Parkinson disease 17

Summary

Parkinson disease 17 (MONDO:0013625) is a disease caused by VPS35 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: VPS35 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 179

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Parkinson disease 17
Mondo ID	MONDO:0013625
OMIM	614203
DOID	DOID:0060897
UMLS	C3280133
MedGen	481763
GARD	0018478
Is cancer (heuristic)	no

Also known as: PARK17 · Parkinson disease 17 · Parkinson disease caused by mutation in VPS35 · Parkinson disease type 17 · VPS35 Parkinson disease

Data availability: 179 ClinVar variants · 4 GenCC gene-disease records · 4 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 › Parkinson disease 17

Related subtypes (6): autosomal dominant Parkinson disease 1, autosomal dominant Parkinson disease 4, autosomal dominant Parkinson disease 8, autosomal recessive Parkinson disease 14, 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

179 retrieved; paginated sample, class counts are floors:

79 uncertain significance, 64 likely benign, 11 conflicting classifications of pathogenicity, 10 benign, 7 not provided, 6 benign/likely benign, 1 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
30196	NM_018206.6(VPS35):c.1858G>A (p.Asp620Asn)	VPS35	Pathogenic	criteria provided, multiple submitters, no conflicts
4278242	NM_018206.6(VPS35):c.2146C>G (p.Gln716Glu)	VPS35	Likely pathogenic	criteria provided, single submitter
1369465	NM_018206.6(VPS35):c.1495C>T (p.Arg499Cys)	VPS35	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
319293	NM_018206.6(VPS35):c.1035G>A (p.Glu345=)	VPS35	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
450710	NM_018206.6(VPS35):c.959C>T (p.Ala320Val)	VPS35	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
487668	NM_018206.6(VPS35):c.151G>A (p.Gly51Ser)	VPS35	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
487669	NM_018206.6(VPS35):c.171G>A (p.Met57Ile)	VPS35	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
487678	NM_018206.6(VPS35):c.2320C>A (p.Leu774Met)	VPS35	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
651640	NM_018206.6(VPS35):c.1420C>G (p.Gln474Glu)	VPS35	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
884711	NM_018206.6(VPS35):c.1809A>T (p.Ala603=)	VPS35	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
884714	NM_018206.6(VPS35):c.1268C>T (p.Pro423Leu)	VPS35	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
885652	NM_018206.6(VPS35):c.648G>A (p.Leu216=)	VPS35	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
887866	NM_018206.6(VPS35):c.2073C>T (p.His691=)	VPS35	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1412147	NC_000016.9:g.(?46694384)(46782105_?)dup	MYLK3	Uncertain significance	criteria provided, single submitter
1021992	NM_018206.6(VPS35):c.1895T>C (p.Ile632Thr)	VPS35	Uncertain significance	criteria provided, single submitter
1050911	NM_018206.6(VPS35):c.13C>T (p.Gln5Ter)	VPS35	Uncertain significance	criteria provided, single submitter
1356064	NM_018206.6(VPS35):c.1142A>G (p.Asn381Ser)	VPS35	Uncertain significance	criteria provided, multiple submitters, no conflicts
1359994	NM_018206.6(VPS35):c.1804G>A (p.Val602Ile)	VPS35	Uncertain significance	criteria provided, single submitter
1375085	NM_018206.6(VPS35):c.977A>T (p.Asp326Val)	VPS35	Uncertain significance	criteria provided, single submitter
1436205	NM_018206.6(VPS35):c.2339G>A (p.Arg780Gln)	VPS35	Uncertain significance	criteria provided, single submitter
1470508	NM_018206.6(VPS35):c.2074G>A (p.Gly692Arg)	VPS35	Uncertain significance	criteria provided, single submitter
1485006	NM_018206.6(VPS35):c.2060G>A (p.Gly687Glu)	VPS35	Uncertain significance	criteria provided, single submitter
1489932	NM_018206.6(VPS35):c.110A>G (p.Asn37Ser)	VPS35	Uncertain significance	criteria provided, multiple submitters, no conflicts
1521803	NM_018206.6(VPS35):c.1262T>A (p.Phe421Tyr)	VPS35	Uncertain significance	criteria provided, multiple submitters, no conflicts
1916253	NM_018206.6(VPS35):c.1541G>A (p.Arg514Gln)	VPS35	Uncertain significance	criteria provided, single submitter
1946516	NM_018206.6(VPS35):c.1538C>A (p.Ala513Glu)	VPS35	Uncertain significance	criteria provided, single submitter
1953047	NM_018206.6(VPS35):c.102+4A>G	VPS35	Uncertain significance	criteria provided, single submitter
1954113	NM_018206.6(VPS35):c.1477C>T (p.Arg493Cys)	VPS35	Uncertain significance	criteria provided, multiple submitters, no conflicts
2005354	NM_018206.6(VPS35):c.340G>A (p.Val114Ile)	VPS35	Uncertain significance	criteria provided, single submitter
2023947	NM_018206.6(VPS35):c.1120G>A (p.Glu374Lys)	VPS35	Uncertain significance	criteria provided, multiple submitters, no conflicts

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
VPS35	Definitive	Autosomal dominant	Parkinson disease	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VPS35	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
VPS35	HGNC:13487	ENSG00000069329	Q96QK1	Vacuolar protein sorting-associated protein 35	gencc,clinvar
MYLK3	HGNC:29826	ENSG00000140795	Q32MK0	Myosin light chain kinase 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VPS35	Vacuolar protein sorting-associated protein 35	Acts as a component of the retromer cargo-selective complex (CSC).
MYLK3	Myosin light chain kinase 3	Kinase that phosphorylates MYL2 in vitro.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · 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
Kinase	1	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VPS35	Other/Unknown	no		Vps35, ARM-type_fold, Vps35_C
MYLK3	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf

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
adrenal tissue	1
corpus callosum	1
ventricular zone	1
cardiac muscle of right atrium	1
heart right ventricle	1
myocardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VPS35	149	ubiquitous	marker	ventricular zone, adrenal tissue, corpus callosum
MYLK3	194	tissue_specific	marker	cardiac muscle of right atrium, myocardium, heart right ventricle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VPS35	3,669
MYLK3	1,564

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VPS35	Q96QK1	13

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MYLK3	Q32MK0	63.26

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
WNT ligand biogenesis and trafficking	1	423.0×	0.002	VPS35

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
neurotransmitter receptor transport, endosome to plasma membrane	1	8426.0×	0.002	VPS35
regulation of terminal button organization	1	8426.0×	0.002	VPS35
positive regulation of locomotion involved in locomotory behavior	1	4213.0×	0.002	VPS35
negative regulation of late endosome to lysosome transport	1	4213.0×	0.002	VPS35
positive regulation of dopamine biosynthetic process	1	4213.0×	0.002	VPS35
negative regulation of protein homooligomerization	1	2808.7×	0.002	VPS35
sarcomerogenesis	1	2808.7×	0.002	MYLK3
mitochondrion to lysosome vesicle-mediated transport	1	2808.7×	0.002	VPS35
negative regulation of protein localization	1	2808.7×	0.002	VPS35
positive regulation of membrane permeability	1	2808.7×	0.002	MYLK3
positive regulation of dopamine receptor signaling pathway	1	2106.5×	0.002	VPS35
positive regulation of Wnt protein secretion	1	2106.5×	0.002	VPS35
regulation of dendritic spine maintenance	1	2106.5×	0.002	VPS35
positive regulation of protein localization to cell periphery	1	1685.2×	0.002	VPS35
positive regulation of tight junction disassembly	1	1685.2×	0.002	MYLK3
negative regulation of lysosomal protein catabolic process	1	1685.2×	0.002	VPS35
voluntary musculoskeletal movement	1	1404.3×	0.002	VPS35
positive regulation of sarcomere organization	1	1404.3×	0.002	MYLK3
regulation of protein metabolic process	1	1053.2×	0.002	VPS35
neurotransmitter receptor transport, endosome to postsynaptic membrane	1	936.2×	0.003	VPS35
transcytosis	1	842.6×	0.003	VPS35
protein localization to endosome	1	766.0×	0.003	VPS35
vesicle-mediated transport in synapse	1	766.0×	0.003	VPS35
mitochondrial fragmentation involved in apoptotic process	1	702.2×	0.003	VPS35
cardiac myofibril assembly	1	648.1×	0.003	MYLK3
regulation of synapse maturation	1	468.1×	0.004	VPS35
regulation of mitochondrion organization	1	421.3×	0.004	VPS35
positive regulation of mitochondrial fission	1	383.0×	0.004	VPS35
regulation of presynapse assembly	1	271.8×	0.006	VPS35
sarcomere organization	1	191.5×	0.008	MYLK3

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · 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
MYLK3	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MYLK3	24	4
VPS35	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	MYLK3
AXITINIB	4	MYLK3
SORAFENIB	4	MYLK3
NINTEDANIB	4	MYLK3
SUNITINIB	4	MYLK3
QUIZARTINIB	4	MYLK3
MIDOSTAURIN	4	MYLK3
DOVITINIB	3	MYLK3
LESTAURTINIB	3	MYLK3
MOLIBRESIB	2	VPS35
FORETINIB	2	MYLK3
CC-401	2	MYLK3
SU-014813	2	MYLK3
SCH-900776	2	MYLK3
BGT-226 FREE BASE	2	MYLK3
AT-9283	2	MYLK3
MILCICLIB	2	MYLK3
TOZASERTIB	2	MYLK3
GSK-1070916	1	MYLK3
KW-2449	1	MYLK3
AZD-7762	1	MYLK3
BMS-387032	1	MYLK3
PF-03758309	1	MYLK3
XL-019	1	MYLK3
PF-03814735	1	MYLK3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MYLK3	95	Binding:95
VPS35	11	Binding:11

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

25 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	MYLK3
AXITINIB	4	MYLK3
SORAFENIB	4	MYLK3
NINTEDANIB	4	MYLK3
SUNITINIB	4	MYLK3
QUIZARTINIB	4	MYLK3
MIDOSTAURIN	4	MYLK3
DOVITINIB	3	MYLK3
LESTAURTINIB	3	MYLK3
MOLIBRESIB	2	VPS35
FORETINIB	2	MYLK3
CC-401	2	MYLK3
SU-014813	2	MYLK3
SCH-900776	2	MYLK3
BGT-226 FREE BASE	2	MYLK3
AT-9283	2	MYLK3
MILCICLIB	2	MYLK3
TOZASERTIB	2	MYLK3
GSK-1070916	1	MYLK3
KW-2449	1	MYLK3
AZD-7762	1	MYLK3
BMS-387032	1	MYLK3
PF-03758309	1	MYLK3
XL-019	1	MYLK3
PF-03814735	1	MYLK3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MYLK3
B	Phased (≥1) drug, not yet approved	1	VPS35
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: 0.