Spinocerebellar ataxia 44

Summary

Spinocerebellar ataxia 44 (MONDO:0033479) is a disease caused by GRM1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GRM1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 29

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		7	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	spinocerebellar ataxia 44
Mondo ID	MONDO:0033479
OMIM	617691
Orphanet	631095
DOID	DOID:0080286
UMLS	C4521563
MedGen	1611168
GARD	0025801
Is cancer (heuristic)	no

Also known as: SCA44 · spinocerebellar ataxia 44

Data availability: 29 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › autosomal dominant cerebellar ataxia › spinocerebellar ataxia 44

Related subtypes (15): GRID2-related autosomal dominant spinocerebellar ataxia, spinocerebellar ataxia 27A, spinocerebellar ataxia 9, spinocerebellar ataxia 43, spinocerebellar ataxia 7, autosomal dominant cerebellar ataxia type I, autosomal dominant cerebellar ataxia type III, autosomal dominant cerebellar ataxia type IV, spinocerebellar ataxia 49, spinocerebellar ataxia 48, spinocerebellar ataxia 47, spinocerebellar ataxia 50, spinocerebellar ataxia 27B, late-onset, spinocerebellar ataxia 51, spinocerebellar ataxia 52

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

29 retrieved; paginated sample, class counts are floors:

13 uncertain significance, 7 benign/likely benign, 5 benign, 2 pathogenic, 1 not provided, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
438856	NM_001278064.2(GRM1):c.785A>G (p.Tyr262Cys)	GRM1	Pathogenic	no assertion criteria provided
438857	NM_001278064.2(GRM1):c.3165dup (p.Gly1056fs)	GRM1	Pathogenic	no assertion criteria provided
438855	NM_001278064.2(GRM1):c.2375A>G (p.Tyr792Cys)	GRM1	Likely pathogenic	criteria provided, single submitter
1031288	NM_001278064.2(GRM1):c.2867A>T (p.Asn956Ile)	GRM1	Uncertain significance	criteria provided, single submitter
1033818	NM_001278064.2(GRM1):c.1165A>C (p.Asn389His)	GRM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1298316	NM_001278064.2(GRM1):c.3236C>T (p.Pro1079Leu)	GRM1	Uncertain significance	no assertion criteria provided
1329473	NM_001278064.2(GRM1):c.3405C>G (p.Ser1135Arg)	GRM1	Uncertain significance	criteria provided, single submitter
1335648	NM_001278064.2(GRM1):c.2909C>T (p.Pro970Leu)	GRM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1698874	NM_001278064.2(GRM1):c.851C>T (p.Ala284Val)	GRM1	Uncertain significance	criteria provided, single submitter
3381245	NM_001278064.2(GRM1):c.1817T>C (p.Val606Ala)	GRM1	Uncertain significance	criteria provided, single submitter
3593214	NM_001278064.2(GRM1):c.3188G>T (p.Arg1063Leu)	GRM1	Uncertain significance	criteria provided, single submitter
3593215	NM_001278064.2(GRM1):c.3461C>T (p.Ser1154Leu)	GRM1	Uncertain significance	criteria provided, single submitter
3779712	NM_001278064.2(GRM1):c.951-3dup	GRM1	Uncertain significance	criteria provided, single submitter
447469	NM_001278064.2(GRM1):c.829C>A (p.Leu277Ile)	GRM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
560384	NM_001278064.2(GRM1):c.951-6T>A	GRM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
804887	NM_001278064.2(GRM1):c.827A>C (p.Lys276Thr)	GRM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
129209	NM_001278064.2(GRM1):c.2793G>A (p.Lys931=)	GRM1	Benign	criteria provided, multiple submitters, no conflicts
129210	NM_001278064.2(GRM1):c.2977T>C (p.Ser993Pro)	GRM1	Benign	criteria provided, multiple submitters, no conflicts
129211	NM_001278064.2(GRM1):c.3168T>G (p.Gly1056=)	GRM1	Benign	criteria provided, multiple submitters, no conflicts
129212	NM_001278064.2(GRM1):c.3213T>G (p.Pro1071=)	GRM1	Benign	criteria provided, multiple submitters, no conflicts
129213	NM_001278064.2(GRM1):c.3495C>A (p.Pro1165=)	GRM1	Benign	criteria provided, multiple submitters, no conflicts
445990	NM_001278064.2(GRM1):c.3214C>G (p.Pro1072Ala)	GRM1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
447463	NM_001278064.2(GRM1):c.3161G>A (p.Gly1054Asp)	GRM1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
585954	NM_001278064.2(GRM1):c.2007G>T (p.Ala669=)	GRM1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
585955	NM_001278064.2(GRM1):c.2043T>C (p.Arg681=)	GRM1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
585957	NM_001278064.2(GRM1):c.2364G>C (p.Ala788=)	GRM1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
585958	NM_001278064.2(GRM1):c.2496T>C (p.Thr832=)	GRM1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
995113	NM_001278064.2(GRM1):c.2651G>A (p.Gly884Glu)	GRM1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1339870	NM_001278064.2(GRM1):c.1602G>A (p.Lys534=)	GRM1	not provided	no classification provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
GRM1	Strong	Autosomal recessive	autosomal recessive spinocerebellar ataxia 13	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GRM1	Orphanet:324262	Autosomal recessive congenital cerebellar ataxia due to MGLUR1 deficiency
GRM1	Orphanet:404507	Chondromyxoid fibroma
GRM1	Orphanet:631095	Spinocerebellar ataxia type 44

