are LoF · LOEUF 0.26

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

238 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic7

VUS162

Likely Benign52

Benign7

Conflicting1

Pathogenic

Likely Pathogenic

162

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	0	0	0	1
Likely Pathogenic	1	6	0	0	7
VUS	10	148	3	1	162
Likely Benign	0	16	8	28	52
Benign	1	2	0	4	7
Conflicting	—				1
Total	13	172	11	33	230

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

View in ClinVar →

12 pathogenic / likely-pathogenic (of 18) ClinVar copy-number / structural variants overlap GRIA1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →