GRIA4

Chr 11AD

glutamate ionotropic receptor AMPA type subunit 4

Also known as: GLUR4, GLUR4C, GLURD, GluA4, GluA4-ATD, NEDSGA

NCBI Gene: 2893 ENSG00000152578 UniProt: P48058 OMIM: 138246

The protein is a subunit of AMPA-sensitive glutamate receptors that form ligand-gated ion channels mediating excitatory neurotransmission in the brain. De novo mutations cause autosomal dominant neurodevelopmental disorder with or without seizures and gait abnormalities. The pathogenic mechanism involves dominant-negative effects from the mutant protein.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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 composed of multiple subunits, arranged to form ligand-gated ion channels. The classification of glutamate receptors is based on their activation by different pharmacologic agonists. The subunit encoded by this gene belongs to a family of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate)-sensitive glutamate receptors, and is subject to RNA editing (AGA->GGA; R->G). Alternative splicing of this gene results in transcript variants encoding different isoforms, which may vary in their signal transduction properties. Some haplotypes of this gene show a positive association with schizophrenia. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.431 OMIM phenotype

Clinical Summary— GRIA4

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Gene-Disease Validity (ClinGen)

neurodevelopmental disorder with or without seizures and gait abnormalities · ADModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.27) despite low pLI — interpret in context.

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ClinVar Variants

11 unique Pathogenic / Likely Pathogenic· 201 VUS of 266 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

0.43LOEUF

pLI 0.018

Z-score 4.70

OE 0.27 (0.17–0.43)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

3.42Z-score

OE missense 0.57 (0.51–0.63)

278 obs / 491.3 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.27 (0.17–0.43)

0≤0.351.4

Missense OE?0.57 (0.51–0.63)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 13 / 48.2Missense obs/exp: 278 / 491.3Syn Z: -0.47

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedGRIA4-related neurodevelopmental disorder with or without seizures and gait abnormalitiesOTHERAD

This gene — mechanism propensity

0.81top 10%

GOF

0.79top 10%

LOF

0.2484th %ile

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

GOFprediction above median · 82% of P/LP are missense

DNprediction 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

266 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic9

VUS201

Likely Benign33

Benign7

Conflicting5

Pathogenic

Likely Pathogenic

201

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	2	0	0	2
Likely Pathogenic	2	7	0	0	9
VUS	13	179	8	1	201
Likely Benign	0	7	5	21	33
Benign	0	0	5	2	7
Conflicting	—				5
Total	15	195	18	24	257

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

View in ClinVar →

21 pathogenic / likely-pathogenic (of 26) ClinVar copy-number / structural variants overlap GRIA4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →