LRRK2

leucine rich repeat kinase 2

4 disorders 2 causative 1 disputed 1 untyped 1 protective 1 risk factor 12q12 gene with protein product

HGNC:18618 Monarch NCBI Gene 120892 ENSG00000188906 UniProt Q5S007 OMIM 609007

Previous symbols: PARK8. Aliases: ROCO2, DKFZp434H2111, FLJ45829, RIPK7.

Normal function · from ai-gene-review (Q5S007, commit 79fe13b38970) · AI-generated, not KB evidence

LRRK2 (Leucine-rich repeat serine/threonine-protein kinase 2) is a large multi-domain ROCO family protein with dual enzymatic activities - a serine/threonine protein kinase (EC 2.7.11.1) and a GTPase (EC 3.6.5.-). The protein contains ARM/ANK/LRR repeats, ROC (Ras of complex proteins) GTPase domain, COR (C-terminal of ROC) domain, kinase domain, and WD40 repeats. LRRK2 phosphorylates a subset of Rab GTPases (primarily Rab8A, Rab10, Rab12, Rab29) at their switch II regions, regulating endolysosomal trafficking and ciliogenesis. It is predominantly cytosolic but dynamically recruited to Golgi, endosomes, and lysosomes where its Rab substrates reside. Mutations in LRRK2 are the most common genetic cause of familial Parkinson's disease (PARK8).

LRRK2 contains a kinase domain that phosphorylates Rab GTPases at threonine residues in their switch II regions. Primary substrates include Rab8A (Thr72), Rab10 (Thr73), Rab12 (Thr73), and Rab29 (Thr71).

molecular function: protein serine/threonine kinase activity

The ROC (Ras of complex proteins) domain of LRRK2 binds and hydrolyzes GTP. GTP binding and hydrolysis regulate kinase domain activity through intramolecular signaling.

molecular function: GTPase activity

LRRK2 ROC domain binds GTP, which is essential for regulating kinase activity. GTP binding status affects the conformation and enzymatic output of the protein.

molecular function: GTP binding

In the knowledge base · computed from kb/ at build time

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.

Disorder	Relationship	Where the gene appears
Amyotrophic Lateral Sclerosis-Parkinsonism-Dementia Complex	disputed germline
LRRK2-Related Parkinson Disease	causativeprotectiverisk factor germline
Parkinson's Disease	causative	mechanism: Autophagy-Lysosome Pathway Dysfunction; LRRK2 GTPase Domain Dysregulation discussion: (unnamed)
Crohn Disease	untyped Risk Factor	mechanism: Macrophage Autophagy Dysfunction

ClinGen gene–disease validity · snapshot 2026-10-03 · matched to entries by MONDO

An entry matches when ClinGen's MONDO disease is the entry's own disease term, a subtype term, or an exact-match mapping. An amber status marks an entry ClinGen supports the gene for (Definitive, Strong or Moderate) whose own record does not type it. A Limited, Disputed or Refuted tier on such an entry is not a gap.

ClinGen disease	MOI	Classification	dismech entry
Parkinson disease MONDO:0005180	AD	Definitive 2021-05-03	Parkinson's Disease causative

Mechanism modules · computed from kb/

disabled_macroautophagy via Parkinson's Disease

Identity from HGNC (snapshot 2026-10-01). Page layers are described in the gene pages documentation.