Dystonia 33

Summary

Dystonia 33 (MONDO:0030513) is a disease with 3 cohort genes.

At a glance

• Cohort genes: 3
• ClinVar variants: 11

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	dystonia 33
Mondo ID	MONDO:0030513
OMIM	619687
DOID	DOID:0060940
UMLS	C5562054
MedGen	1794264
GARD	0025587
Is cancer (heuristic)	no

Also known as: DYT33

Data availability: 11 ClinVar variants · 1 GenCC gene-disease record.

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 › dystonia 33

Related subtypes (23): lymphatic malformation 5, Woodhouse-Sakati syndrome, severe motor and intellectual disabilities-sensorineural deafness-dystonia syndrome, torsion dystonia 7, developmental malformations-deafness-dystonia syndrome, dopa-responsive dystonia due to sepiapterin reductase deficiency, ataxia - oculomotor apraxia type 4, striatonigral degeneration, childhood-onset, dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities, dystonia 28, childhood-onset, isolated dystonia, combined dystonia, dystonia 30, dystonia 31, dystonia 32, dystonia 34, myoclonic, dystonia 35, childhood-onset, familial idiopathic torsion dystonia, dystonia, focal, task-specific, dystonia 37, early-onset, with striatal lesions, dystonia 22, juvenile-onset, dystonia 22, adult-onset, autosomal dominant dopa-responsive dystonia

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

11 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 1 pathogenic/likely pathogenic, 1 likely pathogenic, 1 conflicting classifications of pathogenicity, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1332908	NM_001135651.3(EIF2AK2):c.388G>A (p.Gly130Arg)	EIF2AK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1332910	NM_001135651.3(EIF2AK2):c.388G>C (p.Gly130Arg)	EIF2AK2	Likely pathogenic	criteria provided, single submitter
2184026	NM_001135651.3(EIF2AK2):c.940A>G (p.Lys314Glu)	EIF2AK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3362619	NM_032025.5(EIF2A):c.650G>T (p.Ser217Ile)	EIF2A	Uncertain significance	criteria provided, single submitter
1332909	NM_001135651.3(EIF2AK2):c.95A>C (p.Asn32Thr)	EIF2AK2	Uncertain significance	criteria provided, single submitter
1691705	NM_001135651.3(EIF2AK2):c.413G>C (p.Gly138Ala)	EIF2AK2	Uncertain significance	criteria provided, single submitter
1975850	NM_001135651.3(EIF2AK2):c.1496G>A (p.Arg499Gln)	EIF2AK2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2582388	NM_001135651.3(EIF2AK2):c.950A>G (p.His317Arg)	EIF2AK2	Uncertain significance	criteria provided, single submitter
3065796	NM_001135651.3(EIF2AK2):c.1495C>T (p.Arg499Trp)	EIF2AK2	Uncertain significance	criteria provided, single submitter
3362483	NM_001135651.3(EIF2AK2):c.92C>G (p.Pro31Arg)	EIF2AK2	Uncertain significance	criteria provided, single submitter
3065222	NM_001135651.3(EIF2AK2):c.28T>C (p.Phe10Leu)	EIF2AK2	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 1 · 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
EIF2AK2	Supportive	Autosomal dominant	early-onset generalized limb-onset dystonia	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EIF2AK2	Orphanet:256	Early-onset generalized limb-onset dystonia

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
EIF2AK2	HGNC:9437	ENSG00000055332	P19525	Interferon-induced, double-stranded RNA-activated protein kinase	gencc,clinvar
EIF2A	HGNC:3254	ENSG00000144895	Q9BY44	Eukaryotic translation initiation factor 2A	clinvar
EIF2S1	HGNC:3265	ENSG00000134001	P05198	Eukaryotic translation initiation factor 2 subunit 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EIF2AK2	Interferon-induced, double-stranded RNA-activated protein kinase	IFN-induced dsRNA-dependent serine/threonine-protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) and plays a key role in the innate immune response to viral infection.
EIF2A	Eukaryotic translation initiation factor 2A	Functions in the early steps of protein synthesis of a small number of specific mRNAs.
EIF2S1	Eukaryotic translation initiation factor 2 subunit 1	Member of the eIF2 complex that functions in the early steps of protein synthesis by forming a ternary complex with GTP and initiator tRNA.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 0 · 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
Kinase	1	9.2×	0.230
Scaffold/PPI	1	5.8×	0.230
Enzyme (other)	1	4.0×	0.230

