LRRK1

Chr 15AR

leucine rich repeat kinase 1

NCBI Gene: 79705ENSG00000154237UniProt: Q38SD2

Serine/threonine-protein kinase which phosphorylates RAB proteins involved in intracellular trafficking (PubMed:36040231). Phosphorylates RAB7A; this activity is dependent on protein kinase C (PKC) activation (PubMed:36040231, PubMed:37558661, PubMed:37857821). Plays a role in the negative regulation of bone mass, acting through the maturation of osteoclasts (By similarity)

Primary Disease Associations & Inheritance

Osteosclerotic metaphyseal dysplasiaMIM #615198
AR
557
ClinVar variants
26
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— LRRK1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
26 Pathogenic / Likely Pathogenic· 267 VUS of 557 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.49LOEUF
pLI 0.000
Z-score 5.54
OE 0.37 (0.28–0.49)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.72Z-score
OE missense 0.78 (0.74–0.82)
931 obs / 1195.3 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.37 (0.28–0.49)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.78 (0.74–0.82)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.06
0≤1.21.6
LoF obs/exp: 33 / 89.5Missense obs/exp: 931 / 1195.3Syn Z: -1.04

ClinVar Variant Classifications

557 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic20
Likely Pathogenic6
VUS267
Likely Benign257
Benign4
Conflicting3
20
Pathogenic
6
Likely Pathogenic
267
VUS
257
Likely Benign
4
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
5
0
15
0
20
Likely Pathogenic
4
0
2
0
6
VUS
1
259
6
1
267
Likely Benign
0
10
83
164
257
Benign
0
0
3
1
4
Conflicting
—3
Total10269109166557

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

LRRK1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Osteosclerotic metaphyseal dysplasia

MIM #615198

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Type II kinase inhibitors that target Parkinson's disease-associated LRRK2.
Raig ND et al.·Sci Adv
2025
Osteopetrosis: Gene-based nosology and significance Dysosteosclerosis.
Turan S·Bone
2023
PKC isoforms activate LRRK1 kinase by phosphorylating conserved residues (Ser1064, Ser1074 and Thr1075) within the CORB GTPase domain.
Malik AU et al.·Biochem J
2022
Broadening the phenotype of LRRK1 mutations - Features of malignant osteopetrosis and optic nerve atrophy with intrafamilial variable expressivity.
Chorin O et al.·Eur J Med Genet
2022Case report
Genetic Analysis of LRRK1 and LRRK2 Variants in Essential Tremor Patients.
Chen H et al.·Genet Test Mol Biomarkers
2018Cohort
15q26.3 deletions distal to IGF1R cause growth retardation, congenital heart defect and skeletal anomalies: Case report and review of literature.
Sivakumaran TA et al.·Am J Med Genet A
2023Review
Frequency of Loss of Function Variants in LRRK2 in Parkinson Disease.
Blauwendraat C et al.·JAMA Neurol
2018
Genetic Risk Factors for Essential Tremor: A Review.
Siokas V et al.·Tremor Other Hyperkinet Mov (N Y)
2020Review
Identification of biallelic LRRK1 mutations in osteosclerotic metaphyseal dysplasia and evidence for locus heterogeneity.
Iida A et al.·J Med Genet
2016
Case Report: Osteosclerotic metaphyseal dysplasia with optic nerve involvement and progressive osteonecrosis of the jaw due to a novel LRRK1 mutation.
Pieridou C et al.·Front Endocrinol (Lausanne)
2023Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools