Spinocerebellar ataxia type 28

Summary

Spinocerebellar ataxia type 28 (MONDO:0012450) is a disease caused by AFG3L2 (GenCC Definitive), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: AFG3L2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 96
• Phenotypes (HPO): 20
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

20 HPO clinical features (Orphanet curated; top 20 by frequency):

HPO ID	Term	Frequency
HP:0001260	Dysarthria	Very frequent (80-99%)
HP:0002066	Gait ataxia	Very frequent (80-99%)
HP:0002070	Limb ataxia	Very frequent (80-99%)
HP:0002395	Lower limb hyperreflexia	Very frequent (80-99%)
HP:0000508	Ptosis	Frequent (30-79%)
HP:0000514	Slow saccadic eye movements	Frequent (30-79%)
HP:0000597	Ophthalmoparesis	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0001300	Parkinsonism	Occasional (5-29%)
HP:0030186	Kinetic tremor	Occasional (5-29%)
HP:0000708	Atypical behavior	Very rare (<1-4%)
HP:0000716	Depression	Very rare (<1-4%)
HP:0001257	Spasticity	Very rare (<1-4%)
HP:0001332	Dystonia	Very rare (<1-4%)
HP:0002063	Rigidity	Very rare (<1-4%)
HP:0002346	Head tremor	Very rare (<1-4%)
HP:0002354	Memory impairment	Very rare (<1-4%)
HP:0002451	Limb dystonia	Very rare (<1-4%)
HP:0100543	Cognitive impairment	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spinocerebellar ataxia type 28
Mondo ID	MONDO:0012450
MeSH	C537205
OMIM	610246
Orphanet	101109
DOID	DOID:0050977
ICD-11	2020736035
SNOMED CT	715824008
UMLS	C1853249
MedGen	339941
GARD	0009951
Is cancer (heuristic)	no

Also known as: SCA28 · spinocerebellar ataxia 28 · spinocerebellar ataxia type 28

Data availability: 96 ClinVar variants · 5 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 › spinocerebellar ataxia type 28

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, leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome, spastic ataxia 3, 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

96 retrieved; paginated sample, class counts are floors:

34 uncertain significance, 14 benign, 14 pathogenic, 12 conflicting classifications of pathogenicity, 9 likely pathogenic, 6 benign/likely benign, 3 likely benign, 2 not provided, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1676883	NM_006796.3(AFG3L2):c.1378G>A (p.Asp460Asn)	AFG3L2	Pathogenic	criteria provided, single submitter
214059	NM_006796.3(AFG3L2):c.2067_2068del (p.Tyr689_Ser690delinsTer)	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
30424	NM_006796.3(AFG3L2):c.1997T>G (p.Met666Arg)	AFG3L2	Pathogenic	criteria provided, single submitter
30425	NM_006796.3(AFG3L2):c.2011G>A (p.Gly671Arg)	AFG3L2	Pathogenic	criteria provided, single submitter
3251301	NM_006796.3(AFG3L2):c.1651C>T (p.Arg551Ter)	AFG3L2	Pathogenic	criteria provided, single submitter
3377390	NM_006796.3(AFG3L2):c.1168C>T (p.Arg390Ter)	AFG3L2	Pathogenic	criteria provided, single submitter
38389	NM_006796.3(AFG3L2):c.1997T>C (p.Met666Thr)	AFG3L2	Pathogenic	criteria provided, multiple submitters, no conflicts
38393	NM_006796.3(AFG3L2):c.2098G>A (p.Glu700Lys)	AFG3L2	Pathogenic	criteria provided, single submitter
4847721	NM_006796.3(AFG3L2):c.271G>T (p.Glu91Ter)	AFG3L2	Pathogenic	criteria provided, single submitter
5470	NM_006796.3(AFG3L2):c.2071G>A (p.Glu691Lys)	AFG3L2	Pathogenic	criteria provided, single submitter
5471	NM_006796.3(AFG3L2):c.2021_2022delinsTA (p.Ser674Leu)	AFG3L2	Pathogenic	no assertion criteria provided
5472	NM_006796.3(AFG3L2):c.2081C>A (p.Ala694Glu)	AFG3L2	Pathogenic	no assertion criteria provided
5474	NM_006796.3(AFG3L2):c.1295A>C (p.Asn432Thr)	AFG3L2	Pathogenic	no assertion criteria provided
638488	NM_006796.3(AFG3L2):c.1164+1G>A	AFG3L2	Pathogenic	criteria provided, single submitter
807537	NM_006796.3(AFG3L2):c.2065T>C (p.Tyr689His)	AFG3L2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1327420	NM_006796.3(AFG3L2):c.2062C>A (p.Pro688Thr)	AFG3L2	Likely pathogenic	criteria provided, single submitter
162524	NM_006796.3(AFG3L2):c.1875G>A (p.Met625Ile)	AFG3L2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3775947	NM_006796.3(AFG3L2):c.2105G>T (p.Arg702Leu)	AFG3L2	Likely pathogenic	criteria provided, single submitter
38387	NM_006796.3(AFG3L2):c.1961C>T (p.Thr654Ile)	AFG3L2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
38392	NM_006796.3(AFG3L2):c.2012G>A (p.Gly671Glu)	AFG3L2	Likely pathogenic	no assertion criteria provided
4277436	NM_006796.3(AFG3L2):c.1711G>A (p.Val571Met)	AFG3L2	Likely pathogenic	criteria provided, single submitter
807538	NM_006796.3(AFG3L2):c.1119T>A (p.Ser373Arg)	AFG3L2	Likely pathogenic	criteria provided, single submitter
987295	NM_006796.3(AFG3L2):c.2062C>T (p.Pro688Ser)	AFG3L2	Likely pathogenic	criteria provided, single submitter
992876	NM_006796.3(AFG3L2):c.2073_2096dup (p.Glu691_Asp698dup)	AFG3L2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1203872	NM_006796.3(AFG3L2):c.634G>A (p.Val212Ile)	AFG3L2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1297621	NM_006796.3(AFG3L2):c.1861C>G (p.Leu621Val)	AFG3L2	Conflicting classifications of pathogenicity	no assertion criteria provided
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

