LRRK2

leucine rich repeat kinase 2, the group of ROCO family|Armadillo like helical domain containing

Basic information

Region (hg38): 12:40196743-40369285

Previous symbols: [ "PARK8" ]

Links

ENSG00000188906 ∙ NCBI:120892 ∙ OMIM:609007 ∙ HGNC:18618 ∙ Uniprot:Q5S007 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autosomal dominant Parkinson disease 8 (Strong), mode of inheritance: AD
• hereditary late onset Parkinson disease (Supportive), mode of inheritance: AD
• autosomal dominant Parkinson disease 8 (Definitive), mode of inheritance: AD
• autosomal dominant Parkinson disease 8 (Strong), mode of inheritance: AD
• Parkinson disease (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Parkinson disease 8, autosomal dominant	AD	Neurologic	Response to levodopa has been documented	Neurologic	15541309; 16437584; 16437559; 19458969

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the LRRK2 gene.

• Inborn genetic diseases (2184 variants)
• Autosomal dominant Parkinson disease 8 (723 variants)
• not provided (352 variants)
• not specified (38 variants)
• LRRK2-related condition (4 variants)
• Parkinson disease, late-onset (3 variants)
• Parkinson Disease, Dominant (1 variants)
• Parkinson disease (1 variants)
• Autosomal dominant Parkinson disease 8;Klippel-Feil syndrome 1, autosomal dominant (1 variants)
• Early onset Alzheimer disease with behavioral disturbance (1 variants)
• Leprosy, susceptibility to, 1 (1 variants)
• Spinocerebellar atrophy (1 variants)
• Young-onset Parkinson disease (1 variants)
• Parkinsonism;Frontotemporal dementia;Brain atrophy;Rigidity (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the LRRK2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			9	853	7	869
missense	4	2	1512	58	7	1583
nonsense		1	8			9
start loss						0
frameshift			12			12
inframe indel			5			5
splice donor/acceptor (+/-2bp)			4			4
splice region			20	39	4	63
non coding			33	121	147	301
Total	4	3	1583	1032	161

Highest pathogenic variant AF is 0.0000396

Variants in LRRK2

This is a list of pathogenic ClinVar variants found in the LRRK2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
12-40224884-T-C			Benign (Aug 17, 2018)
12-40224903-G-A			Likely benign (Sep 11, 2018)
12-40225008-G-C		Autosomal dominant Parkinson disease 8	Benign/Likely benign (Aug 17, 2018)
12-40225041-C-T		Autosomal dominant Parkinson disease 8	Uncertain significance (Jan 13, 2018)
12-40225058-C-A		Autosomal dominant Parkinson disease 8	Uncertain significance (Jan 13, 2018)
12-40225088-G-A		Autosomal dominant Parkinson disease 8	Likely benign (Jan 12, 2018)
12-40225140-T-C		Inborn genetic diseases	Likely benign (Oct 19, 2022)
12-40225148-G-A		Inborn genetic diseases	Uncertain significance (Apr 06, 2022)
12-40225148-G-C		Autosomal dominant Parkinson disease 8	Uncertain significance (Jan 04, 2022)
12-40225149-T-C		Inborn genetic diseases	Likely benign (Feb 28, 2023)
12-40225152-G-T		Autosomal dominant Parkinson disease 8	Uncertain significance (Mar 11, 2023)
12-40225153-G-A		Autosomal dominant Parkinson disease 8	Uncertain significance (Mar 02, 2022)
12-40225159-G-A		Autosomal dominant Parkinson disease 8	Uncertain significance (Nov 30, 2021)
12-40225160-A-C		Inborn genetic diseases	Uncertain significance (Sep 30, 2021)
12-40225163-A-C		Inborn genetic diseases	Uncertain significance (Dec 19, 2022)
12-40225164-G-A		Inborn genetic diseases	Likely benign (Aug 02, 2020)
12-40225167-C-G		Inborn genetic diseases	Uncertain significance (Sep 13, 2023)
12-40225168-G-A		Inborn genetic diseases	Uncertain significance (Dec 04, 2023)
12-40225170-G-A		Inborn genetic diseases	Likely benign (Mar 18, 2022)
12-40225170-G-C		Inborn genetic diseases	Uncertain significance (Oct 12, 2022)
12-40225176-T-C		Autosomal dominant Parkinson disease 8 • Inborn genetic diseases	Likely benign (Jan 24, 2024)
12-40225180-A-C		Inborn genetic diseases	Uncertain significance (Jul 16, 2021)
12-40225182-G-A		Inborn genetic diseases	Likely benign (Sep 25, 2020)
12-40225185-G-A		Inborn genetic diseases	Likely benign (Nov 29, 2020)
12-40225191-A-G		Inborn genetic diseases	Uncertain significance (Apr 02, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
LRRK2	protein_coding	protein_coding	ENST00000298910	51	172542

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.58e-30	1.00	125453	0	295	125748	0.00117

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.26	1151	1.28e+3	0.901	0.0000638	16658
Missense in Polyphen		299	435.16	0.68711		5736
Synonymous	-0.276	474	466	1.02	0.0000239	4655
Loss of Function	5.14	72	137	0.526	0.00000756	1706

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00495	0.00496
Ashkenazi Jewish	0.000298	0.000298
East Asian	0.000436	0.000435
Finnish	0.000186	0.000185
European (Non-Finnish)	0.00129	0.00128
Middle Eastern	0.000436	0.000435
South Asian	0.000590	0.000588
Other	0.00114	0.00114

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Positively regulates autophagy through a calcium- dependent activation of the CaMKK/AMPK signaling pathway. The process involves activation of nicotinic acid adenine dinucleotide phosphate (NAADP) receptors, increase in lysosomal pH, and calcium release from lysosomes. Together with RAB29, plays a role in the retrograde trafficking pathway for recycling proteins, such as mannose 6 phosphate receptor (M6PR), between lysosomes and the Golgi apparatus in a retromer-dependent manner. Regulates neuronal process morphology in the intact central nervous system (CNS). Plays a role in synaptic vesicle trafficking. Phosphorylates PRDX3. Has GTPase activity. May play a role in the phosphorylation of proteins central to Parkinson disease. {ECO:0000269|PubMed:17114044, ECO:0000269|PubMed:18230735, ECO:0000269|PubMed:20949042, ECO:0000269|PubMed:21850687, ECO:0000269|PubMed:22012985, ECO:0000269|PubMed:23395371, ECO:0000269|PubMed:24687852}.
• Disease: DISEASE: Parkinson disease 8 (PARK8) [MIM:607060]: A slowly progressive neurodegenerative disorder characterized by bradykinesia, rigidity, resting tremor, postural instability, neuronal loss in the substantia nigra, and the presence of neurofibrillary MAPT (tau)-positive and Lewy bodies in some patients. {ECO:0000269|PubMed:15541308, ECO:0000269|PubMed:15541309, ECO:0000269|PubMed:15680455, ECO:0000269|PubMed:15680456, ECO:0000269|PubMed:15680457, ECO:0000269|PubMed:15726496, ECO:0000269|PubMed:15732108, ECO:0000269|PubMed:15811454, ECO:0000269|PubMed:15852371, ECO:0000269|PubMed:15880653, ECO:0000269|PubMed:15925109, ECO:0000269|PubMed:15929036, ECO:0000269|PubMed:16102999, ECO:0000269|PubMed:16157901, ECO:0000269|PubMed:16157908, ECO:0000269|PubMed:16157909, ECO:0000269|PubMed:16172858, ECO:0000269|PubMed:16240353, ECO:0000269|PubMed:16247070, ECO:0000269|PubMed:16250030, ECO:0000269|PubMed:16251215, ECO:0000269|PubMed:16269541, ECO:0000269|PubMed:16272164, ECO:0000269|PubMed:16272257, ECO:0000269|PubMed:16298482, ECO:0000269|PubMed:16321986, ECO:0000269|PubMed:16333314, ECO:0000269|PubMed:16533964, ECO:0000269|PubMed:17114044, ECO:0000269|PubMed:18213618, ECO:0000269|PubMed:21850687, ECO:0000269|PubMed:22956510, ECO:0000269|PubMed:23395371}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Parkinson,s disease - Homo sapiens (human);Allograft Rejection;Parkinsons Disease Pathway;Olfactory bulb development and olfactory learning;MAPK Signaling Pathway;Wnt Signaling Pathway and Pluripotency;Signaling by PTK6;Signal Transduction;PTK6 promotes HIF1A stabilization;Signaling by Non-Receptor Tyrosine Kinases (Consensus)

Intolerance Scores

• loftool: 0.869
• rvis_EVS: -1.13
• rvis_percentile_EVS: 6.51

Haploinsufficiency Scores

• pHI: 0.122
• hipred: Y
• hipred_score: 0.652
• ghis: 0.487

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.462

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Lrrk2
• Phenotype: pigmentation phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); renal/urinary system phenotype; immune system phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); endocrine/exocrine gland phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); homeostasis/metabolism phenotype; cellular phenotype

Zebrafish Information Network

• Gene name: lrrk2
• Affected structure: optic fissure
• Phenotype tag: abnormal
• Phenotype quality: open

Gene ontology

• Biological process: MAPK cascade;activation of MAPKK activity;activation of MAPK activity;negative regulation of protein phosphorylation;positive regulation of protein phosphorylation;protein phosphorylation;endocytosis;autophagy;response to oxidative stress;mitochondrion organization;endoplasmic reticulum organization;Golgi organization;lysosome organization;spermatogenesis;neuromuscular junction development;determination of adult lifespan;cellular response to starvation;regulation of autophagy;positive regulation of autophagy;regulation of protein kinase A signaling;negative regulation of protein processing;negative regulation of neuron projection development;regulation of neuron maturation;negative regulation of macroautophagy;phosphorylation;peptidyl-serine phosphorylation;peptidyl-threonine phosphorylation;calcium-mediated signaling;striatum development;olfactory bulb development;tangential migration from the subventricular zone to the olfactory bulb;positive regulation of protein ubiquitination;negative regulation of protein binding;positive regulation of protein binding;positive regulation of proteasomal ubiquitin-dependent protein catabolic process;obsolete positive regulation of protein import into nucleus, translocation;negative regulation of GTPase activity;cellular response to oxidative stress;cellular protein localization;intracellular signal transduction;regulation of kidney size;exploration behavior;locomotory exploration behavior;regulation of lysosomal lumen pH;regulation of locomotion;regulation of membrane potential;positive regulation of programmed cell death;positive regulation of MAP kinase activity;positive regulation of GTPase activity;GTP metabolic process;protein autophosphorylation;intracellular distribution of mitochondria;neuron projection morphogenesis;mitochondrion localization;positive regulation of nitric-oxide synthase biosynthetic process;regulation of mitochondrial depolarization;regulation of synaptic transmission, glutamatergic;canonical Wnt signaling pathway;excitatory postsynaptic potential;regulation of dopamine receptor signaling pathway;positive regulation of dopamine receptor signaling pathway;regulation of ER to Golgi vesicle-mediated transport;regulation of canonical Wnt signaling pathway;regulation of dendritic spine morphogenesis;protein localization to mitochondrion;protein localization to endoplasmic reticulum exit site;neuron death;cellular response to manganese ion;reactive oxygen species metabolic process;regulation of mitochondrial fission;positive regulation of canonical Wnt signaling pathway;negative regulation of excitatory postsynaptic potential;neuron projection arborization;positive regulation of synaptic vesicle endocytosis;regulation of neuron death;negative regulation of neuron death;positive regulation of histone deacetylase activity;negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway;positive regulation of protein autoubiquitination;regulation of neuroblast proliferation;regulation of synaptic vesicle transport;negative regulation of late endosome to lysosome transport;negative regulation of autophagosome assembly;negative regulation of thioredoxin peroxidase activity by peptidyl-threonine phosphorylation;negative regulation of hydrogen peroxide-induced cell death;negative regulation of protein targeting to mitochondrion;negative regulation of protein processing involved in protein targeting to mitochondrion;cellular response to dopamine;positive regulation of microglial cell activation;positive regulation of tumor necrosis factor secretion;Wnt signalosome assembly;regulation of retrograde transport, endosome to Golgi;regulation of CAMKK-AMPK signaling cascade;regulation of branching morphogenesis of a nerve;regulation of synaptic vesicle exocytosis
• Cellular component: extracellular space;nucleus;cytoplasm;mitochondrion;mitochondrial outer membrane;mitochondrial inner membrane;mitochondrial matrix;lysosome;endosome;endoplasmic reticulum;Golgi apparatus;Golgi-associated vesicle;trans-Golgi network;cytosol;plasma membrane;microvillus;inclusion body;cell junction;axon;dendrite;growth cone;synaptic vesicle membrane;cytoplasmic vesicle;mitochondrial membrane;cytoplasmic side of mitochondrial outer membrane;dendrite cytoplasm;neuron projection;neuronal cell body;terminal bouton;perikaryon;intracellular membrane-bounded organelle;amphisome;autolysosome;membrane raft;extracellular exosome;endoplasmic reticulum exit site;multivesicular body, internal vesicle;postsynapse;glutamatergic synapse;caveola neck;presynaptic cytosol;ribonucleoprotein complex;Wnt signalosome
• Molecular function: SNARE binding;actin binding;GTPase activity;protein kinase activity;protein serine/threonine kinase activity;MAP kinase kinase activity;GTPase activator activity;protein binding;ATP binding;GTP binding;microtubule binding;tubulin binding;kinase activity;Rho GTPase binding;syntaxin-1 binding;receptor signaling complex scaffold activity;clathrin binding;GTP-dependent protein kinase activity;peroxidase inhibitor activity;co-receptor binding;identical protein binding;protein homodimerization activity;ion channel binding;protein kinase A binding;beta-catenin destruction complex binding