Spastic ataxia 5

Summary

Spastic ataxia 5 (MONDO:0013776) is a disease caused by AFG3L2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: AFG3L2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 33
• Phenotypes (HPO): 24

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

24 HPO clinical features (Orphanet curated; top 24 by frequency):

HPO ID	Term	Frequency
HP:0000508	Ptosis	Frequent (30-79%)
HP:0000657	Oculomotor apraxia	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001256	Intellectual disability, mild	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001272	Cerebellar atrophy	Frequent (30-79%)
HP:0001310	Dysmetria	Frequent (30-79%)
HP:0001321	Cerebellar hypoplasia	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0001336	Myoclonus	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002069	Bilateral tonic-clonic seizure	Frequent (30-79%)
HP:0002075	Dysdiadochokinesis	Frequent (30-79%)
HP:0002123	Generalized myoclonic seizure	Frequent (30-79%)
HP:0002313	Spastic paraparesis	Frequent (30-79%)
HP:0002353	EEG abnormality	Frequent (30-79%)
HP:0002460	Distal muscle weakness	Frequent (30-79%)
HP:0002464	Spastic dysarthria	Frequent (30-79%)
HP:0003477	Peripheral axonal neuropathy	Frequent (30-79%)
HP:0003693	Distal amyotrophy	Frequent (30-79%)
HP:0007108	Demyelinating peripheral neuropathy	Frequent (30-79%)
HP:0007141	Sensorimotor neuropathy	Frequent (30-79%)
HP:0007340	Lower limb muscle weakness	Frequent (30-79%)
HP:0008316	Abnormal mitochondria in muscle tissue	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spastic ataxia 5
Mondo ID	MONDO:0013776
OMIM	614487
Orphanet	313772
DOID	DOID:0050944
UMLS	C3280977
MedGen	482607
GARD	0017409
Is cancer (heuristic)	no

Also known as: AFG3L2 autosomal recessive spastic ataxia · AFG3L2-related spastic ataxia-myoclonic epilepsy-neuropathy syndrome · AFG3L2-related spastic ataxia-neuropathy syndrome · autosomal recessive spastic ataxia caused by mutation in AFG3L2 · autosomal recessive spastic ataxia type 5 · spastic ataxia 5, autosomal recessive · spastic ataxia type 5 · SPAX5

Data availability: 33 ClinVar variants · 5 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 recessive disease › autosomal recessive spastic ataxia › spastic ataxia 5

Related subtypes (6): Charlevoix-Saguenay spastic ataxia, spastic ataxia-corneal dystrophy syndrome, spastic ataxia 3, spastic ataxia 4, spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy, spastic ataxia-dysarthria due to glutaminase 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

33 retrieved; paginated sample, class counts are floors:

9 uncertain significance, 7 pathogenic, 6 conflicting classifications of pathogenicity, 5 benign, 5 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1027438	NM_006796.3(AFG3L2):c.634dup (p.Val212fs)	AFG3L2	Pathogenic	criteria provided, single submitter
1676883	NM_006796.3(AFG3L2):c.1378G>A (p.Asp460Asn)	AFG3L2	Pathogenic	criteria provided, single submitter
30423	NM_006796.3(AFG3L2):c.1996A>G (p.Met666Val)	AFG3L2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30427	NM_006796.3(AFG3L2):c.1847A>G (p.Tyr616Cys)	AFG3L2	Pathogenic	criteria provided, multiple submitters, no conflicts
3255229	NM_006796.3(AFG3L2):c.245dup (p.Asn82fs)	AFG3L2	Pathogenic	no assertion criteria provided
805326	NM_006796.3(AFG3L2):c.202C>T (p.Arg68Ter)	AFG3L2	Pathogenic	criteria provided, multiple submitters, no conflicts
973201	NM_006796.3(AFG3L2):c.1901_1902del (p.Val633_Ser634insTer)	AFG3L2	Pathogenic	no assertion criteria provided
973202	NM_006796.3(AFG3L2):c.1858C>A (p.Gln620Lys)	AFG3L2	Pathogenic	no assertion criteria provided
162524	NM_006796.3(AFG3L2):c.1875G>A (p.Met625Ile)	AFG3L2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1810409	NM_006796.3(AFG3L2):c.1749G>A (p.Trp583Ter)	AFG3L2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
374935	NM_006796.3(AFG3L2):c.1951A>G (p.Arg651Gly)	AFG3L2	Likely pathogenic	no assertion criteria provided
3898007	NM_006796.3(AFG3L2):c.226del (p.Tyr76fs)	AFG3L2	Likely pathogenic	criteria provided, single submitter
4292705	NM_006796.3(AFG3L2):c.1026+2T>G	AFG3L2	Likely pathogenic	criteria provided, single submitter
214057	NM_006796.3(AFG3L2):c.2314C>T (p.Leu772Phe)	AFG3L2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214062	NM_006796.3(AFG3L2):c.2167G>A (p.Val723Met)	AFG3L2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2161341	NM_006796.3(AFG3L2):c.2312C>T (p.Ser771Leu)	AFG3L2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2664732	NM_006796.3(AFG3L2):c.1714G>A (p.Ala572Thr)	AFG3L2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
546814	NM_006796.3(AFG3L2):c.1385C>T (p.Ala462Val)	AFG3L2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
973204	NM_006796.3(AFG3L2):c.916A>G (p.Lys306Glu)	AFG3L2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030157	NM_006796.3(AFG3L2):c.1501G>A (p.Glu501Lys)	AFG3L2	Uncertain significance	criteria provided, single submitter
1032494	NM_006796.3(AFG3L2):c.7C>T (p.His3Tyr)	AFG3L2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1256165	NM_006796.3(AFG3L2):c.2314C>A (p.Leu772Ile)	AFG3L2	Uncertain significance	criteria provided, multiple submitters, no conflicts
214053	NM_006796.3(AFG3L2):c.1397C>T (p.Pro466Leu)	AFG3L2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2627484	NM_006796.3(AFG3L2):c.2394G>C (p.Ter798Tyr)	AFG3L2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2627485	NM_006796.3(AFG3L2):c.361A>C (p.Lys121Gln)	AFG3L2	Uncertain significance	criteria provided, single submitter
4076977	NM_006796.3(AFG3L2):c.1663+1G>A	AFG3L2	Uncertain significance	criteria provided, single submitter
446813	NM_006796.3(AFG3L2):c.838C>T (p.Arg280Trp)	AFG3L2	Uncertain significance	criteria provided, multiple submitters, no conflicts
548568	NM_006796.3(AFG3L2):c.571G>A (p.Val191Ile)	AFG3L2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1188960	NM_006796.3(AFG3L2):c.753-55T>C	AFG3L2	Benign	criteria provided, multiple submitters, no conflicts
128286	NM_006796.3(AFG3L2):c.1389G>A (p.Leu463=)	AFG3L2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · 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
AFG3L2	Definitive	Autosomal dominant	spinocerebellar ataxia type 28	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AFG3L2	Orphanet:101109	Spinocerebellar ataxia type 28
AFG3L2	Orphanet:313772	Early-onset spastic ataxia-myoclonic epilepsy-neuropathy syndrome

