Spinocerebellar ataxia type 15/16

Summary

Spinocerebellar ataxia type 15/16 (MONDO:0011694) is a disease caused by ITPR1 (GenCC Strong), with 5 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ITPR1 (GenCC Strong)
• Cohort genes: 5
• ClinVar variants: 75
• Phenotypes (HPO): 8
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		80	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

8 HPO clinical features (Orphanet curated; top 8 by frequency):

HPO ID	Term	Frequency
HP:0001251	Ataxia	Very frequent (80-99%)
HP:0001272	Cerebellar atrophy	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0002066	Gait ataxia	Frequent (30-79%)
HP:0002345	Action tremor	Frequent (30-79%)
HP:0002346	Head tremor	Frequent (30-79%)
HP:0007351	Upper limb postural tremor	Frequent (30-79%)
HP:0030188	Tremor by anatomical site	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spinocerebellar ataxia type 15/16
Mondo ID	MONDO:0011694
MeSH	C564685
OMIM	606658
Orphanet	98769, 98770
DOID	DOID:0050965, DOID:0050966
NCIT	C150250
SNOMED CT	716724006
UMLS	C1847725
MedGen	338301
GARD	0010477
Is cancer (heuristic)	no

Also known as: SCA15 · SCA15/16 · SCA16 (formerly) · SCAR16 · spinocerebellar ataxia 15 · spinocerebellar ataxia 16 · spinocerebellar ataxia 16 (formerly) · spinocerebellar ataxia type 15 · spinocerebellar ataxia type 15/16 · spinocerebellar ataxia type 16

Data availability: 75 ClinVar variants · 3 GenCC gene-disease records · 2 cell lines.

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 15/16

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 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 35, 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

75 retrieved; paginated sample, class counts are floors:

29 uncertain significance, 11 benign/likely benign, 9 benign, 9 conflicting classifications of pathogenicity, 6 likely pathogenic, 6 pathogenic, 4 pathogenic/likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1186673	NM_001378452.1(ITPR1):c.748T>C (p.Phe250Leu)	ITPR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1386082	NM_001378452.1(ITPR1):c.1781C>T (p.Thr594Ile)	ITPR1	Pathogenic	criteria provided, multiple submitters, no conflicts
14801	NM_001378452.1(ITPR1):c.3248C>T (p.Pro1083Leu)	ITPR1	Pathogenic	no assertion criteria provided
208786	NM_001378452.1(ITPR1):c.800C>T (p.Thr267Met)	ITPR1	Pathogenic	criteria provided, multiple submitters, no conflicts
224119	NM_001378452.1(ITPR1):c.7784G>A (p.Gly2595Glu)	ITPR1	Pathogenic	criteria provided, multiple submitters, no conflicts
265201	NM_001378452.1(ITPR1):c.805C>T (p.Arg269Trp)	ITPR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
560157	Single allele	ITPR1	Pathogenic	criteria provided, single submitter
633506	NM_001378452.1(ITPR1):c.742_744del (p.Glu248del)	ITPR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14800	NC_000003.12:g.(4480596_4480597)_(4793914_4793915)del	LOC129936065	Pathogenic	no assertion criteria provided
2734439	NM_182760.4(SUMF1):c.1046G>C (p.Arg349Pro)	SUMF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3338447	GRCh37/hg19 3p26.1(chr3:4669445-4859925)x1	EGOT	Likely pathogenic	no assertion criteria provided
1302005	NM_001378452.1(ITPR1):c.1516C>T (p.Arg506Trp)	ITPR1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3256728	NM_001378452.1(ITPR1):c.773A>T (p.Lys258Met)	ITPR1	Likely pathogenic	no assertion criteria provided
3377473	NM_001378452.1(ITPR1):c.7345A>G (p.Ile2449Val)	ITPR1	Likely pathogenic	criteria provided, single submitter
585154	NM_001378452.1(ITPR1):c.4333G>A (p.Val1445Met)	ITPR1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3220894	NM_014687.4(RUBCN):c.1553dup (p.Glu519fs)	RUBCN	Likely pathogenic	criteria provided, single submitter
39571	NM_001378452.1(ITPR1):c.4684G>A (p.Val1562Met)	BRRIAR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1321595	NM_001378452.1(ITPR1):c.7474G>A (p.Gly2492Ser)	ITPR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1700083	NM_001378452.1(ITPR1):c.7636G>A (p.Val2546Met)	ITPR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2117186	NM_001378452.1(ITPR1):c.7297G>A (p.Glu2433Lys)	ITPR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
345716	NM_001378452.1(ITPR1):c.2732C>T (p.Ala911Val)	ITPR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
453136	NM_001378452.1(ITPR1):c.736G>A (p.Glu246Lys)	ITPR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
520945	NM_001378452.1(ITPR1):c.7648G>A (p.Gly2550Arg)	ITPR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
804937	NM_001378452.1(ITPR1):c.4421C>T (p.Thr1474Ile)	ITPR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
900350	NM_001378452.1(ITPR1):c.256G>A (p.Ala86Thr)	ITPR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3781339	NM_001378452.1(ITPR1):c.4754A>G (p.Asn1585Ser)	BRRIAR	Uncertain significance	criteria provided, single submitter
1028567	NM_001378452.1(ITPR1):c.3026G>A (p.Arg1009Gln)	ITPR1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1028568	NM_001378452.1(ITPR1):c.3206C>T (p.Thr1069Ile)	ITPR1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1028571	NM_001378452.1(ITPR1):c.4541G>A (p.Arg1514His)	ITPR1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1098659	NM_001378452.1(ITPR1):c.3199G>A (p.Gly1067Ser)	ITPR1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 17 · Orphanet: 5 · 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
ITPR1	Definitive	Autosomal dominant	aniridia-cerebellar ataxia-intellectual disability syndrome	17

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ITPR1	Orphanet:1065	Aniridia-cerebellar ataxia-intellectual disability syndrome
ITPR1	Orphanet:208513	Spinocerebellar ataxia type 29
ITPR1	Orphanet:98769	Spinocerebellar ataxia type 15/16
SUMF1	Orphanet:585	Multiple sulfatase deficiency
RUBCN	Orphanet:404499	Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to RUBCN deficiency

Cohort genes → proteins

5 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ITPR1	HGNC:6180	ENSG00000150995	Q14643	Inositol 1,4,5-trisphosphate-gated calcium channel ITPR1	gencc,clinvar
SUMF1	HGNC:20376	ENSG00000144455	Q8NBK3	Formylglycine-generating enzyme	clinvar
RUBCN	HGNC:28991	ENSG00000145016	Q92622	Run domain Beclin-1-interacting and cysteine-rich domain-containing protein	clinvar
EGOT	HGNC:37129	ENSG00000235947		eosinophil granule ontogeny transcript	clinvar
BRRIAR	HGNC:59155			BHLHE40 and RIG-I regulating ITPR1 antisense RNA	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ITPR1	Inositol 1,4,5-trisphosphate-gated calcium channel ITPR1	Inositol 1,4,5-trisphosphate-gated calcium channel that, upon inositol 1,4,5-trisphosphate binding, mediates calcium release from the endoplasmic reticulum (ER).
SUMF1	Formylglycine-generating enzyme	Oxidase that catalyzes the conversion of cysteine to 3-oxoalanine on target proteins, using molecular oxygen and an unidentified reducing agent. 3-oxoalanine modification, which is also named formylglycine (fGly), occurs in the maturation…
RUBCN	Run domain Beclin-1-interacting and cysteine-rich domain-containing protein	Inhibits PIK3C3 activity; under basal conditions negatively regulates PI3K complex II (PI3KC3-C2) function in autophagy.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.4

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
Ion channel	1	22.3×	0.132
Kinase	1	5.5×	0.252
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ITPR1	Ion channel	yes		InsP3_rcpt, RIH_dom, Ion_trans_dom
SUMF1	Kinase	yes	1.8.3.7	SUMF_dom, CTDL_fold, SUMF_sf
RUBCN	Other/Unknown	no		Run_dom, RH_dom, Run_dom_sf
EGOT	Other/Unknown	no
BRRIAR	Other/Unknown	no

Expression context

Cohort genes with no expression data: 1.

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)	4
unknown	1

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	1
cauda epididymis	1
primary visual cortex	1
kidney epithelium	1
renal medulla	1
upper arm skin	1
middle frontal gyrus	1
postcentral gyrus	1
sural nerve	1
bone marrow cell	1
caput epididymis	1
metanephros cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ITPR1	284	ubiquitous	marker	cauda epididymis, Brodmann (1909) area 23, primary visual cortex
SUMF1	258	ubiquitous	marker	kidney epithelium, renal medulla, upper arm skin
RUBCN	285	ubiquitous	marker	sural nerve, postcentral gyrus, middle frontal gyrus
EGOT	118	tissue_specific	yes	bone marrow cell, caput epididymis, metanephros cortex
BRRIAR

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ITPR1	3,483
SUMF1	1,541
RUBCN	925
EGOT	0
BRRIAR	0

Intra-cohort edges

A	B	Sources
ITPR1	SUMF1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SUMF1	Q8NBK3	18
RUBCN	Q92622	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ITPR1	Q14643

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 59. Enrichment computed across 5 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
CLEC7A (Dectin-1) induces NFAT activation	1	519.1×	0.016	ITPR1
The activation of arylsulfatases	1	439.2×	0.016	SUMF1
Nitric oxide stimulates guanylate cyclase	1	407.9×	0.016	ITPR1
Elevation of cytosolic Ca2+ levels	1	356.9×	0.016	ITPR1
Platelet calcium homeostasis	1	356.9×	0.016	ITPR1
cGMP effects	1	356.9×	0.016	ITPR1
VEGFR2 mediated cell proliferation	1	285.5×	0.016	ITPR1
Effects of PIP2 hydrolysis	1	228.4×	0.016	ITPR1
Role of phospholipids in phagocytosis	1	228.4×	0.016	ITPR1
Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation	1	211.5×	0.016	SUMF1
Anti-inflammatory response favouring Leishmania parasite infection	1	196.9×	0.016	ITPR1
Leishmania parasite growth and survival	1	196.9×	0.016	ITPR1
FCERI mediated Ca+2 mobilization	1	178.4×	0.016	ITPR1
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	1	178.4×	0.016	ITPR1
Signaling by the B Cell Receptor (BCR)	1	173.0×	0.016	ITPR1
G-protein mediated events	1	163.1×	0.016	ITPR1
DAG and IP3 signaling	1	158.6×	0.016	ITPR1
Glycosphingolipid metabolism	1	150.3×	0.016	SUMF1
Beta-catenin independent WNT signaling	1	146.4×	0.016	ITPR1
FCGR3A-mediated IL10 synthesis	1	146.4×	0.016	ITPR1
Glycosphingolipid catabolism	1	146.4×	0.016	SUMF1
Fcgamma receptor (FCGR) dependent phagocytosis	1	139.3×	0.016	ITPR1
Platelet homeostasis	1	139.3×	0.016	ITPR1
Fc epsilon receptor (FCERI) signaling	1	135.9×	0.016	ITPR1
Opioid Signalling	1	132.8×	0.016	ITPR1
PLC beta mediated events	1	132.8×	0.016	ITPR1
Glucagon-like Peptide-1 (GLP1) regulates insulin secretion	1	132.8×	0.016	ITPR1
Metabolism	2	11.6×	0.016	ITPR1, SUMF1
C-type lectin receptors (CLRs)	1	119.0×	0.017	ITPR1
Signaling by VEGF	1	109.8×	0.017	ITPR1

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
release of sequestered calcium ion into cytosol by endoplasmic reticulum	1	2808.7×	0.007	ITPR1
protein oxidation	1	1872.4×	0.007	SUMF1
negative regulation of autophagosome maturation	1	1123.5×	0.007	RUBCN
voluntary musculoskeletal movement	1	936.2×	0.007	ITPR1
phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathway	1	702.2×	0.007	ITPR1
epithelial fluid transport	1	702.2×	0.007	ITPR1
negative regulation of calcium-mediated signaling	1	702.2×	0.007	ITPR1
ligand-gated ion channel signaling pathway	1	624.1×	0.007	ITPR1
glycosphingolipid catabolic process	1	510.7×	0.007	SUMF1
calcium import into the mitochondrion	1	401.2×	0.008	ITPR1
regulation of calcium-mediated signaling	1	374.5×	0.008	ITPR1
negative regulation of endocytosis	1	312.1×	0.009	RUBCN
endoplasmic reticulum calcium ion homeostasis	1	280.9×	0.009	ITPR1
multivesicular body sorting pathway	1	267.5×	0.009	RUBCN
intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	1	160.5×	0.014	ITPR1
post-translational protein modification	1	140.4×	0.014	SUMF1
immune system process	1	130.6×	0.014	RUBCN
regulation of cytosolic calcium ion concentration	1	127.7×	0.014	ITPR1
release of sequestered calcium ion into cytosol	1	114.6×	0.015	ITPR1
negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	87.8×	0.017	RUBCN
negative regulation of autophagy	1	86.4×	0.017	RUBCN
positive regulation of insulin secretion	1	85.1×	0.017	ITPR1
phagocytosis	1	80.2×	0.017	RUBCN
regulation of autophagy	1	80.2×	0.017	ITPR1
protein homotetramerization	1	79.1×	0.017	ITPR1
post-embryonic development	1	68.5×	0.018	ITPR1
single fertilization	1	61.1×	0.019	ITPR1
calcium ion transport	1	60.4×	0.019	ITPR1
cell morphogenesis	1	52.5×	0.022	ITPR1
autophagy	1	36.7×	0.030	RUBCN

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 1 of 5 evidence-associated genes (20%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ITPR1	0	0
SUMF1	0	0
RUBCN	0	0
EGOT	0	0
BRRIAR	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
ITPR1	13	Binding:12, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SUMF1	1.8.3.7	formylglycine-generating enzyme

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	SUMF1
D	Druggable family + AlphaFold only, no drug	1	ITPR1
E	Difficult family or no structure, no drug	3	RUBCN, EGOT, BRRIAR

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ITPR1	13	—
SUMF1	0	—
RUBCN	0	—
EGOT	0	—
BRRIAR	0	—

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