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EIF2AK2	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
EIF2A	Scaffold/PPI	no		TIF2A, TIF_beta_prop-like, WD40/YVTN_repeat-like_dom_sf
EIF2S1	Enzyme (other)	yes	3.6.5.3	S1_domain, TIF_2_asu, NA-bd_OB-fold

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
buccal mucosa cell	1
choroid plexus epithelium	1
endometrium epithelium	1
oocyte	1
secondary oocyte	1
tibialis anterior	1
gingival epithelium	1
islet of Langerhans	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EIF2AK2	296	ubiquitous	marker	endometrium epithelium, buccal mucosa cell, choroid plexus epithelium
EIF2A	263	ubiquitous	marker	secondary oocyte, tibialis anterior, oocyte
EIF2S1	301	ubiquitous	marker	islet of Langerhans, monocyte, gingival epithelium

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EIF2S1	5,186
EIF2AK2	4,520
EIF2A	1,752

Intra-cohort edges

A	B	Sources
EIF2A	EIF2AK2	intact, string_interaction
EIF2A	EIF2S1	string_interaction
EIF2AK2	EIF2S1	biogrid_interaction, intact, string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EIF2S1	P05198	33
EIF2AK2	P19525	12
EIF2A	Q9BY44	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. Enrichment computed across 3 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
PKR-mediated signaling	2	141.0×	8e-04	EIF2AK2, EIF2S1
Inhibition of PKR	1	5710.0×	0.001	EIF2AK2
Recycling of eIF2:GDP	1	634.4×	0.007	EIF2S1
Cellular response to mitochondrial stress	1	571.0×	0.007	EIF2S1
SUMOylation of immune response proteins	1	475.8×	0.007	EIF2AK2
PERK regulates gene expression	1	407.9×	0.007	EIF2S1
Response of EIF2AK1 (HRI) to heme deficiency	1	356.9×	0.007	EIF2S1
Evasion by RSV of host interferon responses	1	163.1×	0.013	EIF2AK2
Formation of the ternary complex, and subsequently, the 43S complex	1	107.7×	0.016	EIF2S1
Translation initiation complex formation	1	95.2×	0.016	EIF2S1
Ribosomal scanning and start codon recognition	1	95.2×	0.016	EIF2S1
Interferon alpha/beta signaling	1	76.1×	0.017	EIF2AK2
ISG15 antiviral mechanism	1	75.1×	0.017	EIF2AK2
ABC-family protein mediated transport	1	60.7×	0.020	EIF2S1
Response of EIF2AK4 (GCN2) to amino acid deficiency	1	55.4×	0.020	EIF2S1
L13a-mediated translational silencing of Ceruloplasmin expression	1	50.5×	0.020	EIF2S1
GTP hydrolysis and joining of the 60S ribosomal subunit	1	50.1×	0.020	EIF2S1