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
AFG3L2	HGNC:315	ENSG00000141385	Q9Y4W6	Mitochondrial inner membrane m-AAA protease component AFG3L2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AFG3L2	Mitochondrial inner membrane m-AAA protease component AFG3L2	Catalytic component of the m-AAA protease, a protease that plays a key role in proteostasis of inner mitochondrial membrane proteins, and which is essential for axonal and neuron development.

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
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AFG3L2	Protease	yes	3.4.24.B18	Peptidase_M41, AAA+_ATPase, ATPase_AAA_core

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
Brodmann (1909) area 23	1
endothelial cell	1
jejunal mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AFG3L2	288	ubiquitous	marker	Brodmann (1909) area 23, endothelial cell, jejunal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AFG3L2	4,260

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AFG3L2	Q9Y4W6	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
Processing of SMDT1	1	634.4×	0.005	AFG3L2
Mitochondrial calcium ion transport	1	543.8×	0.005	AFG3L2
Mitochondrial protein degradation	1	114.2×	0.015	AFG3L2
Transport of small molecules	1	25.1×	0.050	AFG3L2
Metabolism of proteins	1	12.4×	0.081	AFG3L2

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
cellular response to glutathione	1	16852.0×	0.001	AFG3L2
regulation of calcium import into the mitochondrion	1	5617.3×	0.002	AFG3L2
mitochondrial protein quality control	1	4213.0×	0.002	AFG3L2
mitochondrial protein processing	1	2808.7×	0.002	AFG3L2
righting reflex	1	1872.4×	0.002	AFG3L2
calcium import into the mitochondrion	1	1203.7×	0.002	AFG3L2
membrane protein proteolysis	1	1053.2×	0.002	AFG3L2
cristae formation	1	1053.2×	0.002	AFG3L2
mitochondrial calcium ion homeostasis	1	991.3×	0.002	AFG3L2
nerve development	1	936.2×	0.002	AFG3L2
muscle cell development	1	936.2×	0.002	AFG3L2
mitochondrial fusion	1	842.6×	0.002	AFG3L2
protein autoprocessing	1	648.1×	0.002	AFG3L2
regulation of multicellular organism growth	1	648.1×	0.002	AFG3L2
neuromuscular junction development	1	526.6×	0.003	AFG3L2
myelination	1	251.5×	0.005	AFG3L2
protein catabolic process	1	237.3×	0.005	AFG3L2
protein processing	1	170.2×	0.007	AFG3L2
protein maturation	1	163.6×	0.007	AFG3L2
axonogenesis	1	160.5×	0.007	AFG3L2
proteolysis	1	34.2×	0.029	AFG3L2

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
AFG3L2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
AFG3L2	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AFG3L2	3.4.24.B18

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	1	AFG3L2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
AFG3L2	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.