Autosomal recessive spinocerebellar ataxia 16

Summary

Autosomal recessive spinocerebellar ataxia 16 (MONDO:0014339) is a disease caused by STUB1 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: STUB1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 45
• Phenotypes (HPO): 54

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

54 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0001260	Dysarthria	Very frequent (80-99%)
HP:0001272	Cerebellar atrophy	Very frequent (80-99%)
HP:0002070	Limb ataxia	Very frequent (80-99%)
HP:0002078	Truncal ataxia	Very frequent (80-99%)
HP:0001166	Arachnodactyly	Frequent (30-79%)
HP:0001181	Adducted thumb	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0002172	Postural instability	Frequent (30-79%)
HP:0002317	Unsteady gait	Frequent (30-79%)
HP:0005328	Progeroid facial appearance	Frequent (30-79%)
HP:0010831	Impaired proprioception	Frequent (30-79%)
HP:0012896	Abnormal motor evoked potentials	Frequent (30-79%)
HP:0000135	Hypogonadism	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000602	Ophthalmoplegia	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000640	Gaze-evoked nystagmus	Occasional (5-29%)
HP:0000666	Horizontal nystagmus	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001321	Cerebellar hypoplasia	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002061	Lower limb spasticity	Occasional (5-29%)
HP:0002063	Rigidity	Occasional (5-29%)
HP:0002167	Abnormality of speech or vocalization	Occasional (5-29%)
HP:0002174	Postural tremor	Occasional (5-29%)
HP:0002346	Head tremor	Occasional (5-29%)
HP:0002354	Memory impairment	Occasional (5-29%)
HP:0002378	Hand tremor	Occasional (5-29%)
HP:0003693	Distal amyotrophy	Occasional (5-29%)
HP:0006801	Hyperactive deep tendon reflexes	Occasional (5-29%)
HP:0007371	Corpus callosum atrophy	Occasional (5-29%)
HP:0011098	Speech apraxia	Occasional (5-29%)
HP:0011448	Ankle clonus	Occasional (5-29%)
HP:0012104	Parietal cortical atrophy	Occasional (5-29%)
HP:0012110	Hypoplasia of the pons	Occasional (5-29%)
HP:0100543	Cognitive impairment	Occasional (5-29%)
HP:0001094	Iridocyclitis	Very rare (<1-4%)
HP:0001105	Retinal atrophy	Very rare (<1-4%)
HP:0001152	Saccadic smooth pursuit	Very rare (<1-4%)
HP:0001250	Seizure	Very rare (<1-4%)
HP:0001596	Alopecia	Very rare (<1-4%)
HP:0001733	Pancreatitis	Very rare (<1-4%)
HP:0001999	Abnormal facial shape	Very rare (<1-4%)
HP:0002679	Abnormality of the sella turcica	Very rare (<1-4%)
HP:0005978	Type II diabetes mellitus	Very rare (<1-4%)
HP:0012547	Abnormal involuntary eye movements	Very rare (<1-4%)
HP:0012569	Delayed menarche	Very rare (<1-4%)
HP:0100651	Type I diabetes mellitus	Very rare (<1-4%)
HP:0000501	Glaucoma	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive spinocerebellar ataxia 16
Mondo ID	MONDO:0014339
OMIM	615768
Orphanet	412057
DOID	DOID:0080029
UMLS	C5190574
MedGen	1674542
GARD	0017689
Is cancer (heuristic)	no

Also known as: autosomal recessive cerebellar ataxia caused by mutation in STUB1 · autosomal recessive spinocerebellar ataxia 16 · autosomal recessive spinocerebellar ataxia type 16 · SCAR16 · spinocerebellar ataxia autosomal recessive type 16 · spinocerebellar ataxia, autosomal recessive 16 · spinocerebellar ataxia, autosomal recessive type 16 · STUB1 autosomal recessive cerebellar ataxia

Data availability: 45 ClinVar variants · 4 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 › autosomal recessive spinocerebellar ataxia 16

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, 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 28, 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

45 retrieved; paginated sample, class counts are floors:

16 uncertain significance, 11 likely pathogenic, 7 pathogenic, 5 pathogenic/likely pathogenic, 4 conflicting classifications of pathogenicity, 1 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
127148	NM_005861.4(STUB1):c.719T>C (p.Met240Thr)	JMJD8	Pathogenic	no assertion criteria provided
3342376	NM_005861.4(STUB1):c.586C>T (p.Gln196Ter)	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
871159	NM_005861.4(STUB1):c.689_692del (p.Tyr230fs)	JMJD8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1027455	NM_005861.4(STUB1):c.791_792del (p.Val264fs)	STUB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
127143	NM_005861.4(STUB1):c.493C>T (p.Leu165Phe)	STUB1	Pathogenic	no assertion criteria provided
127144	NM_005861.4(STUB1):c.389A>T (p.Asn130Ile)	STUB1	Pathogenic	no assertion criteria provided
127145	NM_005861.4(STUB1):c.441G>T (p.Trp147Cys)	STUB1	Pathogenic	no assertion criteria provided
127147	NM_005861.4(STUB1):c.367C>G (p.Leu123Val)	STUB1	Pathogenic/Likely pathogenic	no assertion criteria provided
127149	NM_005861.4(STUB1):c.235G>A (p.Ala79Thr)	STUB1	Pathogenic	no assertion criteria provided
2584742	NM_005861.4(STUB1):c.168C>G (p.Asn56Lys)	STUB1	Pathogenic	criteria provided, single submitter
623185	NM_005861.4(STUB1):c.885dup (p.Glu296Ter)	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
1184458	NM_005861.4(STUB1):c.779A>C (p.His260Pro)	JMJD8	Likely pathogenic	no assertion criteria provided
1301244	NM_005861.4(STUB1):c.544C>T (p.Arg182Ter)	JMJD8	Likely pathogenic	criteria provided, multiple submitters, no conflicts
436888	NM_005861.4(STUB1):c.694_699del (p.Cys232_Gly233del)	JMJD8	Likely pathogenic	criteria provided, single submitter
436889	NM_005861.4(STUB1):c.721C>G (p.Arg241Gly)	JMJD8	Likely pathogenic	criteria provided, single submitter
522378	NM_005861.4(STUB1):c.*240T>C	JMJD8	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
1687153	NM_005861.4(STUB1):c.469C>T (p.Gln157Ter)	STUB1	Likely pathogenic	criteria provided, single submitter
2503107	NM_005861.4(STUB1):c.207C>G (p.Cys69Trp)	STUB1	Likely pathogenic	criteria provided, single submitter
4532287	NM_005861.4(STUB1):c.159+1G>C	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
1335192	NM_005861.4(STUB1):c.860AGG[1] (p.Glu288del)	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
1028430	NM_005861.4(STUB1):c.612+11C>G	JMJD8	Uncertain significance	criteria provided, single submitter
1175878	NM_005861.4(STUB1):c.346A>G (p.Asn116Asp)	JMJD8	Uncertain significance	criteria provided, multiple submitters, no conflicts
1679377	NM_005861.4(STUB1):c.612+4_612+46del	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

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
STUB1	HGNC:11427	ENSG00000103266	Q9UNE7	E3 ubiquitin-protein ligase CHIP	gencc,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.
JMJD8	JmjC domain-containing protein 8	Functions as a positive regulator of TNF-induced NF-kappa-B signaling.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.0

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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

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
JMJD8	Other/Unknown	no		JmjC_dom, Cupin_8, JMJD6_ArgDemeth/LysHydrox

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
lateral nuclear group of thalamus	1
parietal lobe	1
postcentral gyrus	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
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
JMJD8	639

Structural data

PDB: 1 · AlphaFold-only: 1 · 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

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 2 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 2 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	8426.0×	0.002	STUB1
regulation of pyruvate kinase activity	1	8426.0×	0.002	JMJD8
regulation of glucocorticoid metabolic process	1	4213.0×	0.003	STUB1
negative regulation of vascular associated smooth muscle contraction	1	2106.5×	0.004	STUB1
negative regulation of peroxisome proliferator activated receptor signaling pathway	1	1404.3×	0.004	STUB1
chaperone-mediated autophagy	1	1404.3×	0.004	STUB1
positive regulation of smooth muscle cell apoptotic process	1	1203.7×	0.004	STUB1
ERBB2 signaling pathway	1	936.2×	0.005	STUB1
negative regulation of smooth muscle cell apoptotic process	1	702.2×	0.005	STUB1
cellular response to misfolded protein	1	702.2×	0.005	STUB1
regulation of glycolytic process	1	601.9×	0.005	JMJD8
negative regulation of cardiac muscle hypertrophy	1	561.7×	0.005	STUB1
positive regulation of mitophagy	1	561.7×	0.005	STUB1
positive regulation of ERAD pathway	1	443.5×	0.006	STUB1
positive regulation of proteolysis	1	401.2×	0.006	STUB1
protein quality control for misfolded or incompletely synthesized proteins	1	383.0×	0.006	STUB1
positive regulation of sprouting angiogenesis	1	337.0×	0.006	JMJD8
protein monoubiquitination	1	172.0×	0.011	STUB1
cellular response to heat	1	172.0×	0.011	STUB1
endoplasmic reticulum unfolded protein response	1	147.8×	0.012	STUB1
protein K63-linked ubiquitination	1	133.8×	0.013	STUB1
response to ischemia	1	125.8×	0.013	STUB1
protein autoubiquitination	1	117.0×	0.014	STUB1
positive regulation of protein ubiquitination	1	106.7×	0.014	STUB1
positive regulation of proteasomal ubiquitin-dependent protein catabolic process	1	105.3×	0.014	STUB1
ERAD pathway	1	90.6×	0.016	STUB1
negative regulation of transforming growth factor beta receptor signaling pathway	1	86.9×	0.016	STUB1
MAPK cascade	1	76.6×	0.017	STUB1
regulation of protein stability	1	62.9×	0.020	STUB1
cellular response to hypoxia	1	60.6×	0.020	STUB1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
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: 2; 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	0
E	Difficult family or no structure, no drug	2	STUB1, JMJD8

Undrugged target profiles

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

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.