LRRK1

Chr 15

leucine rich repeat kinase 1

Also known as: OSMD, RIPK6, Roco1

NCBI Gene: 79705 ENSG00000154237 UniProt: Q38SD2

The protein is a serine/threonine kinase that phosphorylates RAB proteins involved in intracellular trafficking and negatively regulates bone mass through osteoclast maturation. Autosomal recessive mutations cause osteosclerotic metaphyseal dysplasia, a bone disorder characterized by increased bone density and abnormal bone development. The gene is highly constrained against loss-of-function variants (LOEUF 0.493), indicating that complete loss of protein function is likely pathogenic.

ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a multi-domain protein that is a leucine-rich repeat kinase and a GDP/GTP binding protein. The encoded protein is thought to play a role in the regulation of bone mass. Mice lacking a similar gene showed severe osteopetrosis, increased bone mineralization and decreased bone resorption. [provided by RefSeq, Jan 2017]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtOsteosclerotic metaphyseal dysplasia

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.49

LOEUF

GOF

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

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?

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?

LoF OE?0.37 (0.28–0.49)

0≤0.351.4

Missense OE?0.78 (0.74–0.82)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 33 / 89.5Missense obs/exp: 931 / 1195.3Syn Z: -1.04

Background carrier burden — how many people carry a rare variant somewhere in LRRK1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 22

2,435 rare PASS variants

Rare truncating (LoF)

1 in 340

254 rare PASS variants

Rare synonymous (reference)

1 in 26

1,217 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for LRRK1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 33	1 in 420
South Asian	~43k	1 in 17	1 in 1,200
Remaining (unassigned)	~30k	1 in 20	1 in 340
European (Finnish)	~27k	1 in 84	1 in 2,300
Admixed American	~22k	1 in 24	1 in 340
African / African American	~21k	1 in 22	1 in 940
East Asian	~20k	1 in 24	1 in 580
Ashkenazi Jewish	~13k	1 in 110	1 in 2,300
Middle Eastern	~2,884	1 in 20	≈ 1 in 950

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 31 of 33 coding exons well covered in gnomAD exomes; exons 3, 11 marginal. Genomes: all 33.? see exons ↓