Spinocerebellar ataxia, autosomal recessive 28

Summary

Spinocerebellar ataxia, autosomal recessive 28 (MONDO:0032923) is a disease caused by THG1L (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: THG1L (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 9

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	spinocerebellar ataxia, autosomal recessive 28
Mondo ID	MONDO:0032923
OMIM	618800
DOID	DOID:0070409
UMLS	C5394101
MedGen	1712568
GARD	0025776
Is cancer (heuristic)	no

Also known as: SCAR28 · THG1L-related autosomal recessive congenital cerebellar ataxia

Data availability: 9 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 cerebellar ataxia › spinocerebellar ataxia, autosomal recessive 28

Related subtypes (28): Charlevoix-Saguenay spastic ataxia, infantile-onset autosomal recessive nonprogressive cerebellar ataxia, autosomal recessive spinocerebellar ataxia 7, autosomal recessive ataxia, Beauce type, RIDDLE syndrome, autosomal recessive ataxia due to ubiquinone deficiency, autosomal recessive spinocerebellar ataxia 10, ataxia with oculomotor apraxia type 3, autosomal recessive spinocerebellar ataxia 14, autosomal recessive spinocerebellar ataxia 16, Lichtenstein-Knorr syndrome, autosomal recessive spinocerebellar ataxia 20, spinocerebellar ataxia, autosomal recessive 22, spinocerebellar ataxia, autosomal recessive 24, autosomal recessive cerebellar ataxia - epilepsy - intellectual disability syndrome, autosomal recessive congenital cerebellar ataxia, autosomal recessive metabolic cerebellar ataxia, autosomal recessive degenerative and progressive cerebellar ataxia, autosomal recessive syndromic cerebellar ataxia, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy, spinocerebellar ataxia, autosomal recessive 29, spinocerebellar ataxia, autosomal recessive 30, spinocerebellar ataxia, autosomal recessive 31, spinocerebellar ataxia, autosomal recessive 27, spinocerebellar ataxia, autosomal recessive 25, spinocerebellar ataxia, autosomal recessive 26, spinocerebellar ataxia, autosomal recessive 32, spinocerebellar ataxia, autosomal recessive 33

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

9 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 2 benign, 1 pathogenic/likely pathogenic, 1 likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
441070	NM_017872.5(THG1L):c.164T>C (p.Val55Ala)	THG1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4849402	NM_017872.5(THG1L):c.369-2A>G	THG1L	Likely pathogenic	criteria provided, single submitter
1210012	NM_017872.5(THG1L):c.287A>T (p.Asp96Val)	THG1L	Uncertain significance	criteria provided, multiple submitters, no conflicts
1700739	NM_017872.5(THG1L):c.527G>A (p.Arg176Gln)	THG1L	Uncertain significance	criteria provided, multiple submitters, no conflicts
547932	NM_017872.5(THG1L):c.137C>A (p.Thr46Asn)	THG1L	Uncertain significance	criteria provided, multiple submitters, no conflicts
818233	NM_017872.5(THG1L):c.881T>C (p.Leu294Pro)	THG1L	Uncertain significance	criteria provided, single submitter
4759446	NM_017872.5(THG1L):c.187C>A (p.His63Asn)	LOC129995144	Likely benign	criteria provided, single submitter
1233565	NM_017872.5(THG1L):c.695T>C (p.Leu232Pro)	THG1L	Benign	criteria provided, multiple submitters, no conflicts
1342289	NM_017872.5(THG1L):c.628-6T>C	THG1L	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 0 · 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
THG1L	Strong	Autosomal recessive	spinocerebellar ataxia, autosomal recessive 28	5

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
THG1L	HGNC:26053	ENSG00000113272	Q9NWX6	Probable tRNA(His) guanylyltransferase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
THG1L	Probable tRNA(His) guanylyltransferase	Adds a GMP to the 5’-end of tRNA(His) after transcription and RNase P cleavage.

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
THG1L	Enzyme (other)	yes	2.7.7.79	tRNAHis_GuaTrfase_Thg1, tRNAHis_GuaTrfase_cat, Thg1_C_dom

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
cartilage tissue	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
THG1L	231	ubiquitous	marker	monocyte, mononuclear cell, cartilage tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
THG1L	1,092

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
THG1L	Q9NWX6	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
tRNA processing	1	356.9×	0.005	THG1L
tRNA modification in the nucleus and cytosol	1	292.8×	0.005	THG1L
Metabolism of RNA	1	41.7×	0.024	THG1L

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
stress-induced mitochondrial fusion	1	8426.0×	7e-04	THG1L
tRNA processing	1	842.6×	0.002	THG1L
mitochondrial fusion	1	842.6×	0.002	THG1L
tRNA modification	1	601.9×	0.002	THG1L
protein homotetramerization	1	237.3×	0.005	THG1L
response to oxidative stress	1	130.6×	0.008	THG1L

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
THG1L	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
THG1L	2.7.7.79	tRNAHis guanylyltransferase

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	THG1L
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)
THG1L	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.