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

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
AFG3L2	HGNC:315	ENSG00000141385	Q9Y4W6	Mitochondrial inner membrane m-AAA protease component AFG3L2	gencc,clinvar
TUBB6	HGNC:20776	ENSG00000176014	Q9BUF5	Tubulin beta-6 chain	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.
TUBB6	Tubulin beta-6 chain	Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	18.3×	0.108
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AFG3L2	Protease	yes	3.4.24.B18	Peptidase_M41, AAA+_ATPase, ATPase_AAA_core
TUBB6	Other/Unknown	no		Tubulin, Beta_tubulin, Tubulin_FtsZ_GTPase

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	1
endothelial cell	1
jejunal mucosa	1
lower esophagus	1
lower esophagus muscularis layer	1
saphenous vein	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
TUBB6	279	ubiquitous	marker	lower esophagus, lower esophagus muscularis layer, saphenous vein

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TUBB6	4,838
AFG3L2	4,260

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AFG3L2	Q9Y4W6	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TUBB6	Q9BUF5	92.77

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 90. Enrichment computed across 2 evidence-associated genes (2 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 2 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	317.2×	0.030	AFG3L2
Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane	1	271.9×	0.030	TUBB6
Transport of connexons to the plasma membrane	1	271.9×	0.030	TUBB6
Mitochondrial calcium ion transport	1	271.9×	0.030	AFG3L2
Gap junction trafficking and regulation	1	237.9×	0.030	TUBB6
Gap junction trafficking	1	237.9×	0.030	TUBB6
Post-chaperonin tubulin folding pathway	1	237.9×	0.030	TUBB6
Formation of tubulin folding intermediates by CCT/TriC	1	211.5×	0.030	TUBB6
Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding	1	203.9×	0.030	TUBB6
Prefoldin mediated transfer of substrate to CCT/TriC	1	196.9×	0.030	TUBB6
Activation of AMPK downstream of NMDARs	1	190.3×	0.030	TUBB6
RHO GTPases activate IQGAPs	1	173.0×	0.030	TUBB6
Sealing of the nuclear envelope (NE) by ESCRT-III	1	173.0×	0.030	TUBB6
HCMV Infection	1	163.1×	0.030	TUBB6
Chaperonin-mediated protein folding	1	150.3×	0.030	TUBB6
Gap junction assembly	1	146.4×	0.030	TUBB6
Nuclear Envelope (NE) Reassembly	1	146.4×	0.030	TUBB6
Selective autophagy	1	139.3×	0.030	TUBB6
Protein folding	1	129.8×	0.030	TUBB6
Assembly and cell surface presentation of NMDA receptors	1	126.9×	0.030	TUBB6
Cargo trafficking to the periciliary membrane	1	124.1×	0.030	TUBB6
Aggrephagy	1	124.1×	0.030	TUBB6
Carboxyterminal post-translational modifications of tubulin	1	119.0×	0.030	TUBB6
Recycling pathway of L1	1	112.0×	0.030	TUBB6
COPI-independent Golgi-to-ER retrograde traffic	1	103.8×	0.030	TUBB6
Post NMDA receptor activation events	1	102.0×	0.030	TUBB6
Intraflagellar transport	1	100.2×	0.030	TUBB6
Antimicrobial mechanism of IFN-stimulated genes	1	98.5×	0.030	TUBB6
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	1	96.8×	0.030	TUBB6
Activation of NMDA receptors and postsynaptic events	1	92.1×	0.030	TUBB6

