Autosomal recessive spinocerebellar ataxia 18

Summary

Autosomal recessive spinocerebellar ataxia 18 (MONDO:0014530) is a disease caused by GRID2 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GRID2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 29
• Phenotypes (HPO): 11

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

Signs & symptoms

Clinical features (HPO)

11 HPO clinical features (Orphanet curated; top 11 by frequency):

HPO ID	Term	Frequency
HP:0002070	Limb ataxia	Very frequent (80-99%)
HP:0002078	Truncal ataxia	Very frequent (80-99%)
HP:0000640	Gaze-evoked nystagmus	Frequent (30-79%)
HP:0000666	Horizontal nystagmus	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0002167	Abnormality of speech or vocalization	Frequent (30-79%)
HP:0004302	Functional motor deficit	Frequent (30-79%)
HP:0006855	Cerebellar vermis atrophy	Frequent (30-79%)
HP:0012444	Brain atrophy	Frequent (30-79%)
HP:0100543	Cognitive impairment	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive spinocerebellar ataxia 18
Mondo ID	MONDO:0014530
OMIM	616204
Orphanet	363432
DOID	DOID:0080042
UMLS	C4015505
MedGen	863942
GARD	0017557
Is cancer (heuristic)	no

Also known as: autosomal recessive cerebellar ataxia - pyramidal signs - nystagmus - oculomotor apraxia syndrome caused by mutation in GRID2 · autosomal recessive cerebellar ataxia-pyramidal signs-nystagmus-oculomotor apraxia syndrome caused by mutation in GRID2 · autosomal recessive congenital cerebellar ataxia due to ionotropic glutamate receptor delta-2 subunit deficiency · autosomal recessive spinocerebellar ataxia type 18 · GRID2 autosomal recessive cerebellar ataxia - pyramidal signs - nystagmus - oculomotor apraxia syndrome · GRID2 autosomal recessive cerebellar ataxia-pyramidal signs-nystagmus-oculomotor apraxia syndrome · SCAR18 · spinocerebellar ataxia, autosomal recessive 18 · spinocerebellar ataxia, autosomal recessive type 18

Data availability: 29 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › inborn disorder of amino acid transport › autosomal recessive cerebellar ataxia - pyramidal signs - nystagmus - oculomotor apraxia syndrome › autosomal recessive spinocerebellar ataxia 18

