X-linked progressive cerebellar ataxia

Summary

X-linked progressive cerebellar ataxia (MONDO:0010547) is a disease caused by ATP2B3 (GenCC Strong), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: ATP2B3 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 37
• Phenotypes (HPO): 26
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

26 HPO clinical features (Orphanet curated; top 26 by frequency):

HPO ID	Term	Frequency
HP:0002073	Progressive cerebellar ataxia	Very frequent (80-99%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0001152	Saccadic smooth pursuit	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001310	Dysmetria	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0001761	Pes cavus	Frequent (30-79%)
HP:0002070	Limb ataxia	Frequent (30-79%)
HP:0002075	Dysdiadochokinesis	Frequent (30-79%)
HP:0002080	Intention tremor	Frequent (30-79%)
HP:0002312	Clumsiness	Frequent (30-79%)
HP:0002317	Unsteady gait	Frequent (30-79%)
HP:0002359	Frequent falls	Frequent (30-79%)
HP:0002464	Spastic dysarthria	Frequent (30-79%)
HP:0002503	Spinocerebellar tract degeneration	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0003445	EMG: neuropathic changes	Frequent (30-79%)
HP:0003447	Axonal loss	Frequent (30-79%)
HP:0006855	Cerebellar vermis atrophy	Frequent (30-79%)
HP:0007141	Sensorimotor neuropathy	Frequent (30-79%)
HP:0007240	Progressive gait ataxia	Frequent (30-79%)
HP:0008944	Distal lower limb amyotrophy	Frequent (30-79%)
HP:0200101	Decreased/absent ankle reflexes	Frequent (30-79%)
HP:0002395	Lower limb hyperreflexia	Occasional (5-29%)
HP:0003487	Babinski sign	Occasional (5-29%)
HP:0009027	Foot dorsiflexor weakness	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked progressive cerebellar ataxia
Mondo ID	MONDO:0010547
MeSH	C563134
OMIM	302500
Orphanet	1175
DOID	DOID:0111829
UMLS	C0796205
MedGen	163229
GARD	0016558
Is cancer (heuristic)	no

Also known as: SCAX1 · spinocerebellar ataxia, X-linked 1 · spinocerebellar ataxia, X-linked 1, X-linked recessive · spinocerebellar ataxia, X-linked type 1

Data availability: 37 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 › X-linked disease › X-linked cerebellar ataxia › X-linked progressive cerebellar ataxia

Related subtypes (8): ataxia - deafness - intellectual disability syndrome, fragile X-associated tremor/ataxia syndrome, X-linked non progressive cerebellar ataxia, X-linked sideroblastic anemia with ataxia, X-linked spinocerebellar ataxia type 3, X-linked spinocerebellar ataxia type 4, spinocerebellar ataxia, X-linked 2, X-linked intellectual disability-ataxia-apraxia syndrome

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

37 retrieved; paginated sample, class counts are floors:

18 uncertain significance, 13 benign, 3 likely pathogenic, 2 likely benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1098287	NM_001001344.3(ATP2B3):c.2770A>G (p.Thr924Ala)	ATP2B3	Likely pathogenic	criteria provided, single submitter
242886	NM_001001344.3(ATP2B3):c.3594G>T (p.Lys1198Asn)	ATP2B3	Likely pathogenic	criteria provided, single submitter
39839	NM_001001344.3(ATP2B3):c.3320G>A (p.Gly1107Asp)	ATP2B3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1028404	NM_001001344.3(ATP2B3):c.1976C>T (p.Pro659Leu)	ATP2B3	Uncertain significance	criteria provided, single submitter
1028405	NM_001001344.3(ATP2B3):c.3316C>T (p.Arg1106Trp)	ATP2B3	Uncertain significance	criteria provided, single submitter
1033156	NM_001001344.3(ATP2B3):c.2158G>C (p.Gly720Arg)	ATP2B3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1048094	NM_001001344.3(ATP2B3):c.2086C>T (p.Arg696Cys)	ATP2B3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1333741	NM_001001344.3(ATP2B3):c.1445G>A (p.Arg482His)	ATP2B3	Uncertain significance	criteria provided, single submitter
1333742	NM_001001344.3(ATP2B3):c.2357G>A (p.Arg786Gln)	ATP2B3	Uncertain significance	criteria provided, single submitter
1705366	NM_001001344.3(ATP2B3):c.2541C>G (p.Asp847Glu)	ATP2B3	Uncertain significance	criteria provided, single submitter
2373738	NM_001001344.3(ATP2B3):c.472G>T (p.Ala158Ser)	ATP2B3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2441939	NM_001001344.3(ATP2B3):c.4G>A (p.Gly2Ser)	ATP2B3	Uncertain significance	criteria provided, single submitter
3064192	NM_001001344.3(ATP2B3):c.971A>G (p.Asp324Gly)	ATP2B3	Uncertain significance	criteria provided, single submitter
3066350	NM_001001344.3(ATP2B3):c.3547A>T (p.Asn1183Tyr)	ATP2B3	Uncertain significance	criteria provided, single submitter
3256651	NM_001001344.3(ATP2B3):c.2419G>A (p.Val807Met)	ATP2B3	Uncertain significance	criteria provided, single submitter
3391022	NM_001001344.3(ATP2B3):c.3241G>C (p.Glu1081Gln)	ATP2B3	Uncertain significance	criteria provided, single submitter
4533355	NM_001001344.3(ATP2B3):c.1399G>A (p.Ala467Thr)	ATP2B3	Uncertain significance	criteria provided, single submitter
498692	NM_001001344.3(ATP2B3):c.3626C>A (p.Pro1209His)	ATP2B3	Uncertain significance	criteria provided, multiple submitters, no conflicts
560961	NM_001001344.3(ATP2B3):c.3313T>A (p.Phe1105Ile)	ATP2B3	Uncertain significance	criteria provided, single submitter
638365	NM_001001344.3(ATP2B3):c.3284G>A (p.Arg1095Gln)	ATP2B3	Uncertain significance	criteria provided, single submitter
807831	NM_001001344.3(ATP2B3):c.2105G>A (p.Arg702His)	ATP2B3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1192342	NM_001001344.3(ATP2B3):c.664+41G>A	ATP2B3	Benign	criteria provided, multiple submitters, no conflicts
1192343	NM_001001344.3(ATP2B3):c.665-116A>G	ATP2B3	Benign	criteria provided, multiple submitters, no conflicts
1192344	NM_001001344.3(ATP2B3):c.1824-58G>A	ATP2B3	Benign	criteria provided, multiple submitters, no conflicts
1192372	NM_001001344.3(ATP2B3):c.2839+33A>G	ATP2B3	Benign	criteria provided, multiple submitters, no conflicts
1192373	NM_001001344.3(ATP2B3):c.3160-57A>G	ATP2B3	Benign	criteria provided, multiple submitters, no conflicts
3338255	NM_001001344.3(ATP2B3):c.3115C>T (p.Leu1039Phe)	ATP2B3	Benign	criteria provided, single submitter
4526382	NM_001001344.3(ATP2B3):c.3357A>C (p.Lys1119Asn)	ATP2B3	Likely benign	criteria provided, single submitter
4812943	NM_001001344.3(ATP2B3):c.1646G>C (p.Gly549Ala)	ATP2B3	Likely benign	criteria provided, single submitter
518408	NM_001001344.3(ATP2B3):c.790+17G>C	ATP2B3	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 3 · 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
ATP2B3	Strong	X-linked	X-linked progressive cerebellar ataxia	5
GJB1	Strong	X-linked	Charcot-Marie-Tooth disease X-linked dominant 1	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATP2B3	Orphanet:314978	X-linked non progressive cerebellar ataxia
GJB1	Orphanet:101075	X-linked Charcot-Marie-Tooth disease type 1
GJB1	Orphanet:1175	X-linked progressive cerebellar ataxia

