Spinocerebellar ataxia type 19/22

disease

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Also known as SCA19SCA19/22spinocerebellar ataxia 19spinocerebellar ataxia 19 and 22spinocerebellar ataxia type 19

Summary

Spinocerebellar ataxia type 19/22 (MONDO:0011819) is a disease caused by KCND3 (GenCC Strong), with 3 cohort genes and 1 clinical trial.

At a glance

Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
Causal gene: KCND3 (GenCC Strong)
Cohort genes: 3
ClinVar variants: 365
Phenotypes (HPO): 19
Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		12	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

19 HPO clinical features (Orphanet curated; top 19 by frequency):

HPO ID	Term	Frequency
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0001251	Ataxia	Very frequent (80-99%)
HP:0000020	Urinary incontinence	Frequent (30-79%)
HP:0001265	Hyporeflexia	Frequent (30-79%)
HP:0001272	Cerebellar atrophy	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0002070	Limb ataxia	Frequent (30-79%)
HP:0002078	Truncal ataxia	Frequent (30-79%)
HP:0002172	Postural instability	Frequent (30-79%)
HP:0006938	Impaired vibration sensation at ankles	Frequent (30-79%)
HP:0000602	Ophthalmoplegia	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000651	Diplopia	Occasional (5-29%)
HP:0001260	Dysarthria	Occasional (5-29%)
HP:0001350	Slurred speech	Occasional (5-29%)
HP:0002136	Broad-based gait	Occasional (5-29%)
HP:0002370	Poor coordination	Occasional (5-29%)
HP:0002396	Cogwheel rigidity	Occasional (5-29%)
HP:0007772	Impaired smooth pursuit	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spinocerebellar ataxia type 19/22
Mondo ID	MONDO:0011819
MeSH	C537198, C542540
OMIM	607346
Orphanet	98772
DOID	DOID:0050970
NCIT	C163756
SNOMED CT	719251009
UMLS	C1846367
MedGen	339504
GARD	0012365
Is cancer (heuristic)	no

Also known as: SCA19 · SCA19/22 · spinocerebellar ataxia 19 · spinocerebellar ataxia 19 and 22 · spinocerebellar ataxia type 19

Data availability: 365 ClinVar variants · 5 GenCC gene-disease records · 3 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 19/22

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

365 retrieved; paginated sample, class counts are floors:

151 likely benign, 129 uncertain significance, 31 conflicting classifications of pathogenicity, 25 benign/likely benign, 10 benign, 9 likely pathogenic, 8 pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
192255	NM_001378969.1(KCND3):c.1174G>A (p.Val392Ile)	KCND3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
211216	NM_001378969.1(KCND3):c.1034G>T (p.Gly345Val)	KCND3	Pathogenic	criteria provided, single submitter
375399	NM_001378969.1(KCND3):c.1153T>C (p.Ser385Pro)	KCND3	Pathogenic	criteria provided, single submitter
626316	NM_001378969.1(KCND3):c.950G>A (p.Cys317Tyr)	KCND3	Pathogenic	criteria provided, single submitter
626317	NM_001378969.1(KCND3):c.1013T>A (p.Val338Glu)	KCND3	Pathogenic	criteria provided, single submitter
626318	NM_001378969.1(KCND3):c.1123C>T (p.Pro375Ser)	KCND3	Pathogenic	criteria provided, single submitter
626319	NM_001378969.1(KCND3):c.1130C>T (p.Thr377Met)	KCND3	Pathogenic	criteria provided, multiple submitters, no conflicts
66061	NM_001378969.1(KCND3):c.677TCT[1] (p.Phe227del)	KCND3	Pathogenic	criteria provided, multiple submitters, no conflicts
66062	NM_001378969.1(KCND3):c.1054A>C (p.Thr352Pro)	KCND3	Pathogenic	criteria provided, single submitter
995131	NM_001378969.1(KCND3):c.1150G>A (p.Gly384Ser)	KCND3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1699176	NM_001378969.1(KCND3):c.905G>C (p.Arg302Pro)	KCND3	Likely pathogenic	criteria provided, single submitter
1699397	NM_001378969.1(KCND3):c.911C>T (p.Ser304Phe)	KCND3	Likely pathogenic	criteria provided, single submitter
2441718	NM_001378969.1(KCND3):c.1138G>T (p.Gly380Trp)	KCND3	Likely pathogenic	criteria provided, single submitter
2582302	NM_001378969.1(KCND3):c.1129A>G (p.Thr377Ala)	KCND3	Likely pathogenic	criteria provided, single submitter
2627229	NM_001378969.1(KCND3):c.848C>G (p.Ser283Cys)	KCND3	Likely pathogenic	criteria provided, single submitter
2627944	NM_001378969.1(KCND3):c.877_885dup (p.Arg296_Ile297insValPheArg)	KCND3	Likely pathogenic	criteria provided, single submitter
4056391	NM_001378969.1(KCND3):c.905G>A (p.Arg302His)	KCND3	Likely pathogenic	criteria provided, single submitter
66064	NM_001378969.1(KCND3):c.1169G>A (p.Ser390Asn)	KCND3	Likely pathogenic	criteria provided, single submitter
976123	NM_001378969.1(KCND3):c.869G>A (p.Arg290Gln)	KCND3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1027415	NM_001378969.1(KCND3):c.611C>T (p.Thr204Met)	KCND3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1256137	NM_001378969.1(KCND3):c.1314G>A (p.Ser438=)	KCND3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1315586	NM_001378969.1(KCND3):c.983T>G (p.Leu328Arg)	KCND3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1411863	NM_001378969.1(KCND3):c.1648C>T (p.Arg550Cys)	KCND3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1445313	NM_001378969.1(KCND3):c.1702C>T (p.Arg568Cys)	KCND3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1647285	NM_001378969.1(KCND3):c.1492T>C (p.Leu498=)	KCND3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1772163	NM_001378969.1(KCND3):c.1417G>A (p.Glu473Lys)	KCND3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1778229	NM_001378969.1(KCND3):c.1696C>T (p.Arg566Cys)	KCND3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1782617	NM_001378969.1(KCND3):c.1919C>T (p.Thr640Met)	KCND3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1782672	NM_001378969.1(KCND3):c.1920G>A (p.Thr640=)	KCND3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
192253	NM_001378969.1(KCND3):c.1348C>T (p.Leu450Phe)	KCND3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 4 · 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
KCND3	Strong	Autosomal dominant	spinocerebellar ataxia type 19/22	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KCND3	Orphanet:130	Brugada syndrome
KCND3	Orphanet:98772	Spinocerebellar ataxia type 19/22
EEF2	Orphanet:101112	Spinocerebellar ataxia type 26
LAMA4	Orphanet:154	Familial isolated dilated cardiomyopathy

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
KCND3	HGNC:6239	ENSG00000171385	Q9UK17	A-type voltage-gated potassium channel KCND3	gencc,clinvar
EEF2	HGNC:3214	ENSG00000167658	P13639	Elongation factor 2	clinvar
LAMA4	HGNC:6484	ENSG00000112769	Q16363	Laminin subunit alpha-4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KCND3	A-type voltage-gated potassium channel KCND3	Pore-forming (alpha) subunit of voltage-gated A-type potassium channels that mediates transmembrane potassium transport in excitable membranes, in brain and heart.
EEF2	Elongation factor 2	Catalyzes the GTP-dependent ribosomal translocation step during translation elongation.
LAMA4	Laminin subunit alpha-4	Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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	37.2×	0.080
Enzyme (other)	1	4.0×	0.345
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KCND3	Ion channel	yes		BTB/POZ_dom, T1-type_BTB, K_chnl_volt-dep_Kv
EEF2	Enzyme (other)	yes	3.6.5.3	EFG_V-like, T_Tr_GTP-bd_dom, EFTu-like_2
LAMA4	Other/Unknown	no		EGF, Laminin_G, LE_dom

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
cerebellar vermis	1
lateral nuclear group of thalamus	1
substantia nigra pars reticulata	1
cartilage tissue	1
parotid gland	1
stromal cell of endometrium	1
lower esophagus	1
lower esophagus muscularis layer	1
nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KCND3	262	broad	marker	cerebellar vermis, substantia nigra pars reticulata, lateral nuclear group of thalamus
EEF2	301	ubiquitous	marker	parotid gland, cartilage tissue, stromal cell of endometrium
LAMA4	268	ubiquitous	marker	lower esophagus muscularis layer, lower esophagus, nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EEF2	8,196
LAMA4	2,688
KCND3	2,215

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EEF2	P13639	31
KCND3	Q9UK17	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LAMA4	Q16363	73.75

