LRP2

Chr 2AR

LDL receptor related protein 2

Also known as: DBS, GP330, LRP-2

NCBI Gene: 4036ENSG00000081479UniProt: P98164

The protein encoded by this gene, low density lipoprotein-related protein 2 (LRP2) or megalin, is a multi-ligand endocytic receptor that is expressed in many different tissues but primarily in absorptive epithilial tissues such as the kidney. This glycoprotein has a large amino-terminal extracellular domain, a single transmembrane domain, and a short carboxy-terminal cytoplasmic tail. The extracellular ligand-binding-domains bind diverse macromolecules including albumin, apolipoproteins B and E, and lipoprotein lipase. The LRP2 protein is critical for the reuptake of numerous ligands, including lipoproteins, sterols, vitamin-binding proteins, and hormones. This protein also has a role in cell-signaling; extracellular ligands include parathyroid horomones and the morphogen sonic hedgehog while cytosolic ligands include MAP kinase scaffold proteins and JNK interacting proteins. Recycling of this membrane receptor is regulated by phosphorylation of its cytoplasmic domain. Mutations in this gene cause Donnai-Barrow syndrome (DBS) and facio-oculoacoustico-renal syndrome (FOAR).[provided by RefSeq, Aug 2009]

Primary Disease Associations & Inheritance

Donnai-Barrow syndromeMIM #222448
AR
500
ClinVar variants
36
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— LRP2
🧬
Gene-