LRP4

Chr 11ARAD

LDL receptor related protein 4

ENSG00000134569UniProt: O75096

Mediates SOST-dependent inhibition of bone formation. Functions as a specific facilitator of SOST-mediated inhibition of Wnt signaling. Plays a key role in the formation and the maintenance of the neuromuscular junction (NMJ), the synapse between motor neuron and skeletal muscle. Directly binds AGRIN and recruits it to the MUSK signaling complex. Mediates the AGRIN-induced phosphorylation of MUSK, the kinase of the complex. The activation of MUSK in myotubes induces the formation of NMJ by regulating different processes including the transcription of specific genes and the clustering of AChR in the postsynaptic membrane. Alternatively, may be involved in the negative regulation of the canonical Wnt signaling pathway, being able to antagonize the LRP6-mediated activation of this pathway. More generally, has been proposed to function as a cell surface endocytic receptor binding and internalizing extracellular ligands for degradation by lysosomes. May play an essential role in the process of digit differentiation (By similarity)

Primary Disease Associations & Inheritance

?Myasthenic syndrome, congenital, 17MIM #616304
AR
Cenani-Lenz syndactyly syndromeMIM #212780
AR
Sclerosteosis 2MIM #614305
ADAR
478
ClinVar variants
14
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— LRP4
🧬
Gene-Disease Validity (ClinGen)
Cenani-Lenz syndactyly syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.31) despite low pLI — interpret in context.
📋
ClinVar Variants
14 Pathogenic / Likely Pathogenic· 310 VUS of 478 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esummary.fcgi

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.
0.42LOEUF
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?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.
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?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.0.31 (0.23–0.42)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.74 (0.70–0.79)
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.1.02
0≤1.21.6
LoF obs/exp: 30 / 97.9Missense obs/exp: 832 / 1120.5Syn Z: -0.31

ClinVar Variant Classifications

478 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7
Likely Pathogenic7
VUS310
Likely Benign143
Conflicting11
7
Pathogenic
7
Likely Pathogenic
310
VUS
143
Likely Benign
11
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
6
0
7
Likely Pathogenic
5
1
1
0
7
VUS
4
278
20
8
310
Likely Benign
0
2
51
90
143
Benign
0
0
0
0
0
Conflicting
—11
Total102817898478

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

View in ClinVar →

Protein Context — Lollipop Plot

LRP4 · protein map & ClinVar variants

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

Gene2Phenotype Curations

LRP4-related Cenani-Lenz syndactyly syndrome

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersSkeletal
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Myasthenic syndrome, congenital, 17

MIM #616304

Molecular basis of disorder known

Autosomal recessive

Cenani-Lenz syndactyly syndrome

MIM #212780

Molecular basis of disorder known

Autosomal recessive

Sclerosteosis 2

MIM #614305

Molecular basis of disorder known

Autosomal dominantAutosomal recessive
📖
GeneReview available — LRP4
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Myasthenia gravis: subgroup classification and therapeutic strategies.
Gilhus NE et al.·Lancet Neurol
2015Review
Myasthenia gravis-Pathophysiology, diagnosis, and treatment.
Tannemaat MR et al.·Handb Clin Neurol
2024Review
Safety and efficacy of nipocalimab in adults with generalised myasthenia gravis (Vivacity-MG3): a phase 3, randomised, double-blind, placebo-controlled study.
Antozzi C et al.·Lancet Neurol
2025Clinical trial
Myasthenia gravis.
Pasnoor M et al.·Handb Clin Neurol
2024Review
Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review.
Ohno K et al.·Int J Mol Sci
2023Review
Myasthenia gravis: a clinical-immunological update.
Binks S et al.·J Neurol
2016Review
Neuromuscular Junction Formation, Aging, and Disorders.
Li L et al.·Annu Rev Physiol
2018Review
Immunotherapies in MuSK-positive Myasthenia Gravis; an IgG4 antibody-mediated disease.
Vakrakou AG et al.·Front Immunol
2023Review
Triple-seronegative myasthenia gravis: clinical and epidemiological characteristics.
Rodrigues PRDVP et al.·Arq Neuropsiquiatr
2024
Prevalence, Incidence, and Mortality of Myasthenia Gravis and Myasthenic Syndromes: A Systematic Review.
Sciancalepore F et al.·Neuroepidemiology
2025Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Low Prevalence and Inconsistency of LRP4-IgG Detection in Suspected Myasthenia Gravis: A Multicenter CBA Comparison.
Gligora I et al.·Neurol Neuroimmunol Neuroinflamm
2026🔓 Open Access
LRP4+ Astrocytes: A Unique Subpopulation Crucial for Blood Vessel Maintenance and Function in the Somatosensory Cortex of Normal and 5xFAD Mice.
Arzola E et al.·Glia
2026🔓 Open Access
Adipocytic sclerostin loop3-LRP4 interaction required by sclerostin to impair whole-body lipid and glucose metabolism.
Jiang H et al.·Nat Commun
2026🔓 Open Access
WNT10A-SMOC2-LRP4 network affects permanent tooth development via potential tooth-bone interaction.
Chen Y et al.·BMC Oral Health
2025🔓 Open Access
KIAA1429-mediated M6A methylation inhibits osteoclast differentiation via stabilizing Lrp4 mRNA and protects against osteoporosis.
Liu J et al.·Cell Mol Biol Lett
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
High Blood Pressure

STUDY OF THE DOUBLE POLYMORPHISM (THR 555ILE) AND (GLU568PRO) OF THE CORIN GENE AS A RISK FACTOR FOR ARTERIAL HYPERTENSION IN A POPULATION OF AFRICAN DESCENT IN GUADELOUPE

RECRUITING
NCT07330804Phase NACentre Hospitalier Universitaire de la GuadeloupeStarted 2025-01-16
double polymorphism

External Resources

Links to major genomics databases and tools