autosomal dominant Parkinson disease 8

Summary

autosomal dominant Parkinson disease 8 (MONDO:0011764) is a disease caused by LRRK2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: LRRK2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 1,018

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant Parkinson disease 8
Mondo ID	MONDO:0011764
OMIM	607060
DOID	DOID:0060371
UMLS	C1846862
MedGen	339628
GARD	0018476
Is cancer (heuristic)	no

Also known as: autosomal dominant Parkinson disease 8 · autosomal dominant Parkinson disease type 8 · LRRK2 Parkinson disease · PARK8 · Parkinson disease 8 · Parkinson disease 8, autosomal dominant · Parkinson disease caused by mutation in LRRK2

Data availability: 1,018 ClinVar variants · 3 GenCC gene-disease records · 293 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 8

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

600 retrieved; paginated sample, class counts are floors:

342 uncertain significance, 190 likely benign, 21 benign/likely benign, 20 benign, 16 conflicting classifications of pathogenicity, 5 pathogenic, 2 not provided, 1 pathogenic/likely pathogenic; risk factor, 1 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity; risk factor, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1936	NM_198578.4(LRRK2):c.4321C>G (p.Arg1441Gly)	LRRK2	Pathogenic	criteria provided, multiple submitters, no conflicts
1937	NM_198578.4(LRRK2):c.5096A>G (p.Tyr1699Cys)	LRRK2	Pathogenic	no assertion criteria provided
1938	NM_198578.4(LRRK2):c.4321C>T (p.Arg1441Cys)	LRRK2	Pathogenic	criteria provided, multiple submitters, no conflicts
1939	NM_198578.4(LRRK2):c.3364A>G (p.Ile1122Val)	LRRK2	Pathogenic	no assertion criteria provided
1940	NM_198578.4(LRRK2):c.6055G>A (p.Gly2019Ser)	LRRK2	Pathogenic/Likely pathogenic; risk factor	criteria provided, multiple submitters, no conflicts
1941	NM_198578.4(LRRK2):c.6059T>C (p.Ile2020Thr)	LRRK2	Pathogenic	criteria provided, single submitter
1942	NM_198578.4(LRRK2):c.4322G>A (p.Arg1441His)	LRRK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
225276	NM_198578.4(LRRK2):c.4321C>A (p.Arg1441Ser)	LRRK2	Likely pathogenic	criteria provided, single submitter
1306222	NM_198578.4(LRRK2):c.4943A>G (p.Gln1648Arg)	LRRK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1386227	NM_198578.4(LRRK2):c.3846A>T (p.Arg1282Ser)	LRRK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1392440	NM_198578.4(LRRK2):c.784A>G (p.Met262Val)	LRRK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1420340	NM_198578.4(LRRK2):c.6928A>G (p.Thr2310Ala)	LRRK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1493722	NM_198578.4(LRRK2):c.1324C>T (p.His442Tyr)	LRRK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1535918	NM_198578.4(LRRK2):c.5948+8G>C	LRRK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1755967	NM_198578.4(LRRK2):c.6886G>A (p.Val2296Ile)	LRRK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1943	NM_198578.4(LRRK2):c.7153G>A (p.Gly2385Arg)	LRRK2	Conflicting classifications of pathogenicity; risk factor	criteria provided, conflicting classifications
236286	NM_198578.4(LRRK2):c.856C>G (p.Leu286Val)	LRRK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
236296	NM_198578.4(LRRK2):c.6929C>T (p.Thr2310Met)	LRRK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2608716	NM_198578.4(LRRK2):c.1341G>A (p.Glu447=)	LRRK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2723217	NM_198578.4(LRRK2):c.5173C>A (p.Arg1725=)	LRRK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2970995	NM_198578.4(LRRK2):c.7337G>A (p.Arg2446His)	LRRK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
308615	NM_198578.4(LRRK2):c.1446A>G (p.Ala482=)	LRRK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
308616	NM_198578.4(LRRK2):c.2070+9T>A	LRRK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
308620	NM_198578.4(LRRK2):c.2826T>C (p.His942=)	LRRK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
308625	NM_198578.4(LRRK2):c.3435A>C (p.Ser1145=)	LRRK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1007154	NM_198578.4(LRRK2):c.4468G>A (p.Ala1490Thr)	LRRK2	Uncertain significance	criteria provided, single submitter
1011348	NM_198578.4(LRRK2):c.6589A>G (p.Ser2197Gly)	LRRK2	Uncertain significance	criteria provided, single submitter
1015545	NM_198578.4(LRRK2):c.3901G>A (p.Glu1301Lys)	LRRK2	Uncertain significance	criteria provided, single submitter
1015784	NM_198578.4(LRRK2):c.3184A>C (p.Asn1062His)	LRRK2	Uncertain significance	criteria provided, single submitter
1042541	NM_198578.4(LRRK2):c.605A>G (p.Asn202Ser)	LRRK2	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 6 · 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
LRRK2	Definitive	Autosomal dominant	Parkinson disease	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LRRK2	Orphanet:2828	Young-onset Parkinson disease
LRRK2	Orphanet:411602	Hereditary late-onset Parkinson disease
GDF6	Orphanet:2345	Isolated Klippel-Feil syndrome
GDF6	Orphanet:3237	Multiple synostoses syndrome
GDF6	Orphanet:65	Leber congenital amaurosis
GDF6	Orphanet:98938	Colobomatous microphthalmia

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
LRRK2	HGNC:18618	ENSG00000188906	Q5S007	Leucine-rich repeat serine/threonine-protein kinase 2	gencc,clinvar
GDF6	HGNC:4221	ENSG00000156466	Q6KF10	Growth/differentiation factor 6	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LRRK2	Leucine-rich repeat serine/threonine-protein kinase 2	Serine/threonine-protein kinase which phosphorylates a broad range of proteins involved in multiple processes such as neuronal plasticity, innate immunity, autophagy, and vesicle trafficking.
GDF6	Growth/differentiation factor 6	Growth factor that controls proliferation and cellular differentiation in the retina and bone formation.

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)
LRRK2	Kinase	yes		Prot_kinase_dom, Leu-rich_rpt, Leu-rich_rpt_typical-subtyp
GDF6	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like

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
buccal mucosa cell	1
leukocyte	1
monocyte	1
placenta	1
primordial germ cell in gonad	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LRRK2	220	broad	marker	buccal mucosa cell, monocyte, leukocyte
GDF6	104	broad	marker	placenta, primordial germ cell in gonad, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LRRK2	7,628
GDF6	1,127

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LRRK2	Q5S007	44

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GDF6	Q6KF10	70.88

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
PTK6 promotes HIF1A stabilization	1	1631.4×	0.002	LRRK2
Signaling by PTK6	1	543.8×	0.002	LRRK2
Signaling by Non-Receptor Tyrosine Kinases	1	543.8×	0.002	LRRK2
Signal Transduction	1	10.2×	0.098	LRRK2

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
cell migration involved in metanephros development	1	8426.0×	0.003	GDF6
cellular response to curcumin	1	8426.0×	0.003	LRRK2
Wnt signalosome assembly	1	8426.0×	0.003	LRRK2
regulation of kidney size	1	4213.0×	0.003	LRRK2
negative regulation of late endosome to lysosome transport	1	4213.0×	0.003	LRRK2
obsolete negative regulation of protein processing involved in protein targeting to mitochondrion	1	4213.0×	0.003	LRRK2
retinal cell apoptotic process	1	4213.0×	0.003	GDF6
regulation of neuron maturation	1	2808.7×	0.003	LRRK2
regulation of cAMP/PKA signal transduction	1	2808.7×	0.003	LRRK2
positive regulation of protein autoubiquitination	1	2808.7×	0.003	LRRK2
regulation of synaptic vesicle transport	1	2808.7×	0.003	LRRK2
negative regulation of motile cilium assembly	1	2808.7×	0.003	LRRK2
regulation of branching morphogenesis of a nerve	1	2808.7×	0.003	LRRK2
regulation of dopamine receptor signaling pathway	1	2106.5×	0.003	LRRK2
positive regulation of dopamine receptor signaling pathway	1	2106.5×	0.003	LRRK2
regulation of retrograde transport, endosome to Golgi	1	2106.5×	0.003	LRRK2
regulation of CAMKK-AMPK signaling cascade	1	2106.5×	0.003	LRRK2
tangential migration from the subventricular zone to the olfactory bulb	1	1685.2×	0.003	LRRK2
regulation of cell projection organization	1	1685.2×	0.003	LRRK2
regulation of neuroblast proliferation	1	1685.2×	0.003	LRRK2
regulation of locomotion	1	1404.3×	0.003	LRRK2
regulation of mitochondrial depolarization	1	1404.3×	0.003	LRRK2
positive regulation of synaptic vesicle endocytosis	1	1404.3×	0.003	LRRK2
obsolete negative regulation of protein targeting to mitochondrion	1	1404.3×	0.003	LRRK2
intracellular distribution of mitochondria	1	1203.7×	0.003	LRRK2
cellular response to manganese ion	1	1203.7×	0.003	LRRK2
cellular response to dopamine	1	1203.7×	0.003	LRRK2
obsolete regulation of lysosomal lumen pH	1	1053.2×	0.003	LRRK2
regulation of ER to Golgi vesicle-mediated transport	1	1053.2×	0.003	LRRK2
protein localization to endoplasmic reticulum exit site	1	1053.2×	0.003	LRRK2

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
LRRK2	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LRRK2	42	4
GDF6	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	LRRK2
FEDRATINIB	4	LRRK2
AXITINIB	4	LRRK2
RUXOLITINIB	4	LRRK2
PALBOCICLIB	4	LRRK2
ENTRECTINIB	4	LRRK2
TOFACITINIB CITRATE	4	LRRK2
TOFACITINIB	4	LRRK2
VANDETANIB	4	LRRK2
BOSUTINIB	4	LRRK2
BRIGATINIB	4	LRRK2
NINTEDANIB	4	LRRK2
SUNITINIB	4	LRRK2
ERLOTINIB	4	LRRK2
MIDOSTAURIN	4	LRRK2
DACTOLISIB	3	LRRK2
ADENINE	3	LRRK2
OLVEREMBATINIB	3	LRRK2
CANERTINIB	3	LRRK2
FASUDIL	3	LRRK2
ALVOCIDIB	3	LRRK2
ABIVERTINIB	3	LRRK2
ALISERTIB	3	LRRK2
DOVITINIB	3	LRRK2
LESTAURTINIB	3	LRRK2
RUBOXISTAURIN	3	LRRK2
SU-014813	2	LRRK2
REBASTINIB	2	LRRK2
CENISERTIB	2	LRRK2
ADAVOSERTIB	2	LRRK2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
LRRK2	809	Binding:799, ADMET:7, Functional:3

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
LRRK2	809

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)
PONATINIB	4	LRRK2
FEDRATINIB	4	LRRK2
AXITINIB	4	LRRK2
RUXOLITINIB	4	LRRK2
PALBOCICLIB	4	LRRK2
ENTRECTINIB	4	LRRK2
TOFACITINIB CITRATE	4	LRRK2
TOFACITINIB	4	LRRK2
VANDETANIB	4	LRRK2
BOSUTINIB	4	LRRK2
BRIGATINIB	4	LRRK2
NINTEDANIB	4	LRRK2
SUNITINIB	4	LRRK2
ERLOTINIB	4	LRRK2
MIDOSTAURIN	4	LRRK2
DACTOLISIB	3	LRRK2
ADENINE	3	LRRK2
OLVEREMBATINIB	3	LRRK2
CANERTINIB	3	LRRK2
FASUDIL	3	LRRK2
ALVOCIDIB	3	LRRK2
ABIVERTINIB	3	LRRK2
ALISERTIB	3	LRRK2
DOVITINIB	3	LRRK2
LESTAURTINIB	3	LRRK2
RUBOXISTAURIN	3	LRRK2
SU-014813	2	LRRK2
REBASTINIB	2	LRRK2
CENISERTIB	2	LRRK2
ADAVOSERTIB	2	LRRK2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	LRRK2
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	GDF6

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)
GDF6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.