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
ATP2B3	HGNC:816	ENSG00000067842	Q16720	Plasma membrane calcium-transporting ATPase 3	gencc,clinvar
GJB1	HGNC:4283	ENSG00000169562	P08034	Gap junction beta-1 protein	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATP2B3	Plasma membrane calcium-transporting ATPase 3	ATP-driven Ca(2+) ion pump involved in the maintenance of basal intracellular Ca(2+) levels at the presynaptic terminals.
GJB1	Gap junction beta-1 protein	One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.

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)
ATP2B3	Transcription factor	no	7.2.2.10	P_typ_ATPase, ATPase_P-typ_cation-transptr_N, ATPase_P-typ_cation-transptr_C
GJB1	Other/Unknown	no		Connexin, Connexin32, Connexin_N

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	1
endothelial cell	1
middle temporal gyrus	1
C1 segment of cervical spinal cord	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATP2B3	145	tissue_specific	yes	endothelial cell, Brodmann (1909) area 23, middle temporal gyrus
GJB1	207	broad	marker	right lobe of liver, C1 segment of cervical spinal cord, liver

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP2B3	3,203
GJB1	1,494

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GJB1	P08034	15

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ATP2B3	Q16720	74.57

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. Enrichment computed across 2 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
Oligomerization of connexins into connexons	1	1903.3×	0.004	GJB1
Transport of connexins along the secretory pathway	1	1903.3×	0.004	GJB1
Reduction of cytosolic Ca++ levels	1	475.8×	0.010	ATP2B3
Platelet calcium homeostasis	1	356.9×	0.010	ATP2B3
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	184.2×	0.014	GJB1
Gap junction assembly	1	146.4×	0.014	GJB1
Platelet homeostasis	1	139.3×	0.014	ATP2B3
Ion transport by P-type ATPases	1	103.8×	0.015	ATP2B3
Ion homeostasis	1	102.0×	0.015	ATP2B3
Cardiac conduction	1	54.4×	0.026	ATP2B3
Ion channel transport	1	48.0×	0.026	ATP2B3
Muscle contraction	1	38.6×	0.030	ATP2B3
Hemostasis	1	18.0×	0.059	ATP2B3
Transport of small molecules	1	12.6×	0.078	ATP2B3

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
calcium ion export across plasma membrane	1	1404.3×	0.003	ATP2B3
gap junction assembly	1	1053.2×	0.003	GJB1
regulation of cardiac conduction	1	421.3×	0.006	ATP2B3
regulation of cytosolic calcium ion concentration	1	191.5×	0.009	ATP2B3
monoatomic ion transmembrane transport	1	104.0×	0.013	ATP2B3
cell-cell signaling	1	34.8×	0.033	GJB1
nervous system development	1	23.0×	0.043	GJB1

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
ATP2B3	0	0
GJB1	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
GJB1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ATP2B3	7.2.2.10	P-type Ca2+ transporter

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	ATP2B3, GJB1

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)
ATP2B3	0	—
GJB1	1	—

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