Spinocerebellar ataxia type 35

Summary

Spinocerebellar ataxia type 35 (MONDO:0013485) is a disease caused by TGM6 (GenCC Strong), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TGM6 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 117
• Phenotypes (HPO): 18
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		28	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

18 HPO clinical features (Orphanet curated; top 18 by frequency):

HPO ID	Term	Frequency
HP:0002073	Progressive cerebellar ataxia	Very frequent (80-99%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001272	Cerebellar atrophy	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001310	Dysmetria	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0002066	Gait ataxia	Frequent (30-79%)
HP:0002070	Limb ataxia	Frequent (30-79%)
HP:0002080	Intention tremor	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0000467	Neck muscle weakness	Occasional (5-29%)
HP:0000473	Torticollis	Occasional (5-29%)
HP:0000641	Dysmetric saccades	Occasional (5-29%)
HP:0002342	Intellectual disability, moderate	Occasional (5-29%)
HP:0007024	Pseudobulbar paralysis	Occasional (5-29%)
HP:0000602	Ophthalmoplegia	Excluded (0%)
HP:0000639	Nystagmus	Excluded (0%)
HP:0009830	Peripheral neuropathy	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spinocerebellar ataxia type 35
Mondo ID	MONDO:0013485
OMIM	613908
Orphanet	276193
DOID	DOID:0050982
ICD-11	1674449075
SNOMED CT	719300001
UMLS	C3888031
MedGen	854733
GARD	0012366
Is cancer (heuristic)	no

Also known as: SCA35 · spinocerebellar ataxia 35 · spinocerebellar ataxia type 35

Data availability: 117 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 dominant disease › autosomal dominant cerebellar ataxia › autosomal dominant cerebellar ataxia type I › spinocerebellar ataxia type 35

Related subtypes (29): Machado-Joseph disease, spinocerebellar ataxia type 29, spinocerebellar ataxia type 34, spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, spinocerebellar ataxia type 4, cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome, autosomal dominant cerebellar ataxia, deafness and narcolepsy, spinocerebellar ataxia type 12, spinocerebellar ataxia type 13, spinocerebellar ataxia type 14, spinocerebellar ataxia type 15/16, spinocerebellar ataxia type 17, spinocerebellar ataxia type 19/22, spinocerebellar ataxia type 21, spinocerebellar ataxia type 18, spinocerebellar ataxia type 20, spinocerebellar ataxia type 25, spinocerebellar ataxia type 8, spinocerebellar ataxia type 27, spinocerebellar ataxia type 23, spinocerebellar ataxia type 28, spinocerebellar ataxia type 32, spinocerebellar ataxia type 36, cerebellar dysfunction with variable cognitive and behavioral abnormalities, spinocerebellar ataxia type 37, spinocerebellar ataxia type 40, spinocerebellar ataxia 46, neurodevelopmental disorder with motor abnormalities, seizures, and facial dysmorphism

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

117 retrieved; paginated sample, class counts are floors:

34 uncertain significance, 25 conflicting classifications of pathogenicity, 23 benign/likely benign, 21 benign, 6 likely benign, 4 likely pathogenic, 4 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1298293	NM_198994.3(TGM6):c.1429_1430insTCTCT (p.Gly477fs)	TGM6	Pathogenic	no assertion criteria provided
1299628	NM_198994.3(TGM6):c.1336+1G>T	TGM6	Pathogenic	criteria provided, single submitter
190253	NM_198994.3(TGM6):c.331C>T (p.Arg111Cys)	TGM6	Pathogenic	no assertion criteria provided
190254	NM_198994.3(TGM6):c.1719AGA[1] (p.Glu574del)	TGM6	Pathogenic	no assertion criteria provided
1027361	NM_198994.3(TGM6):c.1005G>A (p.Trp335Ter)	TGM6	Likely pathogenic	criteria provided, single submitter
3256544	NM_198994.3(TGM6):c.850+1G>A	TGM6	Likely pathogenic	criteria provided, single submitter
3256788	NM_198994.3(TGM6):c.110C>A (p.Ser37Ter)	TGM6	Likely pathogenic	no assertion criteria provided
4077695	NM_198994.3(TGM6):c.416G>A (p.Trp139Ter)	TGM6	Likely pathogenic	criteria provided, single submitter
1131237	NM_198994.3(TGM6):c.52G>A (p.Ala18Thr)	TGM6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1333238	NM_198994.3(TGM6):c.1024C>T (p.Arg342Trp)	TGM6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1701415	NM_198994.2(TGM6):c.425_435del11	TGM6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
225059	NM_198994.3(TGM6):c.115A>T (p.Ser39Cys)	TGM6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2437073	NM_198994.3(TGM6):c.897del (p.Ser300fs)	TGM6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2888363	NM_198994.3(TGM6):c.907G>A (p.Asp303Asn)	TGM6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
31085	NM_198994.3(TGM6):c.1550T>G (p.Leu517Trp)	TGM6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
31086	NM_198994.3(TGM6):c.980A>G (p.Asp327Gly)	TGM6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3235020	NM_198994.3(TGM6):c.1132dup (p.Arg378fs)	TGM6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
337909	NM_198994.3(TGM6):c.727G>A (p.Gly243Ser)	TGM6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
337912	NM_198994.3(TGM6):c.816C>T (p.Gly272=)	TGM6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
337913	NM_198994.3(TGM6):c.835G>A (p.Gly279Arg)	TGM6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
337916	NM_198994.3(TGM6):c.940G>A (p.Val314Met)	TGM6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
437001	NM_198994.3(TGM6):c.691C>T (p.Arg231Ter)	TGM6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
448664	NM_198994.3(TGM6):c.1089T>C (p.Ser363=)	TGM6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
805665	NM_198994.3(TGM6):c.621C>A (p.Asp207Glu)	TGM6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
895318	NM_198994.3(TGM6):c.38G>A (p.Arg13Gln)	TGM6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
895399	NM_198994.3(TGM6):c.850+4C>T	TGM6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
896740	NM_198994.3(TGM6):c.390C>T (p.Gly130=)	TGM6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
896799	NM_198994.3(TGM6):c.990-6T>C	TGM6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
897211	NM_198994.3(TGM6):c.543+7A>G	TGM6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
897212	NM_198994.3(TGM6):c.595G>A (p.Gly199Ser)	TGM6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
TGM6	Strong	Autosomal dominant	spinocerebellar ataxia type 35	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TGM6	Orphanet:276193	Spinocerebellar ataxia type 35
TGM6	Orphanet:319465	Inherited acute myeloid leukemia

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
TGM6	HGNC:16255	ENSG00000166948	O95932	Protein-glutamine gamma-glutamyltransferase 6	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TGM6	Protein-glutamine gamma-glutamyltransferase 6	Catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins.

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
Antibody/Immunoglobulin	1	29.2×	0.034

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TGM6	Antibody/Immunoglobulin	yes	2.3.2.13	Transglutaminase_N, Transglutaminase-like, Transglutaminase_C

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
bone marrow cell	1
colonic epithelium	1
kidney epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TGM6	39	tissue_specific	marker	colonic epithelium, bone marrow cell, kidney epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TGM6	385

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TGM6	O95932	90.95

Function

Pathway analysis

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

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
TGM6	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
TGM6	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TGM6	2.3.2.13	protein-glutamine gamma-glutamyltransferase

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	1	TGM6
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)
TGM6	8	—

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