autosomal dominant Parkinson disease 1

Summary

autosomal dominant Parkinson disease 1 (MONDO:0008200) is a disease caused by SNCA (GenCC Strong), with 2 cohort genes and 1 clinical trial.

At a glance

• Causal gene: SNCA (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 74
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant Parkinson disease 1
Mondo ID	MONDO:0008200
MeSH	C566823
OMIM	168601
DOID	DOID:0060367
UMLS	C1868595
MedGen	357008
GARD	0018474
Is cancer (heuristic)	no

Also known as: autosomal dominant Parkinson disease 1 · autosomal dominant Parkinson disease type 1 · PARK1 · Parkinson disease 1, autosomal dominant

Data availability: 74 ClinVar variants · 1 GenCC gene-disease record · 94 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › basal ganglia disorder › parkinsonian disorder › Parkinson disease › late-onset Parkinson disease › autosomal dominant Parkinson disease 1

Related subtypes (6): autosomal dominant Parkinson disease 4, autosomal dominant Parkinson disease 8, autosomal recessive Parkinson disease 14, Parkinson disease 17, Parkinson disease 21, Parkinson disease 22, autosomal dominant

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

74 retrieved; paginated sample, class counts are floors:

27 uncertain significance, 24 likely benign, 8 pathogenic, 6 conflicting classifications of pathogenicity, 5 benign/likely benign, 1 not provided, 1 likely pathogenic, 1 benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
14011	NC_000004.12:g.(?89724098)(89927969_89934809)dup	LOC129389225	Pathogenic	no assertion criteria provided
805243	NM_004562.3(PRKN):c.2T>C (p.Met1Thr)	PACRG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14007	NM_000345.4(SNCA):c.157G>A (p.Ala53Thr)	SNCA	Pathogenic	criteria provided, multiple submitters, no conflicts
14010	NM_000345.4(SNCA):c.136G>A (p.Glu46Lys)	SNCA	Pathogenic	criteria provided, single submitter
1454898	NC_000004.11:g.(?90647779)(90756818_?)dup	SNCA	Pathogenic	criteria provided, single submitter
3759096	NM_000345.4(SNCA):c.158C>A (p.Ala53Glu)	SNCA	Pathogenic	criteria provided, single submitter
531846	NC_000004.11:g.(?90647315)(90756838_?)dup	SNCA	Pathogenic	criteria provided, single submitter
639372	NC_000004.11:g.(?90647315)(90756828_?)dup	SNCA	Pathogenic	criteria provided, single submitter
97000	NM_000345.4(SNCA):c.152G>A (p.Gly51Asp)	SNCA	Pathogenic	criteria provided, single submitter
14008	NM_000345.4(SNCA):c.88G>C (p.Ala30Pro)	SNCA	Likely pathogenic	criteria provided, single submitter
1393530	NM_000345.4(SNCA):c.158C>T (p.Ala53Val)	SNCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1678622	NM_000345.4(SNCA):c.89C>G (p.Ala30Gly)	SNCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1804058	NM_000345.4(SNCA):c.174G>C (p.Lys58Asn)	SNCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
705925	NM_000345.4(SNCA):c.216G>A (p.Thr72=)	SNCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
871101	NM_000345.4(SNCA):c.44T>C (p.Val15Ala)	SNCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
872747	NM_000345.4(SNCA):c.225A>T (p.Thr75=)	SNCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1003636	NM_000345.4(SNCA):c.100A>G (p.Lys34Glu)	SNCA	Uncertain significance	criteria provided, single submitter
1009952	NM_000345.4(SNCA):c.47T>C (p.Val16Ala)	SNCA	Uncertain significance	criteria provided, single submitter
1020728	NM_000345.4(SNCA):c.*464C>A	SNCA	Uncertain significance	criteria provided, single submitter
1051847	NM_000345.4(SNCA):c.71A>G (p.Gln24Arg)	SNCA	Uncertain significance	criteria provided, single submitter
1372807	NC_000004.11:g.(?90647315)(90756828_?)del	SNCA	Uncertain significance	criteria provided, single submitter
1373474	NM_000345.4(SNCA):c.122-2A>C	SNCA	Uncertain significance	criteria provided, single submitter
1388864	NM_000345.4(SNCA):c.163+6C>A	SNCA	Uncertain significance	criteria provided, single submitter
1472092	NM_000345.4(SNCA):c.391-7A>G	SNCA	Uncertain significance	criteria provided, single submitter
1509118	NM_000345.4(SNCA):c.247G>C (p.Glu83Gln)	SNCA	Uncertain significance	criteria provided, single submitter
1524438	NM_000345.4(SNCA):c.359C>T (p.Pro120Leu)	SNCA	Uncertain significance	criteria provided, single submitter
162095	NM_000345.4(SNCA):c.150T>G (p.His50Gln)	SNCA	Uncertain significance	criteria provided, multiple submitters, no conflicts
1970513	NM_000345.4(SNCA):c.203G>A (p.Gly68Glu)	SNCA	Uncertain significance	criteria provided, single submitter
2045977	NM_000345.4(SNCA):c.367G>A (p.Glu123Lys)	SNCA	Uncertain significance	criteria provided, single submitter
2163003	NM_000345.4(SNCA):c.217G>A (p.Gly73Ser)	SNCA	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · 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
SNCA	Definitive	Autosomal dominant	Parkinson disease	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SNCA	Orphanet:171695	Parkinsonian-pyramidal syndrome
SNCA	Orphanet:2828	Young-onset Parkinson disease
SNCA	Orphanet:411602	Hereditary late-onset Parkinson disease

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
SNCA	HGNC:11138	ENSG00000145335	P37840	Alpha-synuclein	gencc,clinvar
PACRG	HGNC:19152	ENSG00000112530	Q96M98	Parkin coregulated gene protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SNCA	Alpha-synuclein	Neuronal protein that plays several roles in synaptic activity such as regulation of synaptic vesicle trafficking and subsequent neurotransmitter release.
PACRG	Parkin coregulated gene protein	Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SNCA	Other/Unknown	no		Synuclein, Synuclein_alpha
PACRG	Other/Unknown	no		Parkin_co-regulated_protein

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
orbitofrontal cortex	1
pons	1
trabecular bone tissue	1
bronchial epithelial cell	1
epithelium of bronchus	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SNCA	280	ubiquitous	marker	trabecular bone tissue, orbitofrontal cortex, pons
PACRG	197	broad	marker	bronchial epithelial cell, right uterine tube, epithelium of bronchus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SNCA	7,615
PACRG	2,520

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SNCA	P37840	232
PACRG	Q96M98	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Antimicrobial mechanism of IFN-stimulated genes	1	196.9×	0.017	SNCA
PKR-mediated signaling	1	141.0×	0.017	SNCA
Interferon Signaling	1	120.2×	0.017	SNCA
Amyloid fiber formation	1	102.9×	0.017	SNCA
Cytokine Signaling in Immune system	1	40.8×	0.034	SNCA
Immune System	1	13.0×	0.081	SNCA
Metabolism of proteins	1	12.4×	0.081	SNCA

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
neutral lipid metabolic process	1	8426.0×	0.002	SNCA
positive regulation of SNARE complex assembly	1	8426.0×	0.002	SNCA
regulation of acyl-CoA biosynthetic process	1	8426.0×	0.002	SNCA
negative regulation of dopamine uptake involved in synaptic transmission	1	8426.0×	0.002	SNCA
negative regulation of norepinephrine uptake	1	8426.0×	0.002	SNCA
response to desipramine	1	8426.0×	0.002	SNCA
regulation of glutamate secretion	1	4213.0×	0.002	SNCA
regulation of norepinephrine uptake	1	4213.0×	0.002	SNCA
positive regulation of hydrogen peroxide catabolic process	1	4213.0×	0.002	SNCA
regulation of synaptic vesicle recycling	1	4213.0×	0.002	SNCA
negative regulation of dopamine metabolic process	1	2808.7×	0.002	SNCA
negative regulation of serotonin uptake	1	2808.7×	0.002	SNCA
negative regulation of thrombin-activated receptor signaling pathway	1	2808.7×	0.002	SNCA
negative regulation of mitochondrial electron transport, NADH to ubiquinone	1	2808.7×	0.002	SNCA
negative regulation of chaperone-mediated autophagy	1	2808.7×	0.002	SNCA
positive regulation of protein localization to cell periphery	1	1685.2×	0.003	SNCA
regulation of locomotion	1	1404.3×	0.003	SNCA
mitochondrial membrane organization	1	1203.7×	0.003	SNCA
response to iron(II) ion	1	1203.7×	0.003	SNCA
negative regulation of exocytosis	1	1203.7×	0.003	SNCA
positive regulation of inositol phosphate biosynthetic process	1	1203.7×	0.003	SNCA
positive regulation of neurotransmitter secretion	1	936.2×	0.003	SNCA
negative regulation of platelet-derived growth factor receptor signaling pathway	1	936.2×	0.003	SNCA
dopamine biosynthetic process	1	936.2×	0.003	SNCA
mitochondrial ATP synthesis coupled electron transport	1	936.2×	0.003	SNCA
dopamine uptake involved in synaptic transmission	1	936.2×	0.003	SNCA
regulation of reactive oxygen species biosynthetic process	1	936.2×	0.003	SNCA
response to magnesium ion	1	702.2×	0.004	SNCA
SNARE complex assembly	1	702.2×	0.004	SNCA
negative regulation of microtubule polymerization	1	648.1×	0.004	SNCA

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
SNCA	ESTRADIOL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SNCA	31	4
PACRG	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ESTRADIOL	4	SNCA
ESTRONE	4	SNCA
TETRACYCLINE	4	SNCA
PHYTONADIONE	4	SNCA
CEFTRIAXONE	4	SNCA
FLORBETAPIR	4	SNCA
ESTRIOL	4	SNCA
RIFAMPIN	4	SNCA
TRETINOIN	4	SNCA
TESTOSTERONE	4	SNCA
BRILLIANT BLUE G	4	SNCA
BROMOCRIPTINE	4	SNCA
PERGOLIDE	4	SNCA
DOPAMINE	4	SNCA
MENADIONE	4	SNCA
GENTIAN VIOLET	4	SNCA
SELEGILINE	4	SNCA
RETINOL	4	SNCA
CURCUMIN	3	SNCA
MENATETRENONE	3	SNCA
HYPERICIN	3	SNCA
EPIGALOCATECHIN GALLATE	3	SNCA
QUERCETIN	3	SNCA
PARAROSANILINE	2	SNCA
LUTEOLIN	2	SNCA
GALLIC ACID	2	SNCA
EMRUSOLMIN	2	SNCA
MINZASOLMIN	2	SNCA
(-)-EPICATECHIN	2	SNCA
BAICALEIN	2	SNCA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SNCA	459	Binding:458, Functional:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SNCA	459

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)
ESTRADIOL	4	SNCA
ESTRONE	4	SNCA
TETRACYCLINE	4	SNCA
PHYTONADIONE	4	SNCA
CEFTRIAXONE	4	SNCA
FLORBETAPIR	4	SNCA
ESTRIOL	4	SNCA
RIFAMPIN	4	SNCA
TRETINOIN	4	SNCA
TESTOSTERONE	4	SNCA
BRILLIANT BLUE G	4	SNCA
BROMOCRIPTINE	4	SNCA
PERGOLIDE	4	SNCA
DOPAMINE	4	SNCA
MENADIONE	4	SNCA
GENTIAN VIOLET	4	SNCA
SELEGILINE	4	SNCA
RETINOL	4	SNCA
CURCUMIN	3	SNCA
MENATETRENONE	3	SNCA
HYPERICIN	3	SNCA
EPIGALOCATECHIN GALLATE	3	SNCA
QUERCETIN	3	SNCA
PARAROSANILINE	2	SNCA
LUTEOLIN	2	SNCA
GALLIC ACID	2	SNCA
EMRUSOLMIN	2	SNCA
MINZASOLMIN	2	SNCA
(-)-EPICATECHIN	2	SNCA
BAICALEIN	2	SNCA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SNCA
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	1	PACRG

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PACRG	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
NCT04084509	Not specified	WITHDRAWN	Molecular and Functional Imaging in SNCA, Parkin and PINK1