GRM4

Chr 6

glutamate metabotropic receptor 4

Also known as: GPRC1D, MGLUR4, mGlu4

NCBI Gene: 2914ENSG00000124493UniProt: Q14833

L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropic glutamate receptors. Glutamatergic neurotransmission is involved in most aspects of normal brain function and can be perturbed in many neuropathologic conditions. The metabotropic glutamate receptors are a family of G protein-coupled receptors, that have been divided into 3 groups on the basis of sequence homology, putative signal transduction mechanisms, and pharmacologic properties. Group I includes GRM1 and GRM5 and these receptors have been shown to activate phospholipase C. Group II includes GRM2 and GRM3 while Group III includes GRM4, GRM6, GRM7 and GRM8. Group II and III receptors are linked to the inhibition of the cyclic AMP cascade but differ in their agonist selectivities. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2012]

137
ClinVar variants
5
Pathogenic / LP
0.99
pLI score· haploinsufficient
0
Active trials
Clinical Summary— GRM4
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
5 Pathogenic / Likely Pathogenic· 121 VUS of 137 total submissions

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.
0.28LOEUF
pLI 0.993
Z-score 4.86
OE 0.14 (0.07–0.28)
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.
2.68Z-score
OE missense 0.70 (0.65–0.76)
447 obs / 637.7 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.0.14 (0.07–0.28)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.70 (0.65–0.76)
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.0.92
0≤1.21.6
LoF obs/exp: 5 / 36.9Missense obs/exp: 447 / 637.7Syn Z: 1.03

ClinVar Variant Classifications

137 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4
Likely Pathogenic1
VUS121
Likely Benign3
Benign8
4
Pathogenic
1
Likely Pathogenic
121
VUS
3
Likely Benign
8
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
4
0
4
Likely Pathogenic
0
0
1
0
1
VUS
0
118
3
0
121
Likely Benign
0
0
1
2
3
Benign
0
1
0
7
8
Total011999137

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

View in ClinVar →

Protein Context — Lollipop Plot

GRM4 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Low expression of GRM4 is associated with poor prognosis and tumor immune infiltration in glioma.
Fan H et al.·Int J Neurosci
2024
Glutamate metabotropic receptor 4 (GRM4) inhibits cell proliferation, migration and invasion in breast cancer and is regulated by miR-328-3p and miR-370-3p.
Xiao B et al.·BMC Cancer
2019
A genetic variant in miRNA binding site of glutamate receptor 4, metabotropic (GRM4) is associated with increased risk of major depressive disorder.
Dadkhah T et al.·J Affect Disord
2017
Cystic angiomatosis in children: clinical experience and review of literature.
Li WC et al.·World J Surg Oncol
2022Review
Mutation screening of the metabotropic glutamate receptor mGluR4 (GRM4) gene in patients with schizophrenia.
Ohtsuki T et al.·Psychiatr Genet
2001Cohort
Clinical significance of glutamate metabotropic receptors in renal cell carcinoma risk and survival.
Huang CY et al.·Cancer Med
2018
Inositol 1,4,5-trisphosphate receptor gene variants are related to the risk of breast cancer in a Chinese population.
Chen J et al.·J Gene Med
2023
Identification of key modules and genes associated with breast cancer prognosis using WGCNA and ceRNA network analysis.
Yin X et al.·Aging (Albany NY)
2020
Glutamatergic gene variants impact the clinical profile of efficacy and side effects of haloperidol.
Giegling I et al.·Pharmacogenet Genomics
2011
The potentially therapeutic targets of pediatric anaplastic ependymoma by transcriptome profiling.
Wang J et al.·Neoplasma
2021
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools