Dystonia 12

Summary

Dystonia 12 (MONDO:0007496) is a disease caused by ATP1A3 (GenCC Strong), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ATP1A3 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 1,088
• Phenotypes (HPO): 20
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		100	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

20 HPO clinical features (Orphanet curated; top 20 by frequency):

HPO ID	Term	Frequency
HP:0000338	Hypomimic face	Frequent (30-79%)
HP:0000473	Torticollis	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001300	Parkinsonism	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002066	Gait ataxia	Frequent (30-79%)
HP:0002067	Bradykinesia	Frequent (30-79%)
HP:0002172	Postural instability	Frequent (30-79%)
HP:0002300	Mutism	Frequent (30-79%)
HP:0002307	Drooling	Frequent (30-79%)
HP:0002451	Limb dystonia	Frequent (30-79%)
HP:0012179	Craniofacial dystonia	Frequent (30-79%)
HP:0000712	Emotional lability	Occasional (5-29%)
HP:0000716	Depression	Occasional (5-29%)
HP:0000739	Anxiety	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001272	Cerebellar atrophy	Occasional (5-29%)
HP:0002322	Resting tremor	Occasional (5-29%)
HP:0001290	Generalized hypotonia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	dystonia 12
Mondo ID	MONDO:0007496
MeSH	C538001
OMIM	128235
Orphanet	71517
DOID	DOID:0090056
NCIT	C157577
SNOMED CT	702323008
UMLS	C1868681
MedGen	358384
GARD	0009628
Is cancer (heuristic)	no

Also known as: ATP1A3 dystonic disorder · dystonia 12 · dystonia type 12 · dystonia-12 · dystonic disorder caused by mutation in ATP1A3 · DYT-ATP1A3 · DYT12 · RDP

Data availability: 1,088 ClinVar variants · 4 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › movement disorder › extrapyramidal and movement disease › dystonic disorder › inherited dystonia › combined dystonia › dystonia 12

Related subtypes (9): myoclonus-dystonia syndrome, X-linked dystonia-parkinsonism, dystonia 16, parkinsonism-dystonia, infantile, paroxysmal dystonia, infantile epileptic-dyskinetic encephalopathy, ataxia - telangiectasia variant, combined cervical dystonia, dystonia-aphonia 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

600 retrieved; paginated sample, class counts are floors:

320 likely benign, 175 uncertain significance, 46 pathogenic, 19 conflicting classifications of pathogenicity, 18 likely pathogenic, 9 pathogenic/likely pathogenic, 8 benign, 3 benign/likely benign, 2 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1039236	NM_152296.5(ATP1A3):c.2144T>C (p.Leu715Pro)	ATP1A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069208	NM_152296.5(ATP1A3):c.1072G>A (p.Gly358Ser)	ATP1A3	Pathogenic	criteria provided, single submitter
1075560	NM_152296.5(ATP1A3):c.1073G>A (p.Gly358Asp)	ATP1A3	Pathogenic	criteria provided, multiple submitters, no conflicts
1187017	NM_152296.5(ATP1A3):c.2677G>A (p.Gly893Arg)	ATP1A3	Pathogenic	criteria provided, multiple submitters, no conflicts
1264343	NM_152296.5(ATP1A3):c.1088T>C (p.Ile363Thr)	ATP1A3	Pathogenic	criteria provided, single submitter
12909	NM_152296.5(ATP1A3):c.1838C>T (p.Thr613Met)	ATP1A3	Pathogenic	criteria provided, multiple submitters, no conflicts
12910	NM_152296.5(ATP1A3):c.821T>C (p.Ile274Thr)	ATP1A3	Pathogenic	no assertion criteria provided
12911	NM_152296.5(ATP1A3):c.829G>A (p.Glu277Lys)	ATP1A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12913	NM_152296.5(ATP1A3):c.2338T>C (p.Phe780Leu)	ATP1A3	Pathogenic	no assertion criteria provided
12914	NM_152296.5(ATP1A3):c.2401G>T (p.Asp801Tyr)	ATP1A3	Pathogenic	criteria provided, single submitter
12915	NM_152296.5(ATP1A3):c.2767G>A (p.Asp923Asn)	ATP1A3	Pathogenic	criteria provided, multiple submitters, no conflicts
1321206	NM_152296.5(ATP1A3):c.1081T>C (p.Ser361Pro)	ATP1A3	Pathogenic	criteria provided, single submitter
1357866	NM_152296.5(ATP1A3):c.1429A>T (p.Lys477Ter)	ATP1A3	Pathogenic	criteria provided, single submitter
139579	NM_152296.5(ATP1A3):c.2839G>C (p.Gly947Arg)	ATP1A3	Pathogenic	criteria provided, single submitter
1414742	NM_152296.5(ATP1A3):c.2652dup (p.Val885fs)	ATP1A3	Pathogenic	criteria provided, single submitter
1432131	NM_152296.5(ATP1A3):c.2673_2678del (p.Ser891_Gly893delinsArg)	ATP1A3	Pathogenic	criteria provided, single submitter
156238	NM_152296.5(ATP1A3):c.2452G>A (p.Glu818Lys)	ATP1A3	Pathogenic	criteria provided, multiple submitters, no conflicts
161121	NM_152296.5(ATP1A3):c.410C>A (p.Ser137Tyr)	ATP1A3	Pathogenic	criteria provided, single submitter
161122	NM_152296.5(ATP1A3):c.410C>T (p.Ser137Phe)	ATP1A3	Pathogenic	criteria provided, multiple submitters, no conflicts
161124	NM_152296.5(ATP1A3):c.821T>A (p.Ile274Asn)	ATP1A3	Pathogenic	criteria provided, single submitter
161129	NM_152296.5(ATP1A3):c.1072G>T (p.Gly358Cys)	ATP1A3	Pathogenic	criteria provided, single submitter
161131	NM_152296.5(ATP1A3):c.2264G>C (p.Gly755Ala)	ATP1A3	Pathogenic	criteria provided, single submitter
161133	NM_152296.5(ATP1A3):c.2263G>T (p.Gly755Cys)	ATP1A3	Pathogenic	criteria provided, multiple submitters, no conflicts
161134	NM_152296.5(ATP1A3):c.2267G>A (p.Arg756His)	ATP1A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
161138	NM_152296.5(ATP1A3):c.2318A>G (p.Asn773Ser)	ATP1A3	Pathogenic	criteria provided, multiple submitters, no conflicts
161141	NM_152296.5(ATP1A3):c.2415C>G (p.Asp805Glu)	ATP1A3	Pathogenic	criteria provided, single submitter
161145	NM_152296.5(ATP1A3):c.2542+1G>A	ATP1A3	Pathogenic	criteria provided, single submitter
161146	NM_152296.5(ATP1A3):c.2600G>A (p.Gly867Asp)	ATP1A3	Pathogenic	criteria provided, multiple submitters, no conflicts
161147	NM_152296.5(ATP1A3):c.2752GTC[1] (p.Val919del)	ATP1A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
161148	NM_152296.5(ATP1A3):c.2767G>T (p.Asp923Tyr)	ATP1A3	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 20 · Orphanet: 12 · 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
ATP1A3	Strong	Autosomal dominant	dystonia 12	20

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATP1A3	Orphanet:1171	Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome
ATP1A3	Orphanet:2131	Alternating hemiplegia of childhood
ATP1A3	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
ATP1A3	Orphanet:71517	Rapid-onset dystonia-parkinsonism
SCN2A	Orphanet:140927	Self-limited neonatal-infantile epilepsy
SCN2A	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
SCN2A	Orphanet:2131	Alternating hemiplegia of childhood
SCN2A	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
SCN2A	Orphanet:306	Self-limited infantile epilepsy
SCN2A	Orphanet:33069	Dravet syndrome
SCN2A	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN2A	Orphanet:697160	Infantile epileptic spasms syndrome

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
ATP1A3	HGNC:801	ENSG00000105409	P13637	Sodium/potassium-transporting ATPase subunit alpha-3	gencc,clinvar
SCN2A	HGNC:10588	ENSG00000136531	Q99250	Sodium channel protein type 2 subunit alpha	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATP1A3	Sodium/potassium-transporting ATPase subunit alpha-3	This is the catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane.
SCN2A	Sodium channel protein type 2 subunit alpha	Mediates the voltage-dependent sodium ion permeability of excitable membranes.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

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	55.8×	0.036
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATP1A3	Transcription factor	no		P_typ_ATPase, ATPase_P-typ_cation-transptr_N, P-type_ATPase_IIC
SCN2A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom

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
cortical plate	1
primary visual cortex	1
superior frontal gyrus	1
Brodmann (1909) area 23	1
cerebellar vermis	1
middle temporal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATP1A3	129	broad	marker	superior frontal gyrus, primary visual cortex, cortical plate
SCN2A	187	broad	marker	middle temporal gyrus, Brodmann (1909) area 23, cerebellar vermis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP1A3	3,876
SCN2A	2,810

Intra-cohort edges

A	B	Sources
ATP1A3	SCN2A	biogrid_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATP1A3	P13637	5
SCN2A	Q99250	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. 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
Cardiac conduction	2	108.8×	0.002	ATP1A3, SCN2A
Muscle contraction	2	77.2×	0.002	ATP1A3, SCN2A
Interaction between L1 and Ankyrins	1	184.2×	0.024	SCN2A
Phase 0 - rapid depolarisation	1	173.0×	0.024	SCN2A
Sensory perception of taste	1	167.9×	0.024	SCN2A
Sensory perception of sweet, bitter, and umami (glutamate) taste	1	139.3×	0.024	SCN2A
Ion transport by P-type ATPases	1	103.8×	0.024	ATP1A3
Ion homeostasis	1	102.0×	0.024	ATP1A3
L1CAM interactions	1	60.1×	0.035	SCN2A
Potential therapeutics for SARS	1	57.1×	0.035	ATP1A3
Ion channel transport	1	48.0×	0.035	ATP1A3
Sensory Perception	1	47.6×	0.035	SCN2A
SARS-CoV Infections	1	27.7×	0.055	ATP1A3
Axon guidance	1	22.6×	0.061	SCN2A
Nervous system development	1	21.5×	0.061	SCN2A
Viral Infection Pathways	1	15.4×	0.080	ATP1A3
Transport of small molecules	1	12.6×	0.088	ATP1A3
Infectious disease	1	12.4×	0.088	ATP1A3
Developmental Biology	1	7.2×	0.141	SCN2A
Disease	1	6.5×	0.147	ATP1A3

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
intrinsic apoptotic signaling pathway in response to osmotic stress	1	4213.0×	0.005	SCN2A
response to glycoside	1	1203.7×	0.005	ATP1A3
cell communication by electrical coupling involved in cardiac conduction	1	702.2×	0.005	ATP1A3
regulation of resting membrane potential	1	648.1×	0.005	ATP1A3
neuron projection maintenance	1	561.7×	0.005	ATP1A3
sodium ion export across plasma membrane	1	526.6×	0.005	ATP1A3
cellular response to steroid hormone stimulus	1	526.6×	0.005	ATP1A3
intracellular potassium ion homeostasis	1	495.6×	0.005	ATP1A3
intracellular sodium ion homeostasis	1	383.0×	0.006	ATP1A3
cardiac muscle cell action potential involved in contraction	1	351.1×	0.006	SCN2A
neuronal action potential	1	240.7×	0.008	SCN2A
cellular response to amyloid-beta	1	195.9×	0.009	ATP1A3
potassium ion import across plasma membrane	1	183.2×	0.009	ATP1A3
proton transmembrane transport	1	156.0×	0.010	ATP1A3
sodium ion transport	1	135.9×	0.010	SCN2A
myelination	1	125.8×	0.010	SCN2A
sodium ion transmembrane transport	1	101.5×	0.012	SCN2A
neuron apoptotic process	1	92.6×	0.012	SCN2A
memory	1	91.6×	0.012	SCN2A
cellular response to hypoxia	1	60.6×	0.017	SCN2A
nervous system development	1	23.0×	0.043	SCN2A

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
ATP1A3	OMEPRAZOLE
SCN2A	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN2A	99	4
ATP1A3	5	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
OMEPRAZOLE	4	ATP1A3
DIGOXIN	4	ATP1A3
DIGITOXIN	4	ATP1A3
LANSOPRAZOLE	4	ATP1A3
BEPRIDIL	4	SCN2A
DIBUCAINE	4	SCN2A
ARTICAINE	4	SCN2A
BUPIVACAINE	4	SCN2A
IMIPRAMINE	4	SCN2A
DROPERIDOL	4	SCN2A
DICYCLOMINE	4	SCN2A
TETRABENAZINE	4	SCN2A
PHENIRAMINE	4	SCN2A
PRILOCAINE	4	SCN2A
PROPOXYCAINE	4	SCN2A
PROPARACAINE	4	SCN2A
HEXYLCAINE	4	SCN2A
PRAMOXINE	4	SCN2A
BENOXINATE	4	SCN2A
QUINIDINE	4	SCN2A
FELODIPINE	4	SCN2A
PHENYTOIN	4	SCN2A
QUININE	4	SCN2A
NISOLDIPINE	4	SCN2A
NIFEDIPINE	4	SCN2A
PRAZOSIN	4	SCN2A
DILTIAZEM	4	SCN2A
PRENYLAMINE	4	SCN2A
COCAINE	4	SCN2A
TRIFLUOPERAZINE	4	SCN2A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SCN2A	203	Binding:172, Functional:20, ADMET:10, Toxicity:1
ATP1A3	45	Binding:45

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SCN2A	203

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

30 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)
OMEPRAZOLE	4	ATP1A3
DIGOXIN	4	ATP1A3
DIGITOXIN	4	ATP1A3
LANSOPRAZOLE	4	ATP1A3
BEPRIDIL	4	SCN2A
DIBUCAINE	4	SCN2A
ARTICAINE	4	SCN2A
BUPIVACAINE	4	SCN2A
IMIPRAMINE	4	SCN2A
DROPERIDOL	4	SCN2A
DICYCLOMINE	4	SCN2A
TETRABENAZINE	4	SCN2A
PHENIRAMINE	4	SCN2A
PRILOCAINE	4	SCN2A
PROPOXYCAINE	4	SCN2A
PROPARACAINE	4	SCN2A
HEXYLCAINE	4	SCN2A
PRAMOXINE	4	SCN2A
BENOXINATE	4	SCN2A
QUINIDINE	4	SCN2A
FELODIPINE	4	SCN2A
PHENYTOIN	4	SCN2A
QUININE	4	SCN2A
NISOLDIPINE	4	SCN2A
NIFEDIPINE	4	SCN2A
PRAZOSIN	4	SCN2A
DILTIAZEM	4	SCN2A
PRENYLAMINE	4	SCN2A
COCAINE	4	SCN2A
TRIFLUOPERAZINE	4	SCN2A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	ATP1A3, SCN2A
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	0

Undrugged target profiles

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

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
NCT03428009	Not specified	RECRUITING	Dystonia Genotype-Phenotype Correlation