LRP4

Chr 11

LDL receptor related protein 4

Also known as: CLSS, CMS17, LRP-4, LRP10, MEGF7, SOST2

NCBI Gene: 4038 ENSG00000134569 UniProt: O75096

This protein functions as a member of the low-density lipoprotein receptor family and regulates Wnt signaling from the cell membrane. Mutations cause Cenani-Lenz syndactyly syndrome and sclerosteosis 2 through autosomal recessive inheritance, and congenital myasthenic syndrome type 17 through autosomal dominant inheritance. The pathogenic mechanism involves gain-of-function effects.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the low-density lipoprotein receptor-related protein family. The encoded protein may be a regulator of Wnt signaling. Mutations in this gene are associated with Cenani-Lenz syndrome. [provided by RefSeq, May 2010]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtCenani-Lenz syndactyly syndrome

UniProtSclerosteosis 2

UniProtMyasthenic syndrome, congenital, 17

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.42

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — LRP4

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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?

0.42LOEUF

pLI 0.000

Z-score 6.36

OE 0.31 (0.23–0.42)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

3.06Z-score

OE missense 0.74 (0.70–0.79)

832 obs / 1120.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.31 (0.23–0.42)

0≤0.351.4

Missense OE?0.74 (0.70–0.79)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 30 / 97.9Missense obs/exp: 832 / 1120.5Syn Z: -0.31

Background carrier burden — how many people carry a rare variant somewhere in LRP4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 31

2,062 rare PASS variants

Rare truncating (LoF)

1 in 1,600

184 rare PASS variants

Rare synonymous (reference)

1 in 43

962 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for LRP4. 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 36	1 in 1,600
South Asian	~43k	1 in 33	1 in 1,300
Remaining (unassigned)	~30k	1 in 26	1 in 2,300
European (Finnish)	~27k	1 in 89	1 in 3,800
Admixed American	~22k	1 in 29	1 in 2,800
African / African American	~21k	1 in 34	1 in 2,000
East Asian	~20k	1 in 33	1 in 1,100
Ashkenazi Jewish	~13k	1 in 130	≈ 1 in 4,400
Middle Eastern	~2,884	1 in 34	≈ 1 in 720

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): 37 of 38 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 38.? see exons ↓