GRM1

Chr 6ADAR

glutamate metabotropic receptor 1

Also known as: GPRC1A, MGLU1, MGLUR1, PPP1R85, SCA44, SCAR13

NCBI Gene: 2911ENSG00000152822UniProt: Q13255OMIM: 604473

This protein is a G-protein coupled receptor for glutamate that activates phospholipase C and a phosphatidylinositol-calcium second messenger system, participating in synaptic plasticity including long-term potentiation in the hippocampus and long-term depression in the cerebellum. Mutations cause spinocerebellar ataxia 44 (autosomal dominant) and spinocerebellar ataxia, autosomal recessive 13, with pathogenicity predicted to result from gain-of-function mechanisms.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
LOFmechanismAD/ARLOEUF 0.412 OMIM phenotypes
Clinical Summary— GRM1
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.24) despite low pLI — interpret in context.
📋
ClinVar Variants
29 unique Pathogenic / Likely Pathogenic· 231 VUS of 465 total submissions
Explore recent and relevant literature in Research Assistant →
📖
GeneReview available — GRM1
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
0.41LOEUF
pLI 0.143
Z-score 4.47
OE 0.24 (0.15–0.41)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
2.58Z-score
OE missense 0.72 (0.67–0.77)
475 obs / 661.9 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.24 (0.15–0.41)
0≤0.351.4
Missense OE0.72 (0.67–0.77)
0≤0.61.4
Synonymous OE1.22
0≤1.21.6
LoF obs/exp: 10 / 40.9Missense obs/exp: 475 / 661.9Syn Z: -2.83
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
strongGRM1-related congenital cerebellar ataxiaLOFAR

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

DN
0.7327th %ile
GOF
0.79top 25%
LOF
0.3452th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Literature Evidence

DNHere, we describe heterozygous dominant mutations in GRM1, which encodes mGluR1, that are associated with distinct disease phenotypes: gain-of-function missense mutations, linked in two different families to adult-onset cerebellar ataxia, and a de novo truncation mutation resulting in a dominant-negPMID:28886343
GOFIn vitro functional expression studies in HEK293FT cells showed that the mutation did not affect mGluR1 clustering at the plasma membrane, but that it resulted in increased transcriptional activation and excessive mGluR1 signaling, consistent with a gain-of-function effect.PMID:28886343

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

465 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic23
Likely Pathogenic6
VUS231
Likely Benign142
Benign48
Conflicting9
23
Pathogenic
6
Likely Pathogenic
231
VUS
142
Likely Benign
48
Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
6
3
14
0
23
Likely Pathogenic
5
1
0
0
6
VUS
3
208
12
8
231
Likely Benign
0
13
24
105
142
Benign
0
1
31
16
48
Conflicting
—9
Total1422681129459

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

View in ClinVar →

Protein Context — Lollipop Plot

GRM1 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Identification of a Novel GRM1 Frameshift Variant in Two Pakistani Families Broadens the Genetic Landscape of Ultra-Rare Spinocerebellar Ataxia Type 13.
Ahmad R et al.·Cerebellum
2025Open Access
Spinocerebellar Ataxia 44 Caused by a Novel GRM1 Variant: Reviewing the Contrasting Pathogenic Mechanisms Underlying Two GRM1-Associated Hereditary Ataxias.
Lan SC et al.·Cerebellum
2025Review
GRM1 as a Candidate Gene for Buffalo Fertility: Insights from Genome-Wide Association Studies and Its Role in the FOXO Signaling Pathway.
Li W et al.·Genes (Basel)
2025Open Access
Erratum: U1 Adaptor Oligonucleotides Targeting BCL2 and GRM1 Suppress Growth of Human Melanoma Xenografts In Vivo.
Goraczniak R et al.·Mol Ther Nucleic Acids
2025Open Access
SCA44- and SCAR13-associated GRM1 mutations affect metabotropic glutamate receptor 1 function through distinct mechanisms.
Wang Y et al.·Br J Pharmacol
2024Functional
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients