autosomal recessive early-onset Parkinson disease 6

Summary

autosomal recessive early-onset Parkinson disease 6 (MONDO:0011613) is a disease caused by PINK1 (GenCC Definitive), with 6 cohort genes.

At a glance

• Causal gene: PINK1 (GenCC Definitive)
• Cohort genes: 6
• ClinVar variants: 357

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive early-onset Parkinson disease 6
Mondo ID	MONDO:0011613
MeSH	C565276
OMIM	605909
DOID	DOID:0060369
UMLS	C1853833
MedGen	342982
GARD	0018605
Is cancer (heuristic)	no

Also known as: autosomal recessive early-onset Parkinson disease 6 · autosomal recessive early-onset Parkinson disease type 6 · PARK6 · Parkinson disease 6, autosomal recessive early-onset · Parkinson disease caused by mutation in PINK1 · PINK1 Parkinson disease

Data availability: 357 ClinVar variants · 4 GenCC gene-disease records.

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 › young-onset Parkinson disease › autosomal recessive early-onset Parkinson disease 6

Related subtypes (8): juvenile-onset Parkinson disease, Parkinson disease 12, autosomal recessive juvenile Parkinson disease 2, Parkinson disease 3, autosomal dominant, autosomal recessive early-onset Parkinson disease 7, Parkinson disease 10, early-onset Parkinson disease 20, autosomal recessive early-onset Parkinson disease 23

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

357 retrieved; paginated sample, class counts are floors:

150 uncertain significance, 100 likely benign, 31 pathogenic, 30 conflicting classifications of pathogenicity, 14 likely pathogenic, 14 benign, 12 benign/likely benign, 5 pathogenic/likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
429877	NM_032409.3(PINK1):c.502G>C (p.Ala168Pro)	MIR6084	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074575	NC_000001.10:g.(?20972043)(20972226_?)del	PINK1	Pathogenic	criteria provided, single submitter
1398596	NM_032409.3(PINK1):c.666G>A (p.Trp222Ter)	PINK1	Pathogenic	criteria provided, single submitter
1399771	NM_032409.3(PINK1):c.1329del (p.Tyr444fs)	PINK1	Pathogenic	criteria provided, single submitter
1454290	NM_032409.3(PINK1):c.85_106del (p.Tyr29fs)	PINK1	Pathogenic	criteria provided, single submitter
189240	NM_032409.3(PINK1):c.620del (p.Arg207fs)	PINK1	Pathogenic	criteria provided, single submitter
2020503	NM_032409.3(PINK1):c.1600C>T (p.Gln534Ter)	PINK1	Pathogenic	criteria provided, single submitter
2042776	NM_032409.3(PINK1):c.1501C>T (p.Arg501Ter)	PINK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2043496	NM_032409.3(PINK1):c.710del (p.Met237fs)	PINK1	Pathogenic	criteria provided, single submitter
2404	NM_032409.3(PINK1):c.926G>A (p.Gly309Asp)	PINK1	Pathogenic	no assertion criteria provided
2405	NM_032409.3(PINK1):c.813C>A (p.His271Gln)	PINK1	Pathogenic	no assertion criteria provided
2406	NM_032409.3(PINK1):c.1311G>A (p.Trp437Ter)	PINK1	Pathogenic	no assertion criteria provided
2407	NM_032409.3(PINK1):c.736C>T (p.Arg246Ter)	PINK1	Pathogenic	criteria provided, single submitter
2408	NM_032409.3(PINK1):c.1040T>C (p.Leu347Pro)	PINK1	Pathogenic	criteria provided, multiple submitters, no conflicts
2409	NM_032409.3(PINK1):c.1570_1573dup (p.Asp525fs)	PINK1	Pathogenic	no assertion criteria provided
2410	NM_032409.3(PINK1):c.1597CAA[3] (p.Gln534dup)	PINK1	Pathogenic	no assertion criteria provided
2412	NC_000001.11:g.20646973_20651575del	PINK1	Pathogenic	no assertion criteria provided
2413	NM_032409.3(PINK1):c.938C>T (p.Thr313Met)	PINK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2414	NM_032409.3(PINK1):c.650C>A (p.Ala217Asp)	PINK1	Pathogenic	no assertion criteria provided
2415	NM_032409.3(PINK1):c.1366C>T (p.Gln456Ter)	PINK1	Pathogenic	criteria provided, multiple submitters, no conflicts
2427034	NC_000001.10:g.(?20972033)(20972236_?)del	PINK1	Pathogenic	criteria provided, single submitter
2854318	NM_032409.3(PINK1):c.1155_1156insTGCCCGCGTCCCTTTCTCCATAAAATTCTTCTTAGTAGCTA (p.Gly386delinsCysProArgProPheLeuHisLysIleLeuLeuSerSerTer)	PINK1	Pathogenic	criteria provided, single submitter
2918812	NM_032409.3(PINK1):c.309del (p.Phe104fs)	PINK1	Pathogenic	criteria provided, single submitter
3242199	NM_032409.3(PINK1):c.268_283del (p.Trp90fs)	PINK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3247755	NC_000001.10:g.(?20960807)(20964608_?)del	PINK1	Pathogenic	criteria provided, single submitter
3660782	NM_032409.3(PINK1):c.1396dup (p.Tyr466fs)	PINK1	Pathogenic	criteria provided, single submitter
431963	NM_032409.3(PINK1):c.1474C>T (p.Arg492Ter)	PINK1	Pathogenic	criteria provided, multiple submitters, no conflicts
4526585	NM_032409.3(PINK1):c.1557del (p.Lys520fs)	PINK1	Pathogenic	criteria provided, single submitter
4753796	NM_032409.3(PINK1):c.619C>T (p.Arg207Ter)	PINK1	Pathogenic	criteria provided, single submitter
581272	NM_032409.3(PINK1):c.599del (p.Ala200fs)	PINK1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 9 · 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
PINK1	Definitive	Autosomal recessive	autosomal recessive early-onset Parkinson disease 6	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PINK1	Orphanet:2828	Young-onset Parkinson disease
MT-ND5	Orphanet:104	Leber hereditary optic neuropathy
MT-ND5	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-ND5	Orphanet:550	MELAS
MT-ND5	Orphanet:551	MERRF
MT-ND6	Orphanet:104	Leber hereditary optic neuropathy
MT-ND6	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-ND6	Orphanet:550	MELAS
MT-ND6	Orphanet:99718	Leber plus disease

Cohort genes → proteins

6 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PINK1	HGNC:14581	ENSG00000158828	Q9BXM7	Serine/threonine-protein kinase PINK1, mitochondrial	gencc,clinvar
PINK1-AS	HGNC:38872	ENSG00000117242		PINK1 antisense RNA	clinvar
AKR7A2	HGNC:389	ENSG00000053371	O43488	Aflatoxin B1 aldehyde reductase member 2	clinvar
MIR6084	HGNC:50235	ENSG00000284005		microRNA 6084	clinvar
MT-ND5	HGNC:7461	ENSG00000198786	P03915	NADH-ubiquinone oxidoreductase chain 5	clinvar
MT-ND6	HGNC:7462	ENSG00000198695	P03923	NADH-ubiquinone oxidoreductase chain 6	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PINK1	Serine/threonine-protein kinase PINK1, mitochondrial	Serine/threonine-protein kinase which acts as a sensor of mitochondrial damage and protects against mitochondrial dysfunction during cellular stress.
AKR7A2	Aflatoxin B1 aldehyde reductase member 2	Catalyzes the NADPH-dependent reduction of succinic semialdehyde to gamma-hydroxybutyrate.
MT-ND5	NADH-ubiquinone oxidoreductase chain 5	Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor.
MT-ND6	NADH-ubiquinone oxidoreductase chain 6	Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 5 · Druggable fraction: 0.17

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	4.6×	0.198
Other/Unknown	5	1.5×	0.198

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PINK1	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
PINK1-AS	Other/Unknown	no
AKR7A2	Other/Unknown	no		NADP_OxRdtase_dom, NAD(P)_OxRdtase_dom_sf, AKR_Detox_Biosynth
MIR6084	Other/Unknown	no
MT-ND5	Other/Unknown	no		Proton_antipo_N, ND/Mrp_TM, NU5C-like
MT-ND6	Other/Unknown	no		NADH_UbQ/plastoQ_OxRdtase_su6, ComplexI_Subunit6

Expression context

Cohort genes with no expression data: 0.

5 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	1
moderate (6-20)	0
broad (>20)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	2
gluteal muscle	1
tendon of biceps brachii	1
skeletal muscle tissue	1
stromal cell of endometrium	1
duodenum	1
mucosa of transverse colon	1
right adrenal gland	1
blood	1
intestine	1
sural nerve	1
heart right ventricle	1
lateral nuclear group of thalamus	1
postcentral gyrus	1
left uterine tube	1
mucosa of stomach	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PINK1	295	ubiquitous	marker	tendon of biceps brachii, gastrocnemius, gluteal muscle
PINK1-AS	135		marker	stromal cell of endometrium, gastrocnemius, skeletal muscle tissue
AKR7A2	283	ubiquitous	marker	mucosa of transverse colon, duodenum, right adrenal gland
MIR6084	3		yes	blood, sural nerve, intestine
MT-ND5	247	ubiquitous	marker	heart right ventricle, postcentral gyrus, lateral nuclear group of thalamus
MT-ND6	134	ubiquitous	marker	mucosa of stomach, left uterine tube, right uterine tube

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PINK1	4,175
MT-ND5	2,825
AKR7A2	1,880
MT-ND6	1,208
PINK1-AS	0
MIR6084	0

Intra-cohort edges

A	B	Sources
MT-ND5	MT-ND6	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MT-ND5	P03915	7
PINK1	Q9BXM7	6
MT-ND6	P03923	5
AKR7A2	O43488	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 6 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Complex I biogenesis	2	82.8×	0.001	MT-ND5, MT-ND6
Mitochondrial protein degradation	2	57.1×	0.001	MT-ND5, MT-ND6
Mitochondrial translation termination	2	54.9×	0.001	MT-ND5, MT-ND6
Respiratory electron transport	2	47.6×	0.001	MT-ND5, MT-ND6
FOXO-mediated transcription of cell death genes	1	178.4×	0.009	PINK1
Aflatoxin activation and detoxification	1	158.6×	0.009	AKR7A2
PINK1-PRKN Mediated Mitophagy	1	89.2×	0.014	PINK1
Biological oxidations	1	32.4×	0.034	AKR7A2
Metabolism	1	2.9×	0.302	AKR7A2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mitochondrial respiratory chain complex I assembly	2	205.5×	0.002	MT-ND5, MT-ND6
mitochondrial electron transport, NADH to ubiquinone	2	179.3×	0.002	MT-ND5, MT-ND6
proton motive force-driven mitochondrial ATP synthesis	2	131.7×	0.002	MT-ND5, MT-ND6
aerobic respiration	2	123.9×	0.002	MT-ND5, MT-ND6
positive regulation of free ubiquitin chain polymerization	1	2106.5×	0.004	PINK1
dopamine secretion	1	1404.3×	0.004	PINK1
positive regulation of synaptic transmission, dopaminergic	1	1404.3×	0.004	PINK1
mitochondrion to lysosome vesicle-mediated transport	1	1404.3×	0.004	PINK1
regulation of synaptic vesicle transport	1	1404.3×	0.004	PINK1
positive regulation of mitochondrial electron transport, NADH to ubiquinone	1	1404.3×	0.004	PINK1
negative regulation of hydrogen peroxide-induced neuron intrinsic apoptotic signaling pathway	1	1404.3×	0.004	PINK1
positive regulation of cristae formation	1	1404.3×	0.004	PINK1
cellular response to hydrogen sulfide	1	1404.3×	0.004	PINK1
electron transport coupled proton transport	1	1053.2×	0.005	MT-ND5
negative regulation of mitochondrial fission	1	842.6×	0.005	PINK1
negative regulation of intrinsic apoptotic signaling pathway in response to hydrogen peroxide	1	842.6×	0.005	PINK1
regulation of hydrogen peroxide metabolic process	1	702.2×	0.005	PINK1
obsolete establishment of protein localization to mitochondrion	1	702.2×	0.005	PINK1
maintenance of protein location in mitochondrion	1	702.2×	0.005	PINK1
regulation of autophagy of mitochondrion	1	702.2×	0.005	PINK1
obsolete regulation of protein targeting to mitochondrion	1	526.6×	0.007	PINK1
negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway	1	526.6×	0.007	PINK1
positive regulation of dopamine secretion	1	421.3×	0.007	PINK1
TORC2 signaling	1	383.0×	0.007	PINK1
daunorubicin metabolic process	1	383.0×	0.007	AKR7A2
negative regulation of mitophagy	1	383.0×	0.007	PINK1
positive regulation of type 2 mitophagy	1	383.0×	0.007	PINK1
cellular response to toxic substance	1	351.1×	0.007	PINK1
aldehyde metabolic process	1	324.1×	0.007	AKR7A2
doxorubicin metabolic process	1	324.1×	0.007	AKR7A2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 6

Druggability breadth: 4 of 6 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PINK1	0	0
PINK1-AS	0	0
AKR7A2	0	0
MIR6084	0	0
MT-ND5	0	0
MT-ND6	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PINK1	24	Binding:24
MT-ND5	4	Binding:4
MT-ND6	4	Binding:4
AKR7A2	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	PINK1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	5	PINK1-AS, AKR7A2, MIR6084, MT-ND5, MT-ND6

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PINK1	24	—
PINK1-AS	0	—
AKR7A2	1	—
MIR6084	0	—
MT-ND5	4	—
MT-ND6	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.