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 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	8426.0×	0.003	AFG3L2
regulation of calcium import into the mitochondrion	1	2808.7×	0.004	AFG3L2
mitochondrial protein quality control	1	2106.5×	0.004	AFG3L2
mitochondrial protein processing	1	1404.3×	0.004	AFG3L2
righting reflex	1	936.2×	0.004	AFG3L2
calcium import into the mitochondrion	1	601.9×	0.004	AFG3L2
membrane protein proteolysis	1	526.6×	0.004	AFG3L2
cristae formation	1	526.6×	0.004	AFG3L2
mitochondrial calcium ion homeostasis	1	495.6×	0.004	AFG3L2
nerve development	1	468.1×	0.004	AFG3L2
muscle cell development	1	468.1×	0.004	AFG3L2
mitochondrial fusion	1	421.3×	0.005	AFG3L2
protein autoprocessing	1	324.1×	0.005	AFG3L2
regulation of multicellular organism growth	1	324.1×	0.005	AFG3L2
neuromuscular junction development	1	263.3×	0.006	AFG3L2
myelination	1	125.8×	0.011	AFG3L2
protein catabolic process	1	118.7×	0.011	AFG3L2
protein processing	1	85.1×	0.014	AFG3L2
protein maturation	1	81.8×	0.014	AFG3L2
axonogenesis	1	80.2×	0.014	AFG3L2
mitotic cell cycle	1	66.9×	0.016	TUBB6
microtubule cytoskeleton organization	1	60.6×	0.017	TUBB6
proteolysis	1	17.1×	0.058	AFG3L2

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
TUBB6	COLCHICINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TUBB6	21	4
AFG3L2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
COLCHICINE	4	TUBB6
VINBLASTINE	4	TUBB6
LEVOFLOXACIN ANHYDROUS	4	TUBB6
DOCETAXEL	4	TUBB6
NOSCAPINE	4	TUBB6
VINBLASTINE SULFATE	4	TUBB6
PACLITAXEL	4	TUBB6
LEVOFLOXACIN	4	TUBB6
VINORELBINE	4	TUBB6
TIRBANIBULIN	4	TUBB6
PODOFILOX	4	TUBB6
VINCRISTINE	4	TUBB6
DOCETAXEL ANHYDROUS	4	TUBB6
PATUPILONE	3	TUBB6
ABT-751	2	TUBB6
MAYTANSINE	2	TUBB6
DOLASTATIN-10	2	TUBB6
INDIBULIN	2	TUBB6
PARBENDAZOLE	2	TUBB6
NOCODAZOLE	2	TUBB6
COMBRETASTATIN	1	TUBB6

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
TUBB6	1,757	Binding:1717, Functional:34, ADMET:6
AFG3L2	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AFG3L2	3.4.24.B18

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TUBB6	1,757

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

21 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)
COLCHICINE	4	TUBB6
VINBLASTINE	4	TUBB6
LEVOFLOXACIN ANHYDROUS	4	TUBB6
DOCETAXEL	4	TUBB6
NOSCAPINE	4	TUBB6
VINBLASTINE SULFATE	4	TUBB6
PACLITAXEL	4	TUBB6
LEVOFLOXACIN	4	TUBB6
VINORELBINE	4	TUBB6
TIRBANIBULIN	4	TUBB6
PODOFILOX	4	TUBB6
VINCRISTINE	4	TUBB6
DOCETAXEL ANHYDROUS	4	TUBB6
PATUPILONE	3	TUBB6
ABT-751	2	TUBB6
MAYTANSINE	2	TUBB6
DOLASTATIN-10	2	TUBB6
INDIBULIN	2	TUBB6
PARBENDAZOLE	2	TUBB6
NOCODAZOLE	2	TUBB6
COMBRETASTATIN	1	TUBB6

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TUBB6
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: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford