PRKN

Summary

PRKN (parkin RBR E3 ubiquitin protein ligase, HGNC:8607) is a protein-coding gene on chromosome 6q26, encoding E3 ubiquitin-protein ligase parkin (O60260). Functions within a multiprotein E3 ubiquitin ligase complex, catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins.

The precise function of this gene is unknown; however, the encoded protein is a component of a multiprotein E3 ubiquitin ligase complex that mediates the targeting of substrate proteins for proteasomal degradation. Mutations in this gene are known to cause Parkinson disease and autosomal recessive juvenile Parkinson disease. Alternative splicing of this gene produces multiple transcript variants encoding distinct isoforms. Additional splice variants of this gene have been described but currently lack transcript support.

Source: NCBI Gene 5071 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Parkinson disease (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 55
• Clinical variants (ClinVar): 658 total — 107 pathogenic, 42 likely-pathogenic
• Phenotypes (HPO): 63
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_004562

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8607
Approved symbol	PRKN
Name	parkin RBR E3 ubiquitin protein ligase
Location	6q26
Locus type	gene with protein product
Status	Approved
Aliases	PDJ, AR-JP, parkin
Ensembl gene	ENSG00000185345
Ensembl biotype	protein_coding
OMIM	602544
Entrez	5071

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 9 protein_coding_CDS_not_defined, 6 protein_coding, 4 nonsense_mediated_decay, 3 retained_intron

ENST00000338468, ENST00000366892, ENST00000366894, ENST00000366896, ENST00000366897, ENST00000366898, ENST00000479615, ENST00000642604, ENST00000647006, ENST00000648830, ENST00000673871, ENST00000674006, ENST00000674176, ENST00000674224, ENST00000674232, ENST00000674250, ENST00000674259, ENST00000674353, ENST00000674395, ENST00000674436, ENST00000674493, ENST00000674501

RefSeq mRNA: 3 — MANE Select: NM_004562 NM_004562, NM_013987, NM_013988

CCDS: CCDS5281, CCDS5282, CCDS5283

Canonical transcript exons

ENST00000366898 — 12 exons

Exon	Start	End
ENSE00001303667	161569355	161569416
ENSE00001305782	161548854	161549003
ENSE00001306985	161360088	161360205
ENSE00001442933	161347417	161350211
ENSE00002151207	161973302	161973417
ENSE00002169394	161785772	161785908
ENSE00003487128	162262525	162262765
ENSE00003536181	162443310	162443473
ENSE00003536545	161386794	161386877
ENSE00003540557	162054091	162054174
ENSE00003576586	162201131	162201252
ENSE00003845334	162727662	162727766

Expression profiles

Bgee: expression breadth ubiquitous, 174 present calls, max score 88.58.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 3.7870 / max 137.0440, expressed in 1099 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
76580	3.1815	993
76579	0.4343	169
76578	0.1713	59

Top tissues by expression

287 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	88.58	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.17	gold quality
hindlimb stylopod muscle	UBERON:0004252	86.98	gold quality
sperm	CL:0000019	86.82	gold quality
muscle of leg	UBERON:0001383	85.48	gold quality
calcaneal tendon	UBERON:0003701	84.98	gold quality
gastrocnemius	UBERON:0001388	84.92	gold quality
male germ cell	CL:0000015	83.69	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.71	gold quality
prefrontal cortex	UBERON:0000451	79.99	gold quality
right atrium auricular region	UBERON:0006631	79.54	gold quality
left testis	UBERON:0004533	79.23	gold quality
muscle organ	UBERON:0001630	79.18	gold quality
heart left ventricle	UBERON:0002084	78.77	gold quality
adrenal tissue	UBERON:0018303	78.69	gold quality
cardiac atrium	UBERON:0002081	78.30	gold quality
apex of heart	UBERON:0002098	78.25	gold quality
cardiac ventricle	UBERON:0002082	78.06	gold quality
right testis	UBERON:0004534	77.73	gold quality
testis	UBERON:0000473	77.26	gold quality
cortical plate	UBERON:0005343	76.82	gold quality
heart	UBERON:0000948	76.76	gold quality
colonic epithelium	UBERON:0000397	76.67	gold quality
right frontal lobe	UBERON:0002810	76.18	gold quality
tendon	UBERON:0000043	75.33	gold quality
cingulate cortex	UBERON:0003027	75.32	gold quality
anterior cingulate cortex	UBERON:0009835	75.09	gold quality
Brodmann (1909) area 9	UBERON:0013540	74.76	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	74.26	gold quality
ventricular zone	UBERON:0003053	74.13	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-CURD-88	yes	18.95
E-ANND-3	no	5.28

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF4, ATF6, ESR1, GATA2, JUN, LEF1, MYC, MYCN, NFE2L2, NFKB, NR0B1, OSR1, POU5F1, RNF2, RUNX2, SIM2, TP53, YY1

miRNA regulators (miRDB)

82 targeting PRKN, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-6499-3P	99.90	66.38	1212
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-34B-5P	99.78	67.56	1175
HSA-MIR-449C-5P	99.78	67.63	1168
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-2682-5P	99.73	67.38	1055

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• cleavage mediated by caspase in apoptosis (PMID:11839750)
• A missense mutation (Arg275Trp) and a duplication of exon 7 of parkin was discovered in a case of early-onset hemiparkinsonism and ipsilateral body hemiatrophy. (PMID:11889248)
• Results suggest that functional parkin proteins may be required during LB formation. (PMID:12000718)
• mutant Parkin in substantia nigra in juvenile parkinsonism may increase oxidative stress and nitric oxide production (PMID:12034719)
• role in Parkinson disease [review] (PMID:12044248)
• Five novel mutations at the parkin locus are reported here consisting of one missense mutation, three exon duplications, and one exon deletion. (PMID:12114481)
• Data confirmed that recessive loss of Parkin is not only a risk factor for juvenile and early onset Parkinsonism but that Parkin haplo-insufficiency may be sufficient for disease in some cases. (PMID:12116199)
• role in pathogenesis of juvenile autosomal dominant Parkinson disease - review (PMID:12138708)
• CHIP is associated with Parkin, a gene responsible for familial Parkinson’s disease, and enhances its ubiquitin ligase activity. (PMID:12150907)
• Genetic variation at the PARKIN gene (including promoter polymorphisms) does not contribute to the risk of developing Parkinson’s disease in the general population. (PMID:12165399)
• relationship between point mutations on exon 2 of parkin gene and sporadic early-onset Parkinson’s disease (PMID:12362318)
• wild-type Parkin aggregates and forms inclusions, which may have implications for the pathogenesis of sporadic PD (PMID:12364339)
• Functional association of the parkin gene promoter with idiopathic Parkinson’s disease. (PMID:12374768)
• Loss of striatal dopamine transporters was widespread and bilateral in the patient carrying the Park2 mutation, suggesting a different pattern of denervation in these individuals. (PMID:12548339)
• Autosomal recessive early onset parkinsonism is linked to three loci: PARK2, PARK6, and PARK7. (PMID:12548343)
• Parkin protein overexpression attenuates the accumulation of cyclin E in toxin-treated primary neurons, including midbrain dopamine neurons, and protects them from apoptosis. (PMID:12628165)
• This protein binds the Rpn10 subunit of 26S proteasomes through its ubiquitin-like domain. (PMID:12634850)
• coexpression of Parkin degrades Pael-R and suppresses its toxicity; study implicates Parkin as a central player in the molecular pathway of Parkinson’s disease (PMID:12670421)
• Point mutation in parkin gene contributes partly to the development of early-onset Parkinson’s disease in Chinese population. (PMID:12673578)
• role for parkin in maintaining dopaminergic neuronal integrity and strengthen the link between autosomal recessive juvenile-onset form of Parkinson’s disease and the more common sporadic form of Parkinson’s disease (review) (PMID:12691660)
• Caspases responsible for parkin cleavage were identified by several experimental paradigms exploring the anti-Fas induced pathway and tnf-alpha pathway. (PMID:12692130)
• This gene, implicated in autosomal recessive juvenile parkinsonism, is a candidate tumor suppressor gene on chromosome 6q25-q27 in breasssssst asnd ovarian cancers. (PMID:12719539)
• parkinsonism due to mutations in the parkin gene is extremely rare in the US population when the disease begins over the age of 30. (PMID:12781599)
• The identification of pathogenic mutations in the three genes alpha-synuclein, parkin, and UCHL1 has elucidated the ubiquitin proteasome system (UPS) and its potential role as a causal pathway in Parkinson’s disease (PD). (PMID:12784265)
• We report a novel heterozygous 40 base pair deletion in exon 3 of the parkin gene that increases the susceptibility of carriers to develop parkinsonism/dystonia and manifests variability in regard to age of onset and phenotype in a single family. (PMID:12815654)
• patients with a single parkin mutation had significantly later and more asymmetrical onset and more frequent levodopa-induced fluctuations and dystonia than patients with two mutations (PMID:12891670)
• parkin interacts with and ubiquitinates synaptotagmin XI (PMID:12925569)
• brain parkin expression is age and species specific (PMID:12972409)
• C-terminal truncations impede parkin folding and reveal a new mechanism for inactivation of parkin. (PMID:12972428)
• RING finger 1 mutations in PARKN produce altered localization of the proteins. (PMID:14519684)
• analysis of Parkin protein expression with antibodies revealed that most of the ovarian cancer cell lines and primary tumors had diminished or absent Parkin expression and it is suggested it may be a tumor suppressor gene (PMID:14614460)
• Two Parkin mutations (C289G and C418R), which replace cysteine residues in the RING domains, decrease the solubility of Parkin in cells. Upon overexpression, the presumably misfolded proteins formed cytoplasmic aggregates. (PMID:14678753)
• Genetics of parkin-linked disease. Review. (PMID:14727181)
• Variants in the regulatory region shared by PARK2 and PACRG therefore act as common risk factors for leprosy (PMID:14737177)
• Review presents evidence for the major role of parkin in vulnerable neurons, i.e., to protect against alpha synuclein toxicity. (PMID:14987449)
• Pael-R is accumulated in Lewy bodies of Parkinson’s disease (PMID:14991825)
• Data show that a phylogenetically conserved N-myc binding site in the parkin promoter interacted with myc-family transcription factors, and N-myc bound to the parkin promoter and repressed transcription activity. (PMID:15078880)
• Parkin expression suppresses alpha-synuclein induced toxicity in drosophila. (PMID:15090075)
• The loss of Parkin contributes to the development of hepatocarcinoma. (PMID:15101042)
• Parkin is a tumor suppressor gene whose inactivation may play an important role in non-small cell lung cancer tumorigenesis (PMID:15102676)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	prkn	ENSDARG00000021555
mus_musculus	Prkn	ENSMUSG00000023826
rattus_norvegicus	Prkn	ENSRNOG00000055547
drosophila_melanogaster	park	FBGN0041100
caenorhabditis_elegans		WBGENE00015926
caenorhabditis_elegans		WBGENE00021721

Paralogs (9): ANKIB1 (ENSG00000001629), RNF14 (ENSG00000013561), RNF19A (ENSG00000034677), RNF19B (ENSG00000116514), RNF144B (ENSG00000137393), RNF217 (ENSG00000146373), RNF144A (ENSG00000151692), ARIH1 (ENSG00000166233), ARIH2 (ENSG00000177479)

Protein

Protein identifiers

E3 ubiquitin-protein ligase parkin — O60260 (reviewed: O60260)

Alternative names: Parkin RBR E3 ubiquitin-protein ligase, Parkinson juvenile disease protein 2

All UniProt accessions (8): A0A669KBE3, A0A6I8PII0, A0A6I8PRS9, B1AKC3, D3JZW5, D3K2X1, O60260, X5DR79

UniProt curated annotations — full annotation on UniProt →

Function. Functions within a multiprotein E3 ubiquitin ligase complex, catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins. Substrates include SYT11 and VDAC1. Other substrates are BCL2, CCNE1, GPR37, RHOT1/MIRO1, MFN1, MFN2, STUB1, SNCAIP, SEPTIN5, TOMM20, USP30, ZNF746, MIRO1 and AIMP2. Mediates monoubiquitination as well as ‘Lys-6’, ‘Lys-11’, ‘Lys-48’-linked and ‘Lys-63’-linked polyubiquitination of substrates depending on the context. Participates in the removal and/or detoxification of abnormally folded or damaged protein by mediating ‘Lys-63’-linked polyubiquitination of misfolded proteins such as PARK7: ‘Lys-63’-linked polyubiquitinated misfolded proteins are then recognized by HDAC6, leading to their recruitment to aggresomes, followed by degradation. Mediates ‘Lys-63’-linked polyubiquitination of a 22 kDa O-linked glycosylated isoform of SNCAIP, possibly playing a role in Lewy-body formation. Mediates monoubiquitination of BCL2, thereby acting as a positive regulator of autophagy. Protects against mitochondrial dysfunction during cellular stress, by acting downstream of PINK1 to coordinate mitochondrial quality control mechanisms that remove and replace dysfunctional mitochondrial components. Depending on the severity of mitochondrial damage and/or dysfunction, activity ranges from preventing apoptosis and stimulating mitochondrial biogenesis to regulating mitochondrial dynamics and eliminating severely damaged mitochondria via mitophagy. Activation and recruitment onto the outer membrane of damaged/dysfunctional mitochondria (OMM) requires PINK1-mediated phosphorylation of both PRKN and ubiquitin. After mitochondrial damage, functions with PINK1 to mediate the decision between mitophagy or preventing apoptosis by inducing either the poly- or monoubiquitination of VDAC1, respectively; polyubiquitination of VDAC1 promotes mitophagy, while monoubiquitination of VDAC1 decreases mitochondrial calcium influx which ultimately inhibits apoptosis. When cellular stress results in irreversible mitochondrial damage, promotes the autophagic degradation of dysfunctional depolarized mitochondria (mitophagy) by promoting the ubiquitination of mitochondrial proteins such as TOMM20, RHOT1/MIRO1, MFN1 and USP30. Preferentially assembles ‘Lys-6’-, ‘Lys-11’- and ‘Lys-63’-linked polyubiquitin chains, leading to mitophagy. The PINK1-PRKN pathway also promotes fission of damaged mitochondria by PINK1-mediated phosphorylation which promotes the PRKN-dependent degradation of mitochondrial proteins involved in fission such as MFN2. This prevents the refusion of unhealthy mitochondria with the mitochondrial network or initiates mitochondrial fragmentation facilitating their later engulfment by autophagosomes. Regulates motility of damaged mitochondria via the ubiquitination and subsequent degradation of MIRO1 and MIRO2; in motor neurons, this likely inhibits mitochondrial intracellular anterograde transport along the axons which probably increases the chance of the mitochondria undergoing mitophagy in the soma. Involved in mitochondrial biogenesis via the ‘Lys-48’-linked polyubiquitination of transcriptional repressor ZNF746/PARIS which leads to its subsequent proteasomal degradation and allows activation of the transcription factor PPARGC1A. Limits the production of reactive oxygen species (ROS). Regulates cyclin-E during neuronal apoptosis. In collaboration with CHPF isoform 2, may enhance cell viability and protect cells from oxidative stress. Independently of its ubiquitin ligase activity, protects from apoptosis by the transcriptional repression of p53/TP53. May protect neurons against alpha synuclein toxicity, proteasomal dysfunction, GPR37 accumulation, and kainate-induced excitotoxicity. May play a role in controlling neurotransmitter trafficking at the presynaptic terminal and in calcium-dependent exocytosis. May represent a tumor suppressor gene.

Subunit / interactions. Forms an E3 ubiquitin ligase complex with UBE2L3 or UBE2L6. Mediates ‘Lys-63’-linked polyubiquitination by associating with UBE2V1. Part of a SCF-like complex, consisting of PRKN, CUL1 and FBXW7. Interacts with SNCAIP. Binds to the C2A and C2B domains of SYT11. Interacts and regulates the turnover of SEPTIN5. Part of a complex, including STUB1, HSP70 and GPR37. The amount of STUB1 in the complex increases during ER stress. STUB1 promotes the dissociation of HSP70 from PRKN and GPR37, thus facilitating PRKN-mediated GPR37 ubiquitination. HSP70 transiently associates with unfolded GPR37 and inhibits the E3 activity of PRKN, whereas, STUB1 enhances the E3 activity of PRKN through promotion of dissociation of HSP70 from PRKN-GPR37 complexes. Interacts with PSMD4 and PACRG. Interacts with LRRK2. Interacts with RANBP2. Interacts with SUMO1 but not SUMO2, which promotes nuclear localization and autoubiquitination. Interacts (via first RING-type domain) with AIMP2 (via N-terminus). Interacts with PSMA7 and RNF41. Interacts with PINK1. Forms a complex with PINK1 and PARK7. Interacts with CHPF, the interaction with isoform 2 may facilitate PRKN transport into the mitochondria. Interacts with MFN2 (phosphorylated), promotes PRKN localization in dysfunctional depolarized mitochondria. Interacts with FBXO7; this promotes translocation to dysfunctional depolarized mitochondria. Interacts with ZNF746. Interacts with heat shock protein 70 family members, including HSPA1L, HSPA1A and HSPA8; interaction HSPA1L promotes translocation to damaged mitochondria. Interacts with BAG4 and, to a lesser extent, BAG5; interaction with BAG4 inhibits translocation to damaged mitochondria. Forms a complex with PRKN and PARK7. Interacts with AMBRA1.

Subcellular location. Cytoplasm. Cytosol. Nucleus. Endoplasmic reticulum. Mitochondrion. Mitochondrion outer membrane. Cell projection. Neuron projection. Postsynaptic density. Presynapse.

Tissue specificity. Highly expressed in the brain including the substantia nigra. Expressed in heart, testis and skeletal muscle. Expression is down-regulated or absent in tumor biopsies, and absent in the brain of PARK2 patients. Overexpression protects dopamine neurons from kainate-mediated apoptosis. Found in serum (at protein level).

Post-translational modifications. ISGylated. Conjugated to ubiquitin-like protein ISG15 upon IFN-beta stimulation. ISGylation positively regulates its E3 ligase activity. Auto-ubiquitinates in an E2-dependent manner leading to its own degradation. Also polyubiquitinated by RNF41 for proteasomal degradation. S-nitrosylated. The inhibition of PRKN ubiquitin E3 ligase activity by S-nitrosylation could contribute to the degenerative process in PD by impairing the ubiquitination of PRKN substrates. Phosphorylated. Activation requires phosphorylation at Ser-65 by PINK1 and binding to PINK1 phosphorylated ubiquitin. Phosphorylation at Thr-175 by PINK1 and at Thr-217 is important for mitochondrial localization.

Disease relevance. Parkinson disease (PARK) [MIM:168600] A complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability. Additional features are characteristic postural abnormalities, dysautonomia, dystonic cramps, and dementia. The pathology of Parkinson disease involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. The disease is progressive and usually manifests after the age of 50 years, although early-onset cases (before 50 years) are known. The majority of the cases are sporadic suggesting a multifactorial etiology based on environmental and genetic factors. However, some patients present with a positive family history for the disease. Familial forms of the disease usually begin at earlier ages and are associated with atypical clinical features. Disease susceptibility may be associated with variants affecting the gene represented in this entry. Heterozygous mutations act as susceptibility alleles for late-onset Parkinson disease. Parkinson disease 2 (PARK2) [MIM:600116] An autosomal recessive form of Parkinson disease, a complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability. PARK2 differs from classic forms of Parkinson disease by early DOPA-induced dyskinesia, diurnal fluctuation of the symptoms, sleep benefit, dystonia and hyper-reflexia. Dementia is absent. Pathologically, patients show loss of dopaminergic neurons in the substantia nigra, similar to that seen in classic Parkinson disease; however, Lewy bodies (intraneuronal accumulations of aggregated proteins) are absent. Disease onset is usually before age 40 years. The disease is caused by variants affecting the gene represented in this entry. Defects in PRKN may be involved in the development and/or progression of ovarian cancer.

Activity regulation. In the autoinhibited state the side chain of Phe-463 inserts into a hydrophobic groove in RING-0, occluding the ubiquitin acceptor site Cys-431, whereas the REP repressor element binds RING-1 and blocks its E2-binding site. Activation of PRKN requires 2 steps: (1) phosphorylation at Ser-65 by PINK1 and (2) binding to phosphorylated ubiquitin, leading to unlock repression of the catalytic Cys-431 by the RING-0 region via an allosteric mechanism and converting PRKN to its fully-active form. According to another report, phosphorylation at Ser-65 by PINK1 is not essential for activation and only binding to phosphorylated ubiquitin is essential to unlock repression. In addition, ISG15 conjugation positively regulates its ubiquitin E3 ligase activity by suppressing the intramolecular interaction that maintains its autoinhibited conformation.

Domain organisation. The ubiquitin-like domain binds the PSMD4 subunit of 26S proteasomes. The RING-type 1 zinc finger domain is required to repress p53/TP53 transcription. Members of the RBR family are atypical E3 ligases. They interact with the E2 conjugating enzyme UBE2L3 and function like HECT-type E3 enzymes: they bind E2s via the first RING domain, but require an obligate trans-thiolation step during the ubiquitin transfer, requiring a conserved cysteine residue in the second RING domain.

Pathway. Protein modification; protein ubiquitination.

Miscellaneous. The parkin locus (PRKN), adjacent to the 6q telomere is hyper-recombinable and lies within FRA6E, the third most common fragile site in tumor tissue.

Similarity. Belongs to the RBR family. Parkin subfamily.

Isoforms (8)

UniProt ID	Names	Canonical?
O60260-1	1	yes
O60260-2	2, SV5DEL
O60260-3	3
O60260-4	4
O60260-5	5
O60260-6	6
O60260-7	7, SV5,9DEL
O60260-8	8, SV9DEL

RefSeq proteins (3): NP_004553, NP_054642, NP_054643 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000626	Ubiquitin-like_dom	Domain
IPR002867	IBR_dom	Domain
IPR003977	Parkin	Family
IPR015496	Ubiquilin	Family
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR041170	Znf-RING_14	Domain
IPR041565	Parkin_Znf-RING	Domain
IPR044066	TRIAD_supradom	Domain
IPR047534	BRcat_RBR_parkin	Domain
IPR047535	RING-HC_RBR_parkin	Domain
IPR047536	Rcat_RBR_parkin	Domain
IPR054694	Parkin-like_IBR	Domain

Pfam: PF00240, PF17976, PF17978, PF22605

Enzyme classification (BRENDA):

• EC 2.3.2.27 — RING-type E3 ubiquitin transferase (BRENDA: 28 organisms, 138 substrates, 10 inhibitors, 1 Km, 1 kcat entries)
• EC 2.3.2.31 — RBR-type E3 ubiquitin transferase (BRENDA: 4 organisms, 35 substrates, 4 inhibitors, 0 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
[UBE2W]-S-UBIQUITINYL-L-CYSTEINE	0.3014	1

UniProt features (164 total): sequence variant 40, strand 28, binding site 24, mutagenesis site 17, turn 13, helix 11, splice variant 10, region of interest 6, zinc finger region 4, sequence conflict 3, modified residue 3, cross-link 2, chain 1, domain 1, active site 1

Structure

Experimental structures (PDB)

21 structures.

PDB	Method	Resolution (Å)
4I1F	X-RAY DIFFRACTION	1.58
5C1Z	X-RAY DIFFRACTION	1.79
6GLC	X-RAY DIFFRACTION	1.8
8WZN	X-RAY DIFFRACTION	1.8
8IKM	X-RAY DIFFRACTION	1.92
4I1H	X-RAY DIFFRACTION	2
4BM9	X-RAY DIFFRACTION	2.25
8WZO	X-RAY DIFFRACTION	2.25
5C9V	X-RAY DIFFRACTION	2.35
8IKV	X-RAY DIFFRACTION	2.35
5C23	X-RAY DIFFRACTION	2.37
5N38	X-RAY DIFFRACTION	2.6
8IKT	X-RAY DIFFRACTION	2.6
5N2W	X-RAY DIFFRACTION	2.68
6HUE	X-RAY DIFFRACTION	2.85
8JWV	X-RAY DIFFRACTION	2.9
8IK6	X-RAY DIFFRACTION	3.3
1IYF	SOLUTION NMR
2JMO	SOLUTION NMR
5TR5	SOLUTION NMR
6N13	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60260-F1	79.10	0.32

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 431

Ligand- & substrate-binding residues (24): 238; 241; 253; 257; 260; 263; 289; 293; 332; 337; 352; 360 …

Post-translational modifications (5): 65, 175, 217, 349, 369

Mutagenesis-validated functional residues (17):

Position	Phenotype
337	impairs the ability to ubiquitinate sncaip.
365	impairs protein folding.
403	decreased autoinhibition and increased e3 activity.
421	impairs the ability of self-ubiquitination and to ubiquitinate sncaip.
429	reduced self-ubiquitination.
431	loss of activity.
431	impairs the ability to ubiquitinate target proteins. no effect on translocation to mitochondria.
433	impaired activity.
444	impaired activity.
65	loss of phosphorylation. undergoes autoubiquitination in the presence of phosphorylated ubiquitin.
65	phosphomimetic mutant; still requires pink1 for activation. prkn is activated in presence of phosphorylated ubiquitin.
175	loss of phosphorylation. reduced mitochondrial localization; when associated with a-217.
175	phosphomimetic mutant. mostly localizes to the mitochondria; when associated with e-217.
217	loss of phosphorylation. reduced mitochondrial localization; when associated with a-175.
217	phosphomimetic mutant. mostly localizes to the mitochondria; when associated with e-175.
238	loss of mitochondrial localization.
332	impairs folding of ibr domain.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-5205685	PINK1-PRKN Mediated Mitophagy
R-HSA-5675482	Regulation of necroptotic cell death
R-HSA-5689877	Josephin domain DUBs
R-HSA-9646399	Aggrephagy
R-HSA-977225	Amyloid fiber formation
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation

MSigDB gene sets: 759 (showing top): GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_SYNAPTIC_VESICLE_LOCALIZATION, GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_MITOCHONDRIAL_FISSION, GOBP_COGNITION, GOBP_LYSOSOMAL_TRANSPORT, GOBP_BEHAVIOR, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_ENDOSOME_ORGANIZATION, TGCGCANK_UNKNOWN

GO Biological Process (128): negative regulation of transcription by RNA polymerase II (GO:0000122), protein polyubiquitination (GO:0000209), mitochondrial fission (GO:0000266), autophagy of mitochondrion (GO:0000422), mitophagy (GO:0000423), startle response (GO:0001964), ubiquitin-dependent protein catabolic process (GO:0006511), protein monoubiquitination (GO:0006513), response to oxidative stress (GO:0006979), mitochondrion organization (GO:0007005), central nervous system development (GO:0007417), learning (GO:0007612), adult locomotory behavior (GO:0008344), response to xenobiotic stimulus (GO:0009410), proteasomal protein catabolic process (GO:0010498), regulation of autophagy (GO:0010506), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), positive regulation of mitochondrial fusion (GO:0010636), negative regulation of mitochondrial fusion (GO:0010637), regulation of mitochondrion organization (GO:0010821), regulation of glucose metabolic process (GO:0010906), positive regulation of mitochondrial membrane potential (GO:0010918), free ubiquitin chain polymerization (GO:0010994), regulation of dopamine secretion (GO:0014059), response to muscle activity (GO:0014850), macroautophagy (GO:0016236), protein ubiquitination (GO:0016567), protein deubiquitination (GO:0016579), regulation of protein ubiquitination (GO:0031396), regulation of protein stability (GO:0031647), protein destabilization (GO:0031648), negative regulation of actin filament bundle assembly (GO:0032232), regulation of lipid transport (GO:0032368), positive regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032436), negative regulation of glucokinase activity (GO:0033132), cellular response to oxidative stress (GO:0034599), cellular response to unfolded protein (GO:0034620), response to endoplasmic reticulum stress (GO:0034976), synaptic transmission, glutamatergic (GO:0035249)

GO Molecular Function (30): G protein-coupled receptor binding (GO:0001664), transcription corepressor activity (GO:0003714), actin binding (GO:0003779), ubiquitin-protein transferase activity (GO:0004842), beta-catenin binding (GO:0008013), zinc ion binding (GO:0008270), tubulin binding (GO:0015631), SH3 domain binding (GO:0017124), enzyme binding (GO:0019899), kinase binding (GO:0019900), protein kinase binding (GO:0019901), PDZ domain binding (GO:0030165), Hsp70 protein binding (GO:0030544), heat shock protein binding (GO:0031072), ubiquitin conjugating enzyme binding (GO:0031624), ubiquitin protein ligase binding (GO:0031625), identical protein binding (GO:0042802), histone deacetylase binding (GO:0042826), ubiquitin binding (GO:0043130), phospholipase binding (GO:0043274), protein-containing complex binding (GO:0044877), protein-folding chaperone binding (GO:0051087), ubiquitin protein ligase activity (GO:0061630), cullin family protein binding (GO:0097602), ubiquitin-specific protease binding (GO:1990381), F-box domain binding (GO:1990444), protein binding (GO:0005515), transferase activity (GO:0016740), ligase activity (GO:0016874), metal ion binding (GO:0046872)

GO Cellular Component (32): Golgi membrane (GO:0000139), ubiquitin ligase complex (GO:0000151), nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), cytosol (GO:0005829), postsynaptic density (GO:0014069), aggresome (GO:0016235), nuclear speck (GO:0016607), synaptic vesicle membrane (GO:0030672), neuron projection (GO:0043005), neuronal cell body (GO:0043025), terminal bouton (GO:0043195), perinuclear region of cytoplasm (GO:0048471), Lewy body (GO:0097413), dopaminergic synapse (GO:0098691), glutamatergic synapse (GO:0098978), Parkin-FBXW7-Cul1 ubiquitin ligase complex (GO:1990452), synaptic vesicle (GO:0008021), membrane (GO:0016020), axon (GO:0030424), protein-containing complex (GO:0032991), cell projection (GO:0042995), synapse (GO:0045202), intracellular vesicle (GO:0097708), presynapse (GO:0098793), postsynapse (GO:0098794), mitochondrion-derived vesicle (GO:0099073)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Mitophagy	1
RIPK1-mediated regulated necrosis	1
Deubiquitination	1
Selective autophagy	1
Metabolism of proteins	1
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	5
protein binding	4
intracellular membrane-bounded organelle	4
protein ubiquitination	3
enzyme binding	3
cellular anatomical structure	3
negative regulation of DNA-templated transcription	2
autophagy	2
gene expression	2
regulation of gene expression	2
mitochondrial fusion	2
regulation of mitochondrial fusion	2
cytoskeletal protein binding	2
protein domain specific binding	2
endomembrane system	2
inclusion body	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
mitochondrion organization	1
organelle fission	1
autophagy of mitochondrion	1
macroautophagy	1
response to external stimulus	1
neuromuscular process	1
modification-dependent protein catabolic process	1
response to stress	1
organelle organization	1
nervous system development	1
system development	1
learning or memory	1
locomotory behavior	1
adult behavior	1
response to chemical	1
protein catabolic process	1
regulation of catabolic process	1
positive regulation of macromolecule biosynthetic process	1
negative regulation of macromolecule biosynthetic process	1
positive regulation of organelle organization	1
positive regulation of developmental process	1
negative regulation of organelle organization	1

Protein interactions and networks

STRING

4050 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PRKN	SNCA	P37840	999
PRKN	PINK1	Q9BXM7	999
PRKN	SNCAIP	Q9Y6H5	997
PRKN	PARK7	Q99497	996
PRKN	LRRK2	Q5S007	981
PRKN	BECN1	Q14457	971
PRKN	UBE2L6	O14933	939
PRKN	MFN2	O95140	939
PRKN	UBE2E2	Q96LR5	919
PRKN	UCHL1	P09936	914
PRKN	SQSTM1	Q13501	901
PRKN	VPS35	Q96QK1	898
PRKN	FBXO7	Q9Y3I1	882
PRKN	GBA1	P04062	880
PRKN	PACRG	Q96M98	878

IntAct

268 interactions, top by confidence:

A	B	Type	Score
PRKN	TRIP13	psi-mi:“MI:0915”(physical association)	0.710
TRIP13	PRKN	psi-mi:“MI:0915”(physical association)	0.710
	PRKN	psi-mi:“MI:0407”(direct interaction)	0.620
PRKN		psi-mi:“MI:0407”(direct interaction)	0.620
PRKN	PRKN	psi-mi:“MI:0407”(direct interaction)	0.620
PRKN	HDAC6	psi-mi:“MI:0915”(physical association)	0.600
PRKN	HDAC6	psi-mi:“MI:0407”(direct interaction)	0.600
HDAC6	PRKN	psi-mi:“MI:0407”(direct interaction)	0.600
PRKN	ZNF746	psi-mi:“MI:0915”(physical association)	0.590
ZNF746	PRKN	psi-mi:“MI:0915”(physical association)	0.590
MFN2	PRKN	psi-mi:“MI:0915”(physical association)	0.580
DLG1	PRKN	psi-mi:“MI:2364”(proximity)	0.570
DLG1	PRKN	psi-mi:“MI:0407”(direct interaction)	0.570
PRKN	DLG1	psi-mi:“MI:0407”(direct interaction)	0.570
HSP90AB1	PRKN	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (5963): PARK2 (Affinity Capture-Western), BECN1 (Affinity Capture-Western), HCVgp1 (Affinity Capture-Western), HCVgp1 (Two-hybrid), PARK2 (Two-hybrid), PARK2 (Co-localization), UCHL1 (Reconstituted Complex), PARK7 (Affinity Capture-Western), PARK2 (Affinity Capture-Western), PARK2 (Affinity Capture-Western), UCHL1 (Affinity Capture-Western), UCHL1 (Biochemical Activity), UBE2N (Reconstituted Complex), UBE2D2 (Reconstituted Complex), UBE2L3 (Reconstituted Complex)

ESM2 similar proteins: A0JP89, A8WZU5, B0JZ65, E0VIU9, O59800, O60140, O60260, O74508, O76924, P06428, P36113, P53971, P87143, P90740, P91351, Q02256, Q04638, Q07913, Q19546, Q21988, Q28D84, Q4V863, Q5A1M3, Q5RFL4, Q5UQ35, Q5ZKB8, Q6BMD1, Q6BSV3, Q6FKZ2, Q6GM71, Q6T486, Q7KTX7, Q7TMI3, Q7Z478, Q810J8, Q84RQ8, Q84RR2, Q949V6, Q96PU4, Q98SM3

Diamond homologs: C4YP88, E0VIU9, G1SK22, O60260, P05759, P0C016, P0C032, P0C224, P0C273, P0C275, P0C276, P0C8R3, P0CG47, P0CG48, P0CG49, P0CG50, P0CG51, P0CG53, P0CG54, P0CG55, P0CG60, P0CG61, P0CG62, P0CG64, P0CG65, P0CG66, P0CG67, P0CG68, P0CG69, P0CG70, P0CG71, P0CG73, P0CG76, P0CG77, P0CG78, P0CG79, P0CG80, P0CG81, P0CG82, P0CG88

SIGNOR signaling

53 interactions.

A	Effect	B	Mechanism
PRKN	up-regulates	EPS15	ubiquitination
CDK5	down-regulates	PRKN	phosphorylation
ABL1	down-regulates	PRKN	phosphorylation
PINK1	up-regulates	PRKN	phosphorylation
UBC	“up-regulates activity”	PRKN	binding
PRKN	“down-regulates quantity by destabilization”	SNCA	ubiquitination
PRKN	“down-regulates quantity by destabilization”	GPR37	ubiquitination
PRKN	“down-regulates quantity by destabilization”	RANBP2	ubiquitination
BAG5	“down-regulates activity”	PRKN	binding
PRKN	“down-regulates quantity by destabilization”	HIF3A	ubiquitination
PRKN	“down-regulates quantity by destabilization”	PHGDH	ubiquitination
PINK1	“up-regulates activity”	PRKN	phosphorylation
Ub:E2	“up-regulates activity”	PRKN	ubiquitination
PRKN	“up-regulates quantity by stabilization”	SNCAIP	ubiquitination
RNF41	“down-regulates quantity by destabilization”	PRKN	polyubiquitination
PRKN	“down-regulates quantity by destabilization”	SYT11	polyubiquitination
PRKN	“down-regulates quantity by destabilization”	RHOT2	polyubiquitination
PRKN	“down-regulates quantity by destabilization”	ZNF746	polyubiquitination
PRKN	“down-regulates quantity”	MFN1	ubiquitination
PRKN	“down-regulates quantity”	MFN2	ubiquitination
PRKN	“down-regulates quantity by destabilization”	ZNF746	ubiquitination
PLK1	“up-regulates activity”	PRKN	phosphorylation
MTOR	“down-regulates activity”	PRKN	phosphorylation
PRKN	“down-regulates quantity by destabilization”	SQSTM1	ubiquitination
PRKN	“down-regulates quantity by destabilization”	PARK7	ubiquitination
PRKN	“down-regulates quantity by destabilization”	BAX	ubiquitination
PRKN	“down-regulates quantity by destabilization”	APEX1	ubiquitination
PRKN	“down-regulates quantity by destabilization”	GRIK2	ubiquitination
PRKN	“down-regulates quantity by destabilization”	HIF1A	ubiquitination
PRKN	“down-regulates quantity by destabilization”	SNCAIP	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 118 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Ras activation upon Ca2+ influx through NMDA receptor	5	36.1×	2e-05
Unblocking of NMDA receptors, glutamate binding and activation	5	34.4×	2e-05
Negative regulation of NMDA receptor-mediated neuronal transmission	5	34.4×	2e-05
Assembly and cell surface presentation of NMDA receptors	10	32.1×	1e-10
Dopamine Neurotransmitter Release Cycle	5	31.4×	3e-05
Long-term potentiation	5	30.1×	4e-05
Neurexins and neuroligins	12	29.9×	2e-12
Protein-protein interactions at synapses	7	23.5×	3e-06

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	9	47.5×	1e-10
protein localization to synapse	6	41.8×	2e-06
receptor clustering	6	34.0×	5e-06
regulation of postsynaptic membrane neurotransmitter receptor levels	6	27.0×	2e-05
excitatory postsynaptic potential	6	24.2×	2e-05
social behavior	5	12.3×	3e-03
epidermal growth factor receptor signaling pathway	5	11.3×	3e-03
protein-containing complex assembly	9	9.3×	6e-05

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

658 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	107
Likely pathogenic	42
Uncertain significance	277
Likely benign	116
Benign	60

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1027679	NM_004562.3(PRKN):c.618+7842_618+7934inv	Pathogenic
1068478	NM_004562.3(PRKN):c.872-1G>C	Pathogenic
1069483	NC_000006.11:g.(?162394324)(162475216_?)dup	Pathogenic
1071389	NC_000006.11:g.(?162864332)(162864519_?)del	Pathogenic
1073295	NC_000006.11:g.(?162206794)(162206950_?)del	Pathogenic
1073296	NC_000006.11:g.(?162475113)(162864519_?)del	Pathogenic
1119999	GRCh37/hg19 6q26(chr6:162622150-162683772)	Pathogenic
1120002	GRCh37/hg19 6q26(chr6:162622150-162622256)	Pathogenic
1120005	GRCh37/hg19 6q26(chr6:162864400-162864441)	Pathogenic
1120006	GRCh37/hg19 6q26(chr6:162394320-162475157)	Pathogenic
1120009	GRCh37/hg19 6q26(chr6:161969922-161990424)	Pathogenic
1334464	NC_000006.11:g.(?162474785)(162475494_?)del	Pathogenic
1335659	GRCh37/hg19 6q26(chr6:162394334-162622284)x1	Pathogenic
1363188	NC_000006.11:g.(?162394314)(162394469_?)del	Pathogenic
1455991	NC_000006.11:g.(?162622143)(162864525_?)dup	Pathogenic
1456905	NM_004562.3(PRKN):c.971del (p.Val324fs)	Pathogenic
1458435	NC_000006.11:g.(?161771131)(161807929_?)del	Pathogenic
1459191	NM_004562.3(PRKN):c.1334G>A (p.Trp445Ter)	Pathogenic
1460162	NC_000006.11:g.(?162394314)(162683817_?)del	Pathogenic
1460217	NC_000006.11:g.(?161969866)(161990468_?)del	Pathogenic
1460246	NC_000006.11:g.(?162622143)(162864525_?)del	Pathogenic
1687195	NM_004562.3(PRKN):c.1083+1del	Pathogenic
1972564	NM_004562.3(PRKN):c.1352del (p.Cys451fs)	Pathogenic
2136491	NM_004562.3(PRKN):c.1286-3C>G	Pathogenic
2191539	NM_004562.3(PRKN):c.1359G>A (p.Trp453Ter)	Pathogenic
2425157	NC_000006.11:g.(?162394314)(162864525_?)del	Pathogenic
2425161	NC_000006.11:g.(?162864322)(162868359_?)del	Pathogenic
2571272	GRCh37/hg19 6q26(chr6:162622163-162864505)x1	Pathogenic
2756740	NM_004562.3(PRKN):c.1046_1047del (p.Lys349fs)	Pathogenic
2817663	NM_004562.3(PRKN):c.844C>T (p.Gln282Ter)	Pathogenic

SpliceAI

4806 predictions. Top by Δscore:

Variant	Effect	Δscore
6:161360082:ACT:A	donor_loss	1.0000
6:161360083:CTCA:C	donor_loss	1.0000
6:161360084:T:TA	donor_loss	1.0000
6:161360085:CACCA:C	donor_loss	1.0000
6:161360086:A:AC	donor_gain	1.0000
6:161360086:A:AG	donor_loss	1.0000
6:161360087:C:A	donor_loss	1.0000
6:161360087:C:CC	donor_gain	1.0000
6:161360201:TAGGC:T	acceptor_gain	1.0000
6:161360202:AGGC:A	acceptor_gain	1.0000
6:161360203:GGC:G	acceptor_gain	1.0000
6:161360204:GC:G	acceptor_gain	1.0000
6:161360205:CC:C	acceptor_gain	1.0000
6:161360206:C:CC	acceptor_gain	1.0000
6:161360215:C:CT	acceptor_gain	1.0000
6:161386788:CTGTA:C	donor_loss	1.0000
6:161386789:TGTAC:T	donor_loss	1.0000
6:161386790:GTAC:G	donor_loss	1.0000
6:161386791:TAC:T	donor_loss	1.0000
6:161386793:C:CG	donor_loss	1.0000
6:161386873:GCAAA:G	acceptor_gain	1.0000
6:161386874:CAAA:C	acceptor_gain	1.0000
6:161386874:CAAAC:C	acceptor_gain	1.0000
6:161386875:AAA:A	acceptor_gain	1.0000
6:161386876:AA:A	acceptor_gain	1.0000
6:161386877:AC:A	acceptor_loss	1.0000
6:161386878:C:CC	acceptor_gain	1.0000
6:161386878:CTGCA:C	acceptor_loss	1.0000
6:161421815:T:A	donor_gain	1.0000
6:161442892:A:AC	donor_gain	1.0000

AlphaMissense

3071 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:161350138:C:A	W453C	0.998
6:161350138:C:G	W453C	0.998
6:161785778:A:G	C289R	0.998
6:161785865:A:G	C260R	0.998
6:161973324:A:G	C238R	0.998
6:161350162:C:A	W445C	0.997
6:161350162:C:G	W445C	0.997
6:161350191:A:G	C436R	0.997
6:161785813:A:G	F277S	0.997
6:161785828:A:G	L272P	0.997
6:161973322:G:C	C238W	0.997
6:161973412:A:C	F208L	0.997
6:161973412:A:T	F208L	0.997
6:161973414:A:G	F208L	0.997
6:161350140:A:G	W453R	0.996
6:161350140:A:T	W453R	0.996
6:161350164:A:G	W445R	0.996
6:161350164:A:T	W445R	0.996
6:161548943:A:G	C332R	0.996
6:161548994:A:C	Y315D	0.996
6:161785854:A:C	C263W	0.996
6:162262737:A:T	V67D	0.996
6:161350108:G:C	F463L	0.995
6:161350108:G:T	F463L	0.995
6:161350110:A:G	F463L	0.995
6:161569377:A:G	F304S	0.995
6:161785776:A:C	C289W	0.995
6:161785856:A:G	C263R	0.995
6:161785863:G:C	C260W	0.995
6:161785886:A:G	C253R	0.995

dbSNP variants (sampled 300 via entrez): RS1000003095 (6:162703397 C>A), RS1000004151 (6:162369919 C>T), RS1000004810 (6:161537248 A>G), RS1000006598 (6:162405697 G>A), RS1000007467 (6:161452821 G>A,C), RS1000009824 (6:162458969 C>T), RS1000011840 (6:161978346 G>A), RS1000014630 (6:162293777 G>A,C), RS1000015583 (6:162699876 G>T), RS1000016807 (6:162421978 G>C), RS1000022038 (6:162396759 C>A,G), RS1000023239 (6:162532704 C>A), RS1000024516 (6:161793240 C>A,T), RS1000026815 (6:162253030 A>T), RS1000027905 (6:161613366 G>T)

Disease associations

OMIM: gene MIM:602544 | disease phenotypes: MIM:600116, MIM:211980, MIM:181500, MIM:167000, MIM:300557, MIM:168600, MIM:209850, MIM:607572

GenCC curated gene-disease

Disease	Classification	Inheritance
Parkinson disease	Definitive	Autosomal recessive
autosomal recessive juvenile Parkinson disease 2	Definitive	Autosomal recessive
young-onset Parkinson disease	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Parkinson disease	Definitive	AR

Mondo (14): autosomal recessive juvenile Parkinson disease 2 (MONDO:0010820), young-onset Parkinson disease (MONDO:0017279), lung cancer (MONDO:0008903), ovarian neoplasm (MONDO:0021068), schizophrenia (MONDO:0005090), lung adenocarcinoma (MONDO:0005061), ovarian cancer (MONDO:0008170), Parkinson disease 12 (MONDO:0010360), complex hereditary spastic paraplegia (MONDO:0015150), Parkinson disease (MONDO:0005180), autism spectrum disorder (MONDO:0005258), autism (MONDO:0005260), lung carcinoma (MONDO:0005138), leprosy, susceptibility to, 2 (MONDO:0011860)

Orphanet (8): Young-onset Parkinson disease (Orphanet:2828), Rare ovarian cancer (Orphanet:213500), Complex hereditary spastic paraplegia (Orphanet:102013), Leprosy (Orphanet:548), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140), NON RARE IN EUROPE: Adenocarcinoma of the lung (Orphanet:415268), NON RARE IN EUROPE: Parkinson disease (Orphanet:319705), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

63 total (30 of 63 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000551	Color vision defect
HP:0000651	Diplopia
HP:0000713	Agitation
HP:0000716	Depression
HP:0000726	Dementia
HP:0000727	Frontal lobe dementia
HP:0000736	Short attention span
HP:0000738	Hallucinations
HP:0000739	Anxiety
HP:0000741	Apathy
HP:0001257	Spasticity
HP:0001288	Gait disturbance
HP:0001300	Parkinsonism
HP:0001332	Dystonia
HP:0001337	Tremor
HP:0001347	Hyperreflexia
HP:0001442	Typified by somatic mosaicism
HP:0002014	Diarrhea
HP:0002018	Nausea
HP:0002019	Constipation
HP:0002059	Cerebral atrophy
HP:0002063	Rigidity
HP:0002066	Gait ataxia
HP:0002067	Bradykinesia
HP:0002141	Gait imbalance
HP:0002172	Postural instability
HP:0002174	Postural tremor
HP:0002322	Resting tremor

GWAS associations

55 associations (top):

Study	Trait	p-value
GCST000274_7	Metabolite levels	1.000000e-07
GCST000745_13	Pancreatic cancer	7.000000e-06
GCST001599_5	Aging	5.000000e-06
GCST001687_3	Disc degeneration (lumbar)	3.000000e-08
GCST002616_1	Mitochondrial DNA levels	3.000000e-06
GCST002616_2	Mitochondrial DNA levels	2.000000e-06
GCST002783_376	Body mass index	1.000000e-09
GCST002783_47	Body mass index	1.000000e-06
GCST002783_509	Body mass index	7.000000e-09
GCST003127_18	Lipoprotein (a) levels	5.000000e-12
GCST003264_1083	Post bronchodilator FEV1/FVC ratio	4.000000e-06
GCST003264_160	Post bronchodilator FEV1/FVC ratio	2.000000e-06
GCST003264_438	Post bronchodilator FEV1/FVC ratio	6.000000e-07
GCST003264_775	Post bronchodilator FEV1/FVC ratio	3.000000e-07
GCST003264_955	Post bronchodilator FEV1/FVC ratio	5.000000e-06
GCST003264_957	Post bronchodilator FEV1/FVC ratio	5.000000e-06
GCST003422_2	Squamous cell carcinoma	3.000000e-06
GCST004092_2	Plasma t-tau levels	6.000000e-06
GCST004313_13	Facial morphology (factor 9, facial height related to vertical position of nasion)	5.000000e-08
GCST004495_70	BMI (adjusted for smoking behaviour)	9.000000e-10
GCST004495_71	BMI (adjusted for smoking behaviour)	1.000000e-08
GCST004497_26	Body mass index (joint analysis main effects and smoking interaction)	2.000000e-09
GCST004497_27	Body mass index (joint analysis main effects and smoking interaction)	2.000000e-08
GCST004499_94	BMI in non-smokers	2.000000e-09
GCST004499_95	BMI in non-smokers	7.000000e-09
GCST004557_195	Body mass index	2.000000e-08
GCST004557_224	Body mass index	3.000000e-10
GCST004557_59	Body mass index	2.000000e-11
GCST004557_95	Body mass index	1.000000e-09
GCST004558_144	Body mass index (joint analysis main effects and physical activity interaction)	5.000000e-10

EFO canonical traits (22, from GWAS)

EFO ID	Trait name
EFO:0022597	aging
EFO:0006312	mitochondrial DNA measurement
EFO:0004340	body mass index
EFO:0006925	lipoprotein A measurement
EFO:0004713	FEV/FVC ratio
EFO:0004760	t-tau measurement
EFO:0007856	facial height measurement
EFO:0004318	smoking behavior
EFO:0008002	physical activity measurement
EFO:0008330	fear of pain measurement
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0009010	HSV2 virologic severity measurement
EFO:0010103	response to peginterferon alfa-2a
EFO:0010096	artificially sweetened beverage consumption measurement
EFO:0004566	body weight gain
EFO:0004725	metabolite measurement
EFO:0010399	triacylglycerol 44:1 measurement
EFO:0004847	age at onset
EFO:0000195	metabolic syndrome
EFO:0004530	triglyceride measurement
EFO:0007874	gut microbiome measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D010051	Ovarian Neoplasms	C04.588.322.455; C12.050.351.500.056.630.705; C12.050.351.937.418.685; C12.100.250.056.630.705; C12.900.418.685; C19.344.410; C19.391.630.705
D010300	Parkinson Disease	C10.228.140.079.862.500; C10.228.662.600.400; C10.574.928.750
C564486	Parkinson Disease 12 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

97 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Rotenone	decreases expression, increases phosphorylation, decreases reaction, affects reaction, increases response to substance (+6 more)	8
Carbonyl Cyanide m-Chlorophenyl Hydrazone	increases ubiquitination, affects expression, affects binding, increases reaction, decreases expression (+7 more)	6
Paraquat	decreases reaction, affects localization, increases expression, affects reaction, increases reaction (+3 more)	4
Aflatoxin B1	decreases expression, decreases methylation, affects methylation	4
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	affects expression, decreases expression, decreases reaction, affects cotreatment, affects reaction	3
Antimycin A	affects localization, affects reaction, decreases expression, affects cotreatment	3
Benzo(a)pyrene	decreases expression, affects methylation	3
Manganese	decreases expression, affects response to substance, decreases transport	3
Oxidopamine	affects reaction, decreases reaction, affects expression, decreases expression	3
lead acetate	affects cotreatment, decreases expression, increases abundance, affects localization	2
salvin	affects reaction, decreases expression, decreases reaction, increases expression, increases ubiquitination	2
chromium hexavalent ion	increases expression, increases reaction	2
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases reaction, increases expression, increases activity	2
MitoTEMPO	decreases reaction, increases expression	2
Acetylcysteine	affects localization, decreases reaction, increases ubiquitination, increases expression, affects cotreatment	2
Dopamine	increases expression, decreases reaction, increases abundance, increases cleavage, increases phosphorylation	2
Doxorubicin	decreases reaction, increases expression, decreases expression	2
Tetrachlorodibenzodioxin	increases activity, increases expression, decreases reaction	2
Tobacco Smoke Pollution	decreases expression, increases methylation	2
Valproic Acid	decreases methylation, increases expression	2
1-Methyl-4-phenylpyridinium	affects expression, decreases expression, increases expression, affects reaction	2
Reactive Oxygen Species	decreases reaction, increases abundance, decreases abundance	2
aristolochic acid I	decreases expression	1
linsidomine	decreases reaction, increases expression	1
quinone	decreases reaction, increases expression	1
lasiocarpine	decreases expression	1
methyleugenol	decreases expression	1
bisphenol A	affects cotreatment, increases methylation	1
titanium dioxide	increases expression	1
mono-(2-ethylhexyl)phthalate	decreases reaction, increases ubiquitination, increases activity, increases degradation, increases reaction (+2 more)	1

Cellosaurus cell lines

122 cell lines: 67 induced pluripotent stem cell, 24 cancer cell line, 15 finite cell line, 13 transformed cell line, 3 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_9916	XTC.UC1	Cancer cell line	Female
CVCL_A8LZ	LCSBi004-A	Induced pluripotent stem cell	Female
CVCL_A8MA	LCSBi004-B	Induced pluripotent stem cell	Female
CVCL_B0N8	HEK293T PRKN KO	Transformed cell line	Female
CVCL_B0N9	Abcam SH-SY5Y PRKN KO	Cancer cell line	Female
CVCL_C0FB	EURACi010-A	Induced pluripotent stem cell	Male
CVCL_C0FD	EURACi012-A	Induced pluripotent stem cell	Male
CVCL_C0JZ	CBIGi001-A-1	Induced pluripotent stem cell	Male
CVCL_C0K1	CBIGi001-A-3	Induced pluripotent stem cell	Male
CVCL_C1PW	HMSCATi004-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

600 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00030979	PHASE4	COMPLETED	Donepezil to Treat Dementia in Parkinson’s Disease
NCT00043849	PHASE4	COMPLETED	Treatment of Agitation/Psychosis in Dementia/Parkinsonism (TAP/DAP)
NCT00095810	PHASE4	COMPLETED	Aripiprazole in Patients With Psychosis Associated With Parkinson’s Disease
NCT00125567	PHASE4	COMPLETED	Stalevo in Early Wearing-Off Patients
NCT00143026	PHASE4	COMPLETED	Study to Compare the Effect of Treatment With Carbidopa/Levodopa/Entacapone on the Quality of Life of Patients With Parkinson’s Disease. This Study is Not Recruiting in the United States
NCT00144300	PHASE4	COMPLETED	Ophthalmologic Safety Study of Pramipexole Immediate Release (IR) Versus Ropinirole in Early Parkinson’s Disease (PD) Patients
NCT00153972	PHASE4	COMPLETED	Dopamine Turnover Rate as Surrogate Parameter for Diagnosis of Early Parkinson’s Disease
NCT00174239	PHASE4	TERMINATED	Study Of Cabaser and Sinemet CR For The Treatment Of Nighttime Symptoms Associated With Parkinson’s Disease.
NCT00215904	PHASE4	COMPLETED	D-serine Adjuvant Treatment for Parkinson’s Disease
NCT00247247	PHASE4	COMPLETED	Comtess® Versus Cabaseril® as Add-on to Levodopa in the Treatment of Parkinsonian Patients Suffering From Wearing- Off.
NCT00272688	PHASE4	COMPLETED	Continuous Delivery of Levodopa in Patients With Advanced Idiopathic Parkinsons Disease - Cost-benefit
NCT00297778	PHASE4	COMPLETED	Pramipexole Versus Placebo in Parkinson’s Disease (PD) Patients With Depressive Symptoms
NCT00304161	PHASE4	COMPLETED	Effectiveness of Antidepressant Treatment for Depression in People With Parkinson’s Disease
NCT00307450	PHASE4	COMPLETED	Efficacy and Safety of Levetiracetam Versus Placebo on Levodopa-induced Dyskinesias in Advanced Parkinson’s Disease
NCT00321854	PHASE4	COMPLETED	Study of (Mirapex) Pramipexole for the Early Treatment of Parkinsons Disease (PD)
NCT00354133	PHASE4	UNKNOWN	Controlled Trial With Deep Brain Stimulation in Patients With Early Parkinson’s Disease
NCT00373087	PHASE4	COMPLETED	COMT Polymorphism and Entacapone Efficacy
NCT00391898	PHASE4	COMPLETED	Efficacy of Levodopa/Carbidopa/Entacapone vs Levodopa/Carbidopa in Parkinson’s Disease Patients With Early Wearing-off
NCT00399477	PHASE4	COMPLETED	A Non-Blinded Study Demonstrating the Effectiveness and Safety of Azilect Alone or in Combination Therapy in Parkinson’s Disease
NCT00402233	PHASE4	COMPLETED	A Randomized, Double-blind, Active (Pramipexole 0.5 mg Tid) and Placebo Controlled, Study of Pramipexole Given 0.5 mg and 0.75 mg Bid Over 12-week Treatment in Early Parkinson’s Disease (PD) Patients
NCT00437125	PHASE4	COMPLETED	Study on the Tolerability of Duloxetine in Depressed Patients With Parkinson’s Disease
NCT00443872	PHASE4	COMPLETED	Efficacy of Orally Disintegrating Selegiline in Parkinson’s Patients Experiencing Adverse Effects With Dopamine Agonists
NCT00455143	PHASE4	TERMINATED	Cognitive Protection - Dexmedetomidine and Cognitive Reserve
NCT00462007	PHASE4	COMPLETED	Study to Evaluate Initiation of Stalevo in Early Wearing-off
NCT00462254	PHASE4	TERMINATED	Ramelteon (ROZEREM) in the Treatment of Sleep Disturbances Associated With Parkinson’s Disease
NCT00477802	PHASE4	TERMINATED	Botulinum Toxin Type A (Botox) in the Management of Levodopa-Induced Peak-Dose Dyskinesias in Parkinson’s Disease
NCT00485069	PHASE4	COMPLETED	REQUIP (Ropinirole Hydrochloride) IR Long-Term Phase 4 Study
NCT00489255	PHASE4	COMPLETED	Safety/Efficacy of Tigan® to Control Nausea/Vomiting Experienced During Apokyn® Initiation and Treatment
NCT00526630	PHASE4	COMPLETED	Methylphenidate for the Treatment of Gait Impairment in Parkinson’s Disease
NCT00561678	PHASE4	COMPLETED	Perioperative Cognitive Function - Dexmedetomidine and Cognitive Reserve
NCT00571285	PHASE4	TERMINATED	Clinical Effects of Vitamin D Repletion in Patients With Parkinson’s Disease
NCT00584025	PHASE4	WITHDRAWN	Keppra IV for the Treatment of Motor Fluctuations in Parkinson’s Disease
NCT00584090	PHASE4	WITHDRAWN	Solifenacin Succinate (VESIcare) for the Treatment of Urinary Incontinence in Parkinson’s Disease
NCT00590122	PHASE4	COMPLETED	Parcopa Versus Carbidopa-levodopa in a Single Dose Cross-over Comparison Study
NCT00594464	PHASE4	COMPLETED	A Trial of Neupro® (Rotigotine Transdermal Patch) in Patients With Parkinson’s Disease Undergoing Surgery
NCT00601978	PHASE4	WITHDRAWN	Carbidopa/Levodopa Versus Carbidopa/Levodopa/Entacapone on Markers of Event Related Potentials (ERPs) in Patients With Idiopathic Parkinson’s Disease (PD) and End-of-dose Wearing Off
NCT00632762	PHASE4	COMPLETED	Long-Term Effects of Amantadine in Parkinsonian (AMANDYSK)
NCT00640159	PHASE4	COMPLETED	Selegiline to Zelapar Switch Study in Parkinson Disease Patients
NCT00642356	PHASE4	TERMINATED	Carbidopa/Levodopa/Entacapone Versus Immediate Release (IR) Carbidopa/Levodopa on Non-motor Symptoms in Patients With Idiopathic Parkinson’s Disease and Demonstrating Non-motor Symptoms of Wearing Off
NCT00646204	PHASE4	COMPLETED	Namenda (Memantine) for Non-motor Symptoms in Parkinson’s Disease