Spinocerebellar ataxia 48

Summary

Spinocerebellar ataxia 48 (MONDO:0032526) is a disease caused by STUB1 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: STUB1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 43

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		50	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	spinocerebellar ataxia 48
Mondo ID	MONDO:0032526
OMIM	618093
Orphanet	631103
DOID	DOID:0111746
UMLS	C4748158
MedGen	1648409
GARD	0025702
Is cancer (heuristic)	no

Also known as: SCA48

Data availability: 43 ClinVar variants · 3 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 › spinocerebellar ataxia 48

Related subtypes (15): GRID2-related autosomal dominant spinocerebellar ataxia, spinocerebellar ataxia 27A, spinocerebellar ataxia 9, spinocerebellar ataxia 43, spinocerebellar ataxia 7, autosomal dominant cerebellar ataxia type I, autosomal dominant cerebellar ataxia type III, autosomal dominant cerebellar ataxia type IV, spinocerebellar ataxia 49, spinocerebellar ataxia 44, spinocerebellar ataxia 47, spinocerebellar ataxia 50, spinocerebellar ataxia 27B, late-onset, spinocerebellar ataxia 51, spinocerebellar ataxia 52

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

43 retrieved; paginated sample, class counts are floors:

15 uncertain significance, 10 likely pathogenic, 7 pathogenic/likely pathogenic, 5 conflicting classifications of pathogenicity, 4 pathogenic, 1 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1683911	NM_005861.4(STUB1):c.829C>T (p.Gln277Ter)	JMJD8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
436887	NM_005861.4(STUB1):c.646dup (p.Ser216fs)	JMJD8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
590271	NM_005861.4(STUB1):c.823_824del (p.Leu275fs)	JMJD8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
807332	NM_005861.4(STUB1):c.673C>T (p.Arg225Ter)	JMJD8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
871159	NM_005861.4(STUB1):c.689_692del (p.Tyr230fs)	JMJD8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
997704	NM_005861.4(STUB1):c.818_819dup (p.Pro274fs)	JMJD8	Pathogenic	criteria provided, single submitter
1027426	NM_005861.4(STUB1):c.199G>A (p.Ala67Thr)	STUB1	Pathogenic	criteria provided, single submitter
1027455	NM_005861.4(STUB1):c.791_792del (p.Val264fs)	STUB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
976748	NM_005861.4(STUB1):c.823dup (p.Leu275fs)	STUB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
997699	NM_005861.4(STUB1):c.97G>A (p.Gly33Ser)	STUB1	Pathogenic	criteria provided, single submitter
997700	NM_005861.4(STUB1):c.682C>T (p.Pro228Ser)	STUB1	Pathogenic	criteria provided, single submitter
1027452	NM_005861.4(STUB1):c.721C>T (p.Arg241Trp)	JMJD8	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1333941	NM_005861.4(STUB1):c.807dup (p.Val270fs)	JMJD8	Likely pathogenic	criteria provided, single submitter
3338115	NM_005861.4(STUB1):c.784C>T (p.Gln262Ter)	JMJD8	Likely pathogenic	criteria provided, single submitter
1027454	NM_005861.4(STUB1):c.170C>T (p.Pro57Leu)	STUB1	Likely pathogenic	criteria provided, single submitter
127150	NM_005861.4(STUB1):c.236C>A (p.Ala79Asp)	STUB1	Likely pathogenic	criteria provided, single submitter
162097	NM_005861.4(STUB1):c.194A>G (p.Asn65Ser)	STUB1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1679956	NM_005861.4(STUB1):c.778dup (p.His260fs)	STUB1	Likely pathogenic	criteria provided, single submitter
1698848	NM_005861.4(STUB1):c.525-1G>A	STUB1	Likely pathogenic	criteria provided, single submitter
3377516	NM_005861.4(STUB1):c.3G>T (p.Met1Ile)	STUB1	Likely pathogenic	criteria provided, single submitter
982033	NM_005861.4(STUB1):c.760C>G (p.Arg254Gly)	STUB1	Likely pathogenic	criteria provided, single submitter
127146	NM_005861.4(STUB1):c.737C>T (p.Thr246Met)	JMJD8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3027432	NM_005861.4(STUB1):c.728C>T (p.Pro243Leu)	JMJD8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
436890	NM_005861.4(STUB1):c.832del (p.Glu278fs)	JMJD8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1217982	NM_005861.4(STUB1):c.427AAG[2] (p.Lys145del)	STUB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
212325	NM_005861.4(STUB1):c.433A>C (p.Lys145Gln)	STUB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3238956	NM_005861.4(STUB1):c.848A>G (p.Asn283Ser)	JMJD8	Uncertain significance	criteria provided, single submitter
3892579	NM_005861.4(STUB1):c.852G>C (p.Leu284Phe)	JMJD8	Uncertain significance	criteria provided, single submitter
4293177	NM_005861.4(STUB1):c.613-12_613-8del	JMJD8	Uncertain significance	criteria provided, single submitter
4293240	NM_005861.4(STUB1):c.634G>C (p.Asp212His)	JMJD8	Uncertain significance	criteria provided, single submitter

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
STUB1	Strong	Autosomal recessive	autosomal recessive spinocerebellar ataxia 16	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
STUB1	Orphanet:412057	Autosomal recessive cerebellar ataxia due to STUB1 deficiency
STUB1	Orphanet:631103	Spinocerebellar ataxia type 48

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
STUB1	HGNC:11427	ENSG00000103266	Q9UNE7	E3 ubiquitin-protein ligase CHIP	gencc,clinvar
RHBDL1	HGNC:10007	ENSG00000103269	O75783	Rhomboid-related protein 1	clinvar
JMJD8	HGNC:14148	ENSG00000161999	Q96S16	JmjC domain-containing protein 8	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
STUB1	E3 ubiquitin-protein ligase CHIP	E3 ubiquitin-protein ligase which targets misfolded chaperone substrates towards proteasomal degradation.
RHBDL1	Rhomboid-related protein 1	May be involved in regulated intramembrane proteolysis and the subsequent release of functional polypeptides from their membrane anchors.
JMJD8	JmjC domain-containing protein 8	Functions as a positive regulator of TNF-induced NF-kappa-B signaling.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

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	12.2×	0.239
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
STUB1	Transcription factor	no	2.3.2.27	Ubox_domain, TPR-like_helical_dom_sf, Znf_RING/FYVE/PHD
RHBDL1	Protease	yes		EF-hand-dom_pair, Peptidase_S54_rhomboid_dom, Rhomboid-like_sf
JMJD8	Other/Unknown	no		JmjC_dom, Cupin_8, JMJD6_ArgDemeth/LysHydrox

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
lateral nuclear group of thalamus	1
parietal lobe	1
postcentral gyrus	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
apex of heart	1
left uterine tube	1
thoracic aorta	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
STUB1	287	ubiquitous	marker	lateral nuclear group of thalamus, postcentral gyrus, parietal lobe
RHBDL1	166	tissue_specific	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
JMJD8	222	ubiquitous	marker	apex of heart, thoracic aorta, left uterine tube

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
STUB1	6,421
RHBDL1	857
JMJD8	639

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
STUB1	Q9UNE7	27

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
JMJD8	Q96S16	91.33
RHBDL1	O75783	72.85

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 3 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
RIPK1-mediated regulated necrosis	1	456.8×	0.005	STUB1
Regulation of necroptotic cell death	1	439.2×	0.005	STUB1
Downregulation of TGF-beta receptor signaling	1	407.9×	0.005	STUB1
Downregulation of ERBB2 signaling	1	380.7×	0.005	STUB1
Regulation of TNFR1 signaling	1	223.9×	0.006	STUB1
Regulation of PTEN stability and activity	1	184.2×	0.006	STUB1
Regulation of RUNX2 expression and activity	1	181.3×	0.006	STUB1
Antigen processing: Ubiquitination & Proteasome degradation	1	37.2×	0.027	STUB1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of chaperone-mediated protein complex assembly	1	5617.3×	0.003	STUB1
regulation of pyruvate kinase activity	1	5617.3×	0.003	JMJD8
regulation of glucocorticoid metabolic process	1	2808.7×	0.005	STUB1
negative regulation of vascular associated smooth muscle contraction	1	1404.3×	0.007	STUB1
negative regulation of peroxisome proliferator activated receptor signaling pathway	1	936.2×	0.007	STUB1
chaperone-mediated autophagy	1	936.2×	0.007	STUB1
positive regulation of smooth muscle cell apoptotic process	1	802.5×	0.007	STUB1
ERBB2 signaling pathway	1	624.1×	0.008	STUB1
negative regulation of smooth muscle cell apoptotic process	1	468.1×	0.008	STUB1
cellular response to misfolded protein	1	468.1×	0.008	STUB1
regulation of glycolytic process	1	401.2×	0.008	JMJD8
negative regulation of cardiac muscle hypertrophy	1	374.5×	0.008	STUB1
positive regulation of mitophagy	1	374.5×	0.008	STUB1
positive regulation of ERAD pathway	1	295.6×	0.009	STUB1
positive regulation of proteolysis	1	267.5×	0.010	STUB1
protein quality control for misfolded or incompletely synthesized proteins	1	255.3×	0.010	STUB1
positive regulation of sprouting angiogenesis	1	224.7×	0.010	JMJD8
protein monoubiquitination	1	114.6×	0.018	STUB1
cellular response to heat	1	114.6×	0.018	STUB1
endoplasmic reticulum unfolded protein response	1	98.5×	0.020	STUB1
protein K63-linked ubiquitination	1	89.2×	0.021	STUB1
response to ischemia	1	83.8×	0.021	STUB1
protein autoubiquitination	1	78.0×	0.022	STUB1
positive regulation of protein ubiquitination	1	71.1×	0.022	STUB1
positive regulation of proteasomal ubiquitin-dependent protein catabolic process	1	70.2×	0.022	STUB1
ERAD pathway	1	60.4×	0.025	STUB1
negative regulation of transforming growth factor beta receptor signaling pathway	1	57.9×	0.025	STUB1
MAPK cascade	1	51.1×	0.027	STUB1
regulation of protein stability	1	41.9×	0.032	STUB1
cellular response to hypoxia	1	40.4×	0.032	STUB1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
STUB1	0	0
RHBDL1	0	0
JMJD8	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
STUB1	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
STUB1	2.3.2.27	RING-type E3 ubiquitin transferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	RHBDL1
E	Difficult family or no structure, no drug	2	STUB1, JMJD8

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
STUB1	8	—
RHBDL1	0	—
JMJD8	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.