Spastic ataxia 3

Summary

Spastic ataxia 3 (MONDO:0012664) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 13
• Phenotypes (HPO): 16

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		54	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

16 HPO clinical features (Orphanet curated; top 16 by frequency):

HPO ID	Term	Frequency
HP:0001321	Cerebellar hypoplasia	Very frequent (80-99%)
HP:0001347	Hyperreflexia	Very frequent (80-99%)
HP:0002497	Spastic ataxia	Very frequent (80-99%)
HP:0000012	Urinary urgency	Frequent (30-79%)
HP:0000666	Horizontal nystagmus	Frequent (30-79%)
HP:0001256	Intellectual disability, mild	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001310	Dysmetria	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0002066	Gait ataxia	Frequent (30-79%)
HP:0002073	Progressive cerebellar ataxia	Frequent (30-79%)
HP:0002120	Cerebral cortical atrophy	Frequent (30-79%)
HP:0002352	Leukoencephalopathy	Frequent (30-79%)
HP:0002464	Spastic dysarthria	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0008619	Bilateral sensorineural hearing impairment	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spastic ataxia 3
Mondo ID	MONDO:0012664
MeSH	C566956
OMIM	611390
Orphanet	314603
DOID	DOID:0050942
UMLS	C1969645
MedGen	370715
GARD	0017425
Is cancer (heuristic)	no

Also known as: ARSAL · autosomal recessive spastic ataxia caused by mutation in MARS2 · autosomal recessive spastic ataxia type 3 · MARS2 autosomal recessive spastic ataxia · spastic ataxia 3, autosomal recessive · spastic ataxia type 3 · SPAX3

Data availability: 13 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial oxidative phosphorylation disorder › spastic ataxia 3

Related subtypes (47): mitochondrial respiratory chain complex deficiency, combined oxidative phosphorylation deficiency, myopathy, lactic acidosis, and sideroblastic anemia, optic atrophy 3, autosomal dominant optic atrophy, classic form, Leigh syndrome, mitochondrial non-syndromic sensorineural hearing loss, maternally-inherited diabetes and deafness, chronic diarrhea with villous atrophy, Kearns-Sayre syndrome, Leber hereditary optic neuropathy, NARP syndrome, deafness, aminoglycoside-induced, hereditary spastic paraplegia 7, spinocerebellar ataxia type 28, leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome, pontocerebellar hypoplasia type 6, autosomal recessive optic atrophy, OPA7 type, acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins, congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome, spastic ataxia 4, hyperuricemia-pulmonary hypertension-renal failure-alkalosis syndrome, hereditary spastic paraplegia 55, cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome, Charcot-Marie-Tooth disease recessive intermediate D, autosomal dominant mitochondrial myopathy with exercise intolerance, Charcot-Marie-Tooth disease type 4K, hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome, hereditary spastic paraplegia 77, fatal infantile encephalocardiomyopathy, FASTKD2-related infantile mitochondrial encephalomyopathy, autosomal dominant optic atrophy and peripheral neuropathy, ataxia neuropathy spectrum, maternally-inherited mitochondrial dystonia, Perrault syndrome, hypertrophic cardiomyopathy and renal tubular disease due to mitochondrial DNA mutation, adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy, mitochondrial DNA maintenance syndrome, coenzyme Q10 deficiency, mitochondrial DNA depletion syndrome, periodic paralysis with later-onset distal motor neuropathy, non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy, Zellweger-like syndrome without peroxisomal anomalies, maternally-inherited progressive external ophthalmoplegia, Leber plus disease, encephalopathy due to mitochondrial and peroxisomal fission defect, severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency

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

13 retrieved; paginated sample, class counts are floors:

6 uncertain significance, 3 pathogenic, 2 likely pathogenic, 1 benign, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
100660	NM_138395.4(MARS2):c.2_*1dup (p.Met1_Ter594=)	LOC129935364	Pathogenic	no assertion criteria provided
100659	NM_138395.4(MARS2):c.682_949del (p.Gly228fs)	MARS2	Pathogenic	no assertion criteria provided
100661	MARS2, DUP2	MARS2	Pathogenic	no assertion criteria provided
4845889	NM_138395.4(MARS2):c.2T>A (p.Met1Lys)	LOC129935364	Likely pathogenic	criteria provided, single submitter
3779834	NM_138395.4(MARS2):c.837G>A (p.Trp279Ter)	MARS2	Likely pathogenic	criteria provided, single submitter
1512982	NM_138395.4(MARS2):c.61C>G (p.Leu21Val)	MARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
638464	NM_138395.4(MARS2):c.341G>T (p.Cys114Phe)	LOC129935366	Uncertain significance	criteria provided, single submitter
1321148	NM_138395.4(MARS2):c.1241G>T (p.Arg414Ile)	MARS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1699106	NM_138395.4(MARS2):c.590T>A (p.Leu197His)	MARS2	Uncertain significance	criteria provided, single submitter
3064187	NM_138395.4(MARS2):c.1595C>G (p.Ala532Gly)	MARS2	Uncertain significance	criteria provided, single submitter
3391357	NM_138395.4(MARS2):c.504G>A (p.Trp168Ter)	MARS2	Uncertain significance	criteria provided, single submitter
638360	NM_138395.4(MARS2):c.799C>T (p.Pro267Ser)	MARS2	Uncertain significance	criteria provided, single submitter
138168	NM_138395.4(MARS2):c.1580T>C (p.Val527Ala)	MARS2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 2 · 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
MARS2	Moderate	Autosomal recessive	spastic ataxia 3	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MARS2	Orphanet:314603	Autosomal recessive spastic ataxia with leukoencephalopathy
MARS2	Orphanet:447954	Combined oxidative phosphorylation defect type 25

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
MARS2	HGNC:25133	ENSG00000247626	Q96GW9	Methionine–tRNA ligase, mitochondrial	gencc,clinvar

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)
MARS2	Other/Unknown	no		tRNAsynth_Ia_anticodon-bd, Rossmann-like_a/b/a_fold, Met-tRNA_synth

Expression context

Cohort genes with no expression data: 0.

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
cardiac muscle of right atrium	1
left ventricle myocardium	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MARS2	178	ubiquitous	yes	cardiac muscle of right atrium, left ventricle myocardium, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MARS2	2,153

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MARS2	Q96GW9	89.66

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
Mitochondrial tRNA aminoacylation	1	519.1×	0.007	MARS2
tRNA Aminoacylation	1	285.5×	0.007	MARS2
Translation	1	62.1×	0.021	MARS2
Metabolism of proteins	1	12.4×	0.081	MARS2

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
methionyl-tRNA aminoacylation	1	8426.0×	2e-04	MARS2
tRNA aminoacylation for protein translation	1	842.6×	0.001	MARS2

Therapeutics

Drug target analysis

Approved (phase 4): 1 · 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).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
MARS2	CHLORAMPHENICOL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MARS2	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CHLORAMPHENICOL	4	MARS2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MARS2	1	ADMET: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

1 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)
CHLORAMPHENICOL	4	MARS2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MARS2
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	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.