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
translational initiation	2	239.0×	7e-04	EIF2A, EIF2S1
cellular response to amino acid starvation	2	212.0×	7e-04	EIF2AK2, EIF2S1
regulation of NLRP3 inflammasome complex assembly	1	2808.7×	0.004	EIF2AK2
regulation of translation in response to endoplasmic reticulum stress	1	1872.4×	0.004	EIF2S1
regulation of hematopoietic stem cell proliferation	1	1872.4×	0.004	EIF2AK2
regulation of translational initiation in response to stress	1	1404.3×	0.004	EIF2S1
response to manganese-induced endoplasmic reticulum stress	1	1404.3×	0.004	EIF2S1
response to amino acid starvation	1	1404.3×	0.004	EIF2A
negative regulation of translational initiation in response to stress	1	1123.5×	0.004	EIF2S1
regulation of hematopoietic progenitor cell differentiation	1	1123.5×	0.004	EIF2AK2
response to kainic acid	1	802.5×	0.005	EIF2S1
positive regulation of type B pancreatic cell apoptotic process	1	802.5×	0.005	EIF2S1
HRI-mediated signaling	1	702.2×	0.005	EIF2S1
SREBP signaling pathway	1	624.1×	0.005	EIF2A
PERK-mediated unfolded protein response	1	624.1×	0.005	EIF2S1
ribosome assembly	1	624.1×	0.005	EIF2A
response to interferon-alpha	1	561.7×	0.005	EIF2AK2
negative regulation of osteoblast proliferation	1	510.7×	0.005	EIF2AK2
regulation of hematopoietic stem cell differentiation	1	510.7×	0.005	EIF2AK2
positive regulation of signal transduction	1	432.1×	0.005	EIF2A
positive regulation of stress-activated MAPK cascade	1	267.5×	0.008	EIF2AK2
negative regulation of intrinsic apoptotic signaling pathway	1	255.3×	0.008	EIF2A
stress granule assembly	1	200.6×	0.010	EIF2S1
regulation of translational initiation	1	156.0×	0.013	EIF2AK2
positive regulation of chemokine production	1	124.8×	0.014	EIF2AK2
negative regulation of viral genome replication	1	124.8×	0.014	EIF2AK2
intrinsic apoptotic signaling pathway	1	119.5×	0.015	EIF2A
cellular response to heat	1	114.6×	0.015	EIF2S1
mitophagy	1	106.0×	0.015	EIF2S1
endoplasmic reticulum unfolded protein response	1	98.5×	0.015	EIF2AK2

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
EIF2AK2	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EIF2AK2	19	4
EIF2A	0	0
EIF2S1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	EIF2AK2
AXITINIB	4	EIF2AK2
PAZOPANIB	4	EIF2AK2
SUNITINIB	4	EIF2AK2
ERLOTINIB	4	EIF2AK2
CRIZOTINIB	4	EIF2AK2
MIDOSTAURIN	4	EIF2AK2
ALVOCIDIB	3	EIF2AK2
DOVITINIB	3	EIF2AK2
LESTAURTINIB	3	EIF2AK2
SU-014813	2	EIF2AK2
R-406	2	EIF2AK2
BI-2536	2	EIF2AK2
RAF-265	2	EIF2AK2
PELITINIB	2	EIF2AK2
KW-2449	1	EIF2AK2
SU-9516	1	EIF2AK2
GSK-690693	1	EIF2AK2
AST-487	1	EIF2AK2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
EIF2AK2	213	Binding:213
EIF2S1	21	Binding:21
EIF2A	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
EIF2S1	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
EIF2AK2	213

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

19 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)
FEDRATINIB	4	EIF2AK2
AXITINIB	4	EIF2AK2
PAZOPANIB	4	EIF2AK2
SUNITINIB	4	EIF2AK2
ERLOTINIB	4	EIF2AK2
CRIZOTINIB	4	EIF2AK2
MIDOSTAURIN	4	EIF2AK2
ALVOCIDIB	3	EIF2AK2
DOVITINIB	3	EIF2AK2
LESTAURTINIB	3	EIF2AK2
SU-014813	2	EIF2AK2
R-406	2	EIF2AK2
BI-2536	2	EIF2AK2
RAF-265	2	EIF2AK2
PELITINIB	2	EIF2AK2
KW-2449	1	EIF2AK2
SU-9516	1	EIF2AK2
GSK-690693	1	EIF2AK2
AST-487	1	EIF2AK2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	EIF2AK2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	EIF2S1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	EIF2A

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)
EIF2S1	21	EIF2AK2
EIF2A	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.