GRIK2

Chr 6ARAD

glutamate ionotropic receptor kainate type subunit 2

Also known as: EAA4, GLR6, GLUK6, GLUR6, GluK2, MRT6, NEDLAS

NCBI Gene: 2898ENSG00000164418UniProt: Q13002

Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes. This gene product belongs to the kainate family of glutamate receptors, which are composed of four subunits and function as ligand-activated ion channels. The subunit encoded by this gene is subject to RNA editing at multiple sites within the first and second transmembrane domains, which is thought to alter the structure and function of the receptor complex. Alternatively spliced transcript variants encoding different isoforms have also been described for this gene. Mutations in this gene have been associated with autosomal recessive cognitive disability. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Intellectual developmental disorder, autosomal recessive 6MIM #611092
AR
Neurodevelopmental disorder with impaired language and ataxia and with or without seizuresMIM #619580
AD
307
ClinVar variants
31
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— GRIK2
🧬
Gene-Disease Validity (ClinGen)
complex neurodevelopmental disorder · ARModerate

Moderate evidence — consider for supplementary testing

2 total gene-disease associations curated

⚡
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.
📋
ClinVar Variants
31 Pathogenic / Likely Pathogenic· 207 VUS of 307 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
LoF intolerant — likely haploinsufficient
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.
0.26LOEUF
pLI 0.998
Z-score 5.41
OE 0.13 (0.07–0.26)
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.
2.91Z-score
OE missense 0.64 (0.58–0.70)
319 obs / 502.3 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.13 (0.07–0.26)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.64 (0.58–0.70)
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: 6 / 45.2Missense obs/exp: 319 / 502.3Syn Z: -0.50

ClinVar Variant Classifications

307 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic22
Likely Pathogenic9
VUS207
Likely Benign56
Benign9
Conflicting4
22
Pathogenic
9
Likely Pathogenic
207
VUS
56
Likely Benign
9
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
3
19
0
22
Likely Pathogenic
2
3
4
0
9
VUS
2
183
17
5
207
Likely Benign
0
9
9
38
56
Benign
0
1
5
3
9
Conflicting
—4
Total41995446307

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

View in ClinVar →

Protein Context — Lollipop Plot

GRIK2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

GRIK2-related intellectual developmental disorder

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

GRIK2-related intellectual disability and hypomyelination

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

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Intellectual developmental disorder, autosomal recessive 6

MIM #611092

Molecular basis of disorder known

Autosomal recessive

Neurodevelopmental disorder with impaired language and ataxia and with or without seizures

MIM #619580

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Pharmacogenomics of suicidal events.
Brent D et al.·Pharmacogenomics
2010Review
A Pathogenic Missense Mutation in Kainate Receptors Elevates Dendritic Excitability and Synaptic Integration through Dysregulation of SK Channels.
Nomura T et al.·J Neurosci
2023
Frequency and transmission of glutamate receptors GRIK2 and GRIK3 polymorphisms in patients with obsessive compulsive disorder.
Delorme R et al.·Neuroreport
2004Cohort
Clustered mutations in the GRIK2 kainate receptor subunit gene underlie diverse neurodevelopmental disorders.
Stolz JR et al.·Am J Hum Genet
2021Case report
Alternative Promoters of GRIK2 (GluR6) Gene in Human Carcinoma Cell Lines Are Regulated by Differential Methylation of CpG Dinucleotides.
Zhawar VK et al.·Genes (Basel)
2022
Suicidal ideation during antidepressant treatment: do genetic predictors exist?
Perroud N·CNS Drugs
2011Review
Gene methylation in gastric cancer.
Qu Y et al.·Clin Chim Acta
2013Review
Deleted genes associated with obesity in Mexican patients diagnosed with nonalcoholic fatty liver disease.
Zambrano-Zaragoza JF et al.·Ann Hum Genet
2022Cohort
Identification of recurrent fusion genes across multiple cancer types.
Yu YP et al.·Sci Rep
2019
Influence of polymorphisms in genes SLC1A1, GRIN2B, and GRIK2 on clozapine-induced obsessive-compulsive symptoms.
Cai J et al.·Psychopharmacology (Berl)
2013
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Mesial Temporal Lobe Epilepsy

AMT-260 Gene Therapy Study in Adults With Unilateral Refractory Mesial Temporal Lobe Epilepsy

RECRUITING
NCT06063850Phase PHASE1, PHASE2UniQure Biopharma B.V.Started 2024-06-12
AAV9-hSyn1-miGRIK2

External Resources

Links to major genomics databases and tools