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GRM1	HGNC:4593	ENSG00000152822	Q13255	Metabotropic glutamate receptor 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GRM1	Metabotropic glutamate receptor 1	G-protein coupled receptor for glutamate.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
GPCR	1	23.9×	0.042

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GRM1	GPCR	yes		GPCR_3_mtglu_rcpt, GPCR_3, GPCR_3_mGluR1

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar vermis	1
lateral nuclear group of thalamus	1
middle temporal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GRM1	94	tissue_specific	marker	lateral nuclear group of thalamus, cerebellar vermis, middle temporal gyrus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GRM1	2,814

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GRM1	Q13255	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Class C/3 (Metabotropic glutamate/pheromone receptors)	1	292.8×	0.007	GRM1
Sensory perception of sweet, bitter, and umami (glutamate) taste	1	278.5×	0.007	GRM1
Neurexins and neuroligins	1	196.9×	0.007	GRM1
G alpha (q) signalling events	1	57.4×	0.017	GRM1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
phospholipase C-activating G protein-coupled glutamate receptor signaling pathway	1	4213.0×	0.002	GRM1
L-glutamate import across plasma membrane	1	1872.4×	0.002	GRM1
synaptic signaling via neuropeptide	1	1532.0×	0.002	GRM1
cellular response to electrical stimulus	1	1296.3×	0.002	GRM1
G protein-coupled glutamate receptor signaling pathway	1	1053.2×	0.002	GRM1
regulation of sensory perception of pain	1	991.3×	0.002	GRM1
regulation of synaptic transmission, glutamatergic	1	510.7×	0.004	GRM1
sensory perception of pain	1	374.5×	0.004	GRM1
locomotory behavior	1	179.3×	0.008	GRM1
phospholipase C-activating G protein-coupled receptor signaling pathway	1	131.7×	0.010	GRM1
positive regulation of MAPK cascade	1	80.6×	0.014	GRM1
chemical synaptic transmission	1	77.3×	0.014	GRM1
G protein-coupled receptor signaling pathway	1	36.2×	0.028	GRM1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GRM1	2	3

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
GLUTAMIC ACID	3	GRM1
FENOBAM ANHYDROUS	2	GRM1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
GRM1	284	Functional:177, Binding:107

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
GRM1	284

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

2 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
GLUTAMIC ACID	3	GRM1
FENOBAM ANHYDROUS	2	GRM1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	GRM1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.