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 23. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Uptake and function of diphtheria toxin	1	634.4×	0.016	EEF2
Phase 1 - inactivation of fast Na+ channels	1	543.8×	0.016	KCND3
Synthesis of diphthamide-EEF2	1	475.8×	0.016	EEF2
Protein methylation	1	223.9×	0.022	EEF2
MET promotes cell motility	1	200.3×	0.022	LAMA4
Attachment of bacteria to epithelial cells	1	165.5×	0.022	LAMA4
Laminin interactions	1	126.9×	0.022	LAMA4
MET activates PTK2 signaling	1	126.9×	0.022	LAMA4
Signaling by MET	1	105.7×	0.022	LAMA4
Formation of the dystrophin-glycoprotein complex (DGC)	1	102.9×	0.022	LAMA4
Voltage gated Potassium channels	1	81.0×	0.025	KCND3
Developmental Lineage of Pancreatic Ductal Cells	1	76.1×	0.025	LAMA4
Non-integrin membrane-ECM interactions	1	51.4×	0.033	LAMA4
ECM proteoglycans	1	50.1×	0.033	LAMA4
Potassium Channels	1	44.8×	0.034	KCND3
Peptide chain elongation	1	42.3×	0.034	EEF2
Cardiac conduction	1	36.2×	0.037	KCND3
Muscle contraction	1	25.7×	0.049	KCND3
Extracellular matrix organization	1	21.0×	0.057	LAMA4
Signaling by Receptor Tyrosine Kinases	1	17.2×	0.065	LAMA4
Neuronal System	1	14.8×	0.073	KCND3
Neutrophil degranulation	1	7.7×	0.130	EEF2
Signal Transduction	1	3.4×	0.267	LAMA4

GO biological processes by enrichment

GO term	Cohort genes	Fold	FDR	Sample cohort genes
translation at postsynapse	1	5617.3×	0.006	EEF2
ventricular cardiac muscle cell membrane repolarization	1	1872.4×	0.009	KCND3
response to folic acid	1	802.5×	0.010	EEF2
cellular response to brain-derived neurotrophic factor stimulus	1	624.1×	0.010	EEF2
membrane repolarization during cardiac muscle cell action potential	1	561.7×	0.010	KCND3
membrane repolarization during ventricular cardiac muscle cell action potential	1	561.7×	0.010	KCND3
membrane repolarization	1	432.1×	0.011	KCND3
translational elongation	1	401.2×	0.011	EEF2
potassium ion export across plasma membrane	1	351.1×	0.011	KCND3
positive regulation of cytoplasmic translation	1	330.4×	0.011	EEF2
glial cell proliferation	1	295.6×	0.011	EEF2
protein tetramerization	1	208.1×	0.014	KCND3
skeletal muscle contraction	1	170.2×	0.015	EEF2
regulation of heart contraction	1	165.2×	0.015	KCND3
response to hydrogen peroxide	1	156.0×	0.015	EEF2
regulation of heart rate by cardiac conduction	1	124.8×	0.016	KCND3
action potential	1	119.5×	0.016	KCND3
skeletal muscle cell differentiation	1	114.6×	0.016	EEF2
negative regulation of cold-induced thermogenesis	1	114.6×	0.016	LAMA4
regulation of embryonic development	1	110.1×	0.016	LAMA4
regulation of cell adhesion	1	102.1×	0.016	LAMA4
response to ischemia	1	83.8×	0.019	EEF2
hematopoietic progenitor cell differentiation	1	79.1×	0.019	EEF2
positive regulation of translation	1	75.9×	0.019	EEF2
muscle contraction	1	69.3×	0.020	KCND3
response to estradiol	1	66.1×	0.020	EEF2
potassium ion transport	1	63.8×	0.020	KCND3
response to endoplasmic reticulum stress	1	55.6×	0.022	EEF2
regulation of cell migration	1	52.5×	0.023	LAMA4
response to ethanol	1	48.9×	0.024	EEF2

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 3 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
KCND3	DULOXETINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCND3	10	4
EEF2	0	0
LAMA4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DULOXETINE	4	KCND3
DARUNAVIR	4	KCND3
DARIFENACIN	4	KCND3
TOLTERODINE	4	KCND3
VARDENAFIL	4	KCND3
PALIPERIDONE	4	KCND3
SOLIFENACIN	4	KCND3
NEBIVOLOL	4	KCND3
SUNITINIB	4	KCND3
DEFERASIROX	4	KCND3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
KCND3	118	Binding:55, Functional:44, ADMET:12, Toxicity:7
EEF2	26	Binding:26

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
EEF2	3.6.5.3	protein-synthesizing GTPase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
KCND3	118

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

10 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.

Compound	Max phase	Cohort target (bioactivity)
DULOXETINE	4	KCND3
DARUNAVIR	4	KCND3
DARIFENACIN	4	KCND3
TOLTERODINE	4	KCND3
VARDENAFIL	4	KCND3
PALIPERIDONE	4	KCND3
SOLIFENACIN	4	KCND3
NEBIVOLOL	4	KCND3
SUNITINIB	4	KCND3
DEFERASIROX	4	KCND3

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	KCND3
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	EEF2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	LAMA4

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)
EEF2	26	—
LAMA4	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

Cohort genes: KCND3, EEF2, LAMA4