Parkinson disease: genes and variants

Genes linked to Parkinson disease

• VPS35: Vacuolar protein sorting-associated protein 35

  It helps retromer complexes retrieve selected cargo from endosomes for recycling to the Golgi or cell surface instead of lysosomal degradation. The p.Asp620Asn variant causes autosomal dominant Parkinson disease and links impaired endosomal trafficking to neurodegeneration.

  1 disease-causing and 63 uncertain variants in VPS35 are linked to Parkinson disease.

• LRRK2: Leucine-rich repeat serine/threonine-protein kinase 2

  Its kinase and GTPase activities regulate Rab proteins, vesicle trafficking, lysosomal function, and cellular stress responses. Gain-of-function variants, especially G2019S, are among the most common genetic causes of autosomal dominant Parkinson disease.

  0 disease-causing and 5 uncertain variants in LRRK2 are linked to Parkinson disease.

• PARK7: Parkinson disease protein 7

  It supports mitochondrial quality control, redox homeostasis, and cellular responses to oxidative stress. Biallelic loss-of-function variants cause a rare autosomal recessive form of early-onset Parkinson disease.

  0 disease-causing and 0 uncertain variants in PARK7 are linked to Parkinson disease.

• PINK1: Serine/threonine-protein kinase PINK1, mitochondrial

  It accumulates on damaged mitochondria and recruits parkin to initiate selective mitophagy and mitochondrial quality control. Biallelic loss-of-function variants cause autosomal recessive early-onset Parkinson disease.

  0 disease-causing and 0 uncertain variants in PINK1 are linked to Parkinson disease.

• ATP13A2: Polyamine-transporting ATPase 13A2

  It supports lysosomal and endolysosomal homeostasis and transports polyamines and other cationic substrates across intracellular membranes. Biallelic pathogenic variants cause Kufor-Rakeb syndrome and related early-onset parkinsonian-neurodegenerative phenotypes.

  0 disease-causing and 0 uncertain variants in ATP13A2 are linked to Parkinson disease.

• AURKA: Aurora kinase A

  It coordinates centrosome maturation, spindle assembly, and chromosome segregation during mitosis. Overexpression or amplification can promote chromosomal instability and tumor progression, making its kinase activity a target of anticancer drug development.

  0 disease-causing and 0 uncertain variants in AURKA are linked to Parkinson disease.

• AURKB: Aurora kinase B

  It controls chromosome alignment, kinetochore-microtubule attachment, the spindle checkpoint, and cytokinesis as part of the chromosomal passenger complex. Excess activity is common in proliferative cancers and can contribute to aneuploidy and treatment resistance.

  0 disease-causing and 0 uncertain variants in AURKB are linked to Parkinson disease.

• AXL: Tyrosine-protein kinase receptor UFO

  Activation by GAS6 promotes cell survival, migration, immune modulation, and resistance to cellular stress. Persistent signaling is common in advanced cancers and can support epithelial-to-mesenchymal transition, metastasis, and resistance to targeted or immune therapies.

  0 disease-causing and 0 uncertain variants in AXL are linked to Parkinson disease.

• CDK1: Cyclin-dependent kinase 1

  It is the central kinase that drives cells into mitosis and coordinates chromosome condensation, nuclear-envelope breakdown, spindle assembly, and other mitotic events. Because proliferating tumor cells depend on tightly regulated CDK1 activity, its pathway is extensively studied as an anticancer target.

  0 disease-causing and 0 uncertain variants in CDK1 are linked to Parkinson disease.

• CDK12: Cyclin-dependent kinase 12

  It promotes transcription of long DNA-repair and genome-maintenance genes through RNA-polymerase-II phosphorylation. Loss-of-function alterations occur in prostate, ovarian, and other cancers and can create a characteristic pattern of genomic instability.

  0 disease-causing and 0 uncertain variants in CDK12 are linked to Parkinson disease.

• CDK4: Cyclin-dependent kinase 4

  Together with D-type cyclins, it phosphorylates RB-family proteins and commits cells to progress from G1 toward DNA replication. Amplification or pathway activation is common in cancer, while rare activating germline variants predispose to familial melanoma.

  0 disease-causing and 0 uncertain variants in CDK4 are linked to Parkinson disease.

• CDKN1C: Cyclin-dependent kinase inhibitor 1C

  It restrains embryonic and placental cell proliferation and is subject to parent-of-origin-specific genomic imprinting. Loss of maternal expression contributes to Beckwith-Wiedemann syndrome, whereas gain-of-function variants can cause growth-restriction syndromes such as IMAGe syndrome.

  0 disease-causing and 0 uncertain variants in CDKN1C are linked to Parkinson disease.

• CDKN2A: Tumor suppressor ARF

  The ARF product of CDKN2A is a tumor-suppressor protein that binds MDM2 and helps preserve p53 activity. By promoting cell-cycle arrest and apoptosis, it provides an important barrier to uncontrolled cell growth from within the nucleolus.

  0 disease-causing and 0 uncertain variants in CDKN2A are linked to Parkinson disease.

• COMT: Catechol O-methyltransferase

  It inactivates catecholamines and catechol-containing drugs through methylation, contributing to dopamine, norepinephrine, and estrogen-metabolite turnover. Common functional variants alter enzyme activity and have modest effects on catecholamine physiology and responses to some medications.

  0 disease-causing and 0 uncertain variants in COMT are linked to Parkinson disease.

• DDC: Aromatic-L-amino-acid decarboxylase

  It converts L-DOPA to dopamine and 5-hydroxytryptophan to serotonin, making it essential for monoamine neurotransmitter synthesis. Biallelic loss-of-function variants cause aromatic L-amino-acid decarboxylase deficiency with severe movement and autonomic abnormalities.

  0 disease-causing and 0 uncertain variants in DDC are linked to Parkinson disease.

• DRD2: D(2) dopamine receptor

  Its activation by dopamine modulates cyclic-AMP signaling and neuronal excitability in circuits governing movement, motivation, reward, and endocrine control. It is a major pharmacologic target of antipsychotic drugs and dopamine agonists, and rare variants can produce movement or neuropsychiatric phenotypes.

  0 disease-causing and 0 uncertain variants in DRD2 are linked to Parkinson disease.

• DRD4: D(4) dopamine receptor

  It modulates dopamine signaling in cortical and limbic circuits and influences cyclic-AMP production and neuronal excitability. Common repeat polymorphisms have been studied extensively for behavioral traits, although their individual effects are modest and not deterministic.

  0 disease-causing and 0 uncertain variants in DRD4 are linked to Parkinson disease.

• GBA1: Lysosomal acid glucosylceramidase

  It degrades glucosylceramide within lysosomes and is essential for normal sphingolipid turnover. Biallelic pathogenic variants cause Gaucher disease, while heterozygous pathogenic variants are among the strongest genetic risk factors for Parkinson disease.

  0 disease-causing and 0 uncertain variants in GBA1 are linked to Parkinson disease.

• GRIN2A: Glutamate receptor ionotropic, NMDA 2A

  It helps determine the kinetics and signaling properties of NMDA receptors, particularly in cortical circuits involved in language and epilepsy. Pathogenic variants cause a spectrum of developmental epileptic encephalopathies and epilepsy-aphasia disorders.

  0 disease-causing and 0 uncertain variants in GRIN2A are linked to Parkinson disease.

• GRIN2B: Glutamate receptor ionotropic, NMDA 2B

  It confers distinct developmental and signaling properties on NMDA receptors and is highly expressed during early brain development. De novo pathogenic variants can cause intellectual disability, developmental delay, epilepsy, abnormal movements, and autism-related phenotypes.

  0 disease-causing and 0 uncertain variants in GRIN2B are linked to Parkinson disease.

• HMGCR: 3-hydroxy-3-methylglutaryl-coenzyme A reductase

  It controls the rate-limiting step of the mevalonate pathway and therefore strongly regulates endogenous cholesterol production. Statins lower LDL cholesterol by inhibiting this activity, causing the liver to increase LDL-receptor-mediated clearance from blood.

  0 disease-causing and 0 uncertain variants in HMGCR are linked to Parkinson disease.

• HTR2A: 5-hydroxytryptamine receptor 2A

  Its activation by serotonin engages Gq signaling in cortical, vascular, and other tissues and influences perception, mood, cognition, and smooth-muscle responses. It is a major target of many antipsychotic drugs and psychedelic compounds, while common genetic effects on behavior are generally modest.

  0 disease-causing and 0 uncertain variants in HTR2A are linked to Parkinson disease.

• HTR2C: 5-hydroxytryptamine receptor 2C

  Its serotonin-dependent signaling in hypothalamic and limbic circuits suppresses appetite and modulates mood, reward, and neuroendocrine function. Altered signaling can affect body weight and psychiatric drug responses, and the receptor is a pharmacologic target of several neuropsychiatric agents.

  0 disease-causing and 0 uncertain variants in HTR2C are linked to Parkinson disease.

• MAOB: Amine oxidase [flavin-containing] B

  It oxidatively degrades dopamine and several trace amines, particularly in brain glial cells and other tissues. Pharmacologic inhibition increases brain dopamine availability and is used in Parkinson disease, while inherited severe deficiency is rare.

  0 disease-causing and 0 uncertain variants in MAOB are linked to Parkinson disease.

• MAPT: Microtubule-associated protein tau

  Its tau isoforms stabilize and organize neuronal microtubules, especially in axons, while also participating in transport and signaling. Pathogenic variants cause inherited frontotemporal dementia, and abnormal tau aggregation defines multiple neurodegenerative tauopathies.

  0 disease-causing and 0 uncertain variants in MAPT are linked to Parkinson disease.

• NAT1: Arylamine N-acetyltransferase 1

  It acetylates aromatic amines and related xenobiotics and participates in metabolism of selected endogenous substrates. Genetic variation can alter activity and exposure to some chemicals, although clinical pharmacogenomic effects are generally less established than for NAT2.

  0 disease-causing and 0 uncertain variants in NAT1 are linked to Parkinson disease.

• PLK1: Serine/threonine-protein kinase PLK1

  It coordinates centrosome maturation, chromosome segregation, spindle function, and cytokinesis during mitosis. Many tumors overexpress PLK1 and depend on its activity for rapid proliferation, making it a prominent anticancer drug target.

  0 disease-causing and 0 uncertain variants in PLK1 are linked to Parkinson disease.

• SMPD1: Sphingomyelin phosphodiesterase

  It hydrolyzes sphingomyelin to ceramide in lysosomes and participates in membrane-lipid turnover and stress signaling. Biallelic loss-of-function variants cause acid sphingomyelinase deficiency, including Niemann-Pick disease types A and B.

  0 disease-causing and 0 uncertain variants in SMPD1 are linked to Parkinson disease.

• SNCA: Alpha-synuclein

  Alpha-synuclein is a neuronal protein that supports synaptic-vesicle trafficking, priming, and neurotransmitter release. Misfolded or aggregated alpha-synuclein is a defining feature of Parkinson disease and Lewy-body disorders.

  0 disease-causing and 0 uncertain variants in SNCA are linked to Parkinson disease.

• TGFBR2: TGF-beta receptor type-2

  It binds TGF-beta ligands and activates TGFBR1 to initiate canonical and noncanonical signaling. Germline pathogenic variants cause Loeys-Dietz syndrome type 2, while somatic loss can remove growth-suppressive TGF-beta responses in cancer.

  0 disease-causing and 0 uncertain variants in TGFBR2 are linked to Parkinson disease.

• PRKN: E3 ubiquitin-protein ligase parkin

  Its parkin ubiquitin-ligase activity marks damaged mitochondrial proteins after PINK1 activation and helps eliminate dysfunctional mitochondria through mitophagy. Biallelic loss-of-function variants are a major cause of autosomal recessive juvenile or early-onset Parkinson disease.

  0 disease-causing and 1 uncertain variants in PRKN are linked to Parkinson disease.

Weakly linked (only a few uncertain records): GRN, TBP and ATXN3.

Known disease-causing variants in Parkinson disease

Diseases related to Parkinson disease

• Alzheimer disease, also linked to AURKA, AURKB, AXL, CDK1 and 11 more
• Schizophrenia, also linked to DRD2, DRD4, GRIN2A, HTR2A and 1 more
• Autosomal dominant Parkinson disease 8, also linked to LRRK2, PRKN and SNCA
• Autism, also linked to DRD2, HTR2A and HTR2C
• Young-onset Parkinson disease, also linked to LRRK2, PARK7 and PRKN
• Epilepsy, also linked to GRIN2A and GRIN2B
• Familial melanoma, also linked to CDK4 and CDKN2A
• Autosomal recessive early-onset Parkinson disease 6, also linked to PARK7 and PINK1
• Melanoma, cutaneous malignant, susceptibility to, 8, also linked to CDK4 and CDKN2A
• Lung adenocarcinoma, also linked to CDK12 and CDKN2A
• Lewy body dementia, also linked to GBA1 and SNCA
• Parkinson disease, late-onset, also linked to GBA1 and MAPT

Frequently asked questions

Which genes are linked to Parkinson disease?

In CATVariant, Parkinson disease is linked to 31 analyzed proteins: VPS35 (Vacuolar protein sorting-associated protein 35), LRRK2 (Leucine-rich repeat serine/threonine-protein kinase 2), PARK7 (Parkinson disease protein 7), PINK1 (Serine/threonine-protein kinase PINK1, mitochondrial), ATP13A2 (Polyamine-transporting ATPase 13A2), AURKA (Aurora kinase A) and 25 more.

How many genetic variants are linked to Parkinson disease?

98 variants: 1 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 69 are of uncertain significance or have conflicting reports.

Which uncertain variants in Parkinson disease look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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