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

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]

Primary Disease Associations & Inheritance

Neurodevelopmental disorder with or without seizures and gait abnormalitiesMIM #617864

274

ClinVar variants

Pathogenic / LP

0.02

pLI score

Active trials

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

31 Pathogenic / Likely Pathogenic· 198 VUS of 274 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

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.

0.43LOEUF

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?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.

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?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.0.27 (0.17–0.43)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.57 (0.51–0.63)

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.1.05

0≤1.21.6

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