Related subtypes (1): autosomal recessive spinocerebellar ataxia 13

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, 9 pathogenic, 3 likely pathogenic, 2 benign, 1 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1723284	NC_000004.11:g.(93511438_94006145)_(94032105_94128554)del	GRID2	Pathogenic	criteria provided, single submitter
180131	NC_000004.12:g.93013415_93157863del	GRID2	Pathogenic	no assertion criteria provided
180132	NM_001510.3(GRID2):c.530-12057_735+24661del36924	GRID2	Pathogenic	no assertion criteria provided
180133	NC_000004.12:g.92559959_92610106del	GRID2	Pathogenic	no assertion criteria provided
180134	NC_000004.12:g.92491792_92826931del	GRID2	Pathogenic	no assertion criteria provided
242880	Single allele	GRID2	Pathogenic	no assertion criteria provided
2446023	NM_001510.4(GRID2):c.1945A>G (p.Thr649Ala)	GRID2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2579188	GRCh38/hg38 4q22.1(chr4:92303869-92304842)x0	GRID2	Pathogenic	criteria provided, single submitter
427806	NM_001510.4(GRID2):c.2128C>T (p.Arg710Trp)	GRID2	Pathogenic	no assertion criteria provided
930201	NM_001510.4(GRID2):c.568C>T (p.Gln190Ter)	GRID2	Pathogenic	criteria provided, single submitter
1696205	NC_000004.11:g.(93511438_94006145)_(94006431_94031898)del	GRID2	Likely pathogenic	criteria provided, single submitter
488523	NM_001510.4(GRID2):c.671G>A (p.Arg224Gln)	GRID2	Likely pathogenic	criteria provided, single submitter
800978	NM_001510.4(GRID2):c.910C>T (p.Arg304Ter)	GRID2	Likely pathogenic	no assertion criteria provided
2050505	NM_001510.4(GRID2):c.2921T>A (p.Phe974Tyr)	GRID2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1027933	NM_001510.4(GRID2):c.1658A>G (p.Glu553Gly)	GRID2	Uncertain significance	criteria provided, single submitter
1031990	NM_001510.4(GRID2):c.121G>T (p.Asp41Tyr)	GRID2	Uncertain significance	criteria provided, single submitter
2441778	NM_001510.4(GRID2):c.-62C>T	GRID2	Uncertain significance	criteria provided, single submitter
2502411	NM_001510.4:c.790-271_1245+268del	GRID2	Uncertain significance	criteria provided, single submitter
2502412	NM_001510.4:c.1246-278_2193+35240del	GRID2	Uncertain significance	criteria provided, single submitter
2920787	NM_001510.4(GRID2):c.101A>G (p.Asp34Gly)	GRID2	Uncertain significance	criteria provided, single submitter
2921265	NM_001510.4(GRID2):c.1100G>A (p.Arg367His)	GRID2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3282704	NM_001510.4(GRID2):c.1171G>A (p.Gly391Arg)	GRID2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3363136	NM_001510.4(GRID2):c.800A>T (p.Asp267Val)	GRID2	Uncertain significance	criteria provided, single submitter
4056501	NM_001510.4(GRID2):c.2411G>C (p.Trp804Ser)	GRID2	Uncertain significance	criteria provided, single submitter
4279533	NM_001510.4(GRID2):c.1964T>G (p.Phe655Cys)	GRID2	Uncertain significance	criteria provided, single submitter
4279534	NM_001440459.1(GRID2):c.2750del (p.Asp917fs)	GRID2	Uncertain significance	criteria provided, single submitter
430178	NM_001510.4(GRID2):c.899G>A (p.Arg300His)	GRID2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1174447	NM_001510.4(GRID2):c.735+21G>C	GRID2	Benign	criteria provided, multiple submitters, no conflicts
1266413	NM_001510.4(GRID2):c.1251T>G (p.Gly417=)	GRID2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
GRID2	Strong	Autosomal recessive	autosomal recessive spinocerebellar ataxia 18	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GRID2	Orphanet:363432	Autosomal recessive congenital cerebellar ataxia due to GRID2 deficiency

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
GRID2	HGNC:4576	ENSG00000152208	O43424	Glutamate receptor ionotropic, delta-2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GRID2	Glutamate receptor ionotropic, delta-2	Member of the ionotropic glutamate receptor family, which plays a crucial role in synaptic organization and signal transduction in the central nervous system.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GRID2	Other/Unknown	no		Iontro_rcpt_C, Iono_Glu_rcpt_met, ANF_lig-bd_rcpt

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
left testis	1
right testis	1
testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GRID2	114	broad	marker	right testis, left testis, testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GRID2	2,019

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GRID2	O43424	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
cerebellar granule cell differentiation	1	2106.5×	0.003	GRID2
positive regulation of long-term synaptic depression	1	1872.4×	0.003	GRID2
synaptic signaling via neuropeptide	1	1532.0×	0.003	GRID2
excitatory synapse assembly	1	1296.3×	0.003	GRID2
prepulse inhibition	1	1123.5×	0.003	GRID2
glutamate receptor signaling pathway	1	936.2×	0.003	GRID2
regulation of postsynaptic density assembly	1	887.0×	0.003	GRID2
regulation of neuron apoptotic process	1	702.2×	0.003	GRID2
regulation of presynapse assembly	1	543.6×	0.003	GRID2
regulation of postsynaptic membrane neurotransmitter receptor levels	1	495.6×	0.003	GRID2
excitatory postsynaptic potential	1	443.5×	0.003	GRID2
regulation of neuron projection development	1	432.1×	0.003	GRID2
synaptic transmission, glutamatergic	1	358.6×	0.004	GRID2
heterophilic cell-cell adhesion	1	337.0×	0.004	GRID2
positive regulation of synapse assembly	1	244.2×	0.005	GRID2
modulation of chemical synaptic transmission	1	183.2×	0.006	GRID2
intracellular protein localization	1	104.7×	0.010	GRID2

Therapeutics

Drug target analysis

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

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
GRID2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GRID2	1	Binding:1

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

0 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.

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	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	GRID2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GRID2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.