autosomal dominant Parkinson disease 4

Summary

autosomal dominant Parkinson disease 4 (MONDO:0011562) is a disease caused by SNCA (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: SNCA (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 13

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant Parkinson disease 4
Mondo ID	MONDO:0011562
MeSH	C565324
OMIM	605543
DOID	DOID:0060895
UMLS	C1854182
MedGen	381361
GARD	0018475
Is cancer (heuristic)	no

Also known as: autosomal dominant Parkinson disease 4 · autosomal dominant Parkinson disease type 4 · PARK4 · Parkinson disease 4, autosomal dominant

Data availability: 13 ClinVar variants · 3 GenCC gene-disease records · 57 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 4

Related subtypes (6): autosomal dominant Parkinson disease 1, 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

13 retrieved; paginated sample, class counts are floors:

4 benign/likely benign, 3 conflicting classifications of pathogenicity, 2 pathogenic, 2 uncertain significance, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
14009	GRCh38/hg38 4q22.1(chr4:88504598-90127832)x3	FAM13A	Pathogenic	no assertion criteria provided
14007	NM_000345.4(SNCA):c.157G>A (p.Ala53Thr)	SNCA	Pathogenic	criteria provided, multiple submitters, no conflicts
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
162095	NM_000345.4(SNCA):c.150T>G (p.His50Gln)	SNCA	Uncertain significance	criteria provided, multiple submitters, no conflicts
652694	NM_000345.4(SNCA):c.349C>A (p.Pro117Thr)	SNCA	Uncertain significance	criteria provided, multiple submitters, no conflicts
1657000	NM_000345.4(SNCA):c.391-16A>G	SNCA	Likely benign	criteria provided, multiple submitters, no conflicts
350103	NM_000345.4(SNCA):c.*139T>G	SNCA	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
350104	NM_000345.4(SNCA):c.408C>T (p.Tyr136=)	SNCA	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
350106	NM_000345.4(SNCA):c.243A>G (p.Thr81=)	SNCA	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
904210	NM_000345.4(SNCA):c.121+11C>T	SNCA	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
907545	NM_000345.4(SNCA):c.*77C>A	SNCA	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · 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
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
FAM13A	Orphanet:2032	Idiopathic pulmonary fibrosis

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
FAM13A	HGNC:19367	ENSG00000138640	O94988	Protein FAM13A	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.

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
FAM13A	Other/Unknown	no		RhoGAP_dom, Rho_GTPase_activation_prot, FAM13

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
jejunal mucosa	1
oocyte	1
secondary oocyte	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
FAM13A	293	ubiquitous	marker	secondary oocyte, oocyte, jejunal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SNCA	7,615
FAM13A	830

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SNCA	P37840	232

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FAM13A	O94988	61.00

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. 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
Antimicrobial mechanism of IFN-stimulated genes	1	98.5×	0.044	SNCA
PKR-mediated signaling	1	70.5×	0.044	SNCA
Interferon Signaling	1	60.1×	0.044	SNCA
Amyloid fiber formation	1	51.4×	0.044	SNCA
RHOA GTPase cycle	1	37.3×	0.048	FAM13A
RAC1 GTPase cycle	1	30.5×	0.049	FAM13A
Cytokine Signaling in Immune system	1	20.4×	0.062	SNCA
Immune System	1	6.5×	0.155	SNCA
Metabolism of proteins	1	6.2×	0.155	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×	0.001	SNCA
positive regulation of SNARE complex assembly	1	8426.0×	0.001	SNCA
regulation of acyl-CoA biosynthetic process	1	8426.0×	0.001	SNCA
negative regulation of dopamine uptake involved in synaptic transmission	1	8426.0×	0.001	SNCA
negative regulation of norepinephrine uptake	1	8426.0×	0.001	SNCA
response to desipramine	1	8426.0×	0.001	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
FAM13A	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	FAM13A

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)
FAM13A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.