GRM1

Chr 6ADAR

glutamate metabotropic receptor 1

NCBI Gene: 2911ENSG00000152822UniProt: Q13255

G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Signaling activates a phosphatidylinositol-calcium second messenger system. May participate in the central action of glutamate in the CNS, such as long-term potentiation in the hippocampus and long-term depression in the cerebellum (PubMed:24603153, PubMed:28886343, PubMed:7476890). May function in the light response in the retina (By similarity). Induces GRID1 and GRID2 cation-channel activation via GNAQ-PLC-PKC pathway in dopaminergic neurons and cerebellar Purkinje cell, respectively (PubMed:24357660, PubMed:27276689)

Primary Disease Associations & Inheritance

Spinocerebellar ataxia 44MIM #617691
AD
Spinocerebellar ataxia, autosomal recessive 13MIM #614831
AR
460
ClinVar variants
28
Pathogenic / LP
0.14
pLI score
0
Active trials
Clinical Summary— GRM1
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.24) despite low pLI — interpret in context.
📋
ClinVar Variants
28 Pathogenic / Likely Pathogenic· 227 VUS of 460 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.41LOEUF
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?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.
2.58Z-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?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.0.24 (0.15–0.41)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.72 (0.67–0.77)
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.1.22
0≤1.21.6
LoF obs/exp: 10 / 40.9Missense obs/exp: 475 / 661.9Syn Z: -2.83

ClinVar Variant Classifications

460 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic22
Likely Pathogenic6
VUS227
Likely Benign139
Benign48
Conflicting9
22
Pathogenic
6
Likely Pathogenic
227
VUS
139
Likely Benign
48
Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
3
3
16
0
22
Likely Pathogenic
4
1
1
0
6
VUS
2
198
19
8
227
Likely Benign
0
13
24
102
139
Benign
0
1
31
16
48
Conflicting
—9
Total921691126451

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.

Gene2Phenotype Curations

GRM1-related congenital cerebellar ataxia

strong
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Spinocerebellar ataxia 44

MIM #617691

Molecular basis of disorder known

Autosomal dominant

Spinocerebellar ataxia, autosomal recessive 13

MIM #614831

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Hereditary ataxias and paraparesias: clinical and genetic update.
Parodi L et al.·Curr Opin Neurol
2018Review
Detection of GRM1 gene rearrangements in chondromyxoid fibroma: a comparison of fluorescence in-situ hybridisation, RNA sequencing and immunohistochemical analysis.
Torrence D et al.·Histopathology
2024
Genetic Variant in GRM1 Underlies Congenital Cerebellar Ataxia with No Obvious Intellectual Disability.
Protasova MS et al.·Int J Mol Sci
2023
Chondromyxoid Fibroma: An Updated Review.
Nishio J et al.·In Vivo
2026Review
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
Concurrent Targeting of Glutaminolysis and Metabotropic Glutamate Receptor 1 (GRM1) Reduces Glutamate Bioavailability in GRM1(+) Melanoma.
Shah R et al.·Cancer Res
2019
Motor neuron pathology in CANVAS due to RFC1 expansions.
Huin V et al.·Brain
2022
A Novel Nonsense Variant in GRM1 Causes Autosomal Recessive Spinocerebellar Ataxia 13 in a Consanguineous Pakistani Family.
Yousaf H et al.·Genes (Basel)
2022Case report
Metabotropic glutamate receptor 1 (Grm1) is an oncogene in epithelial cells.
Martino JJ et al.·Oncogene
2013
Activation of the glutamate receptor GRM1 enhances angiogenic signaling to drive melanoma progression.
Wen Y et al.·Cancer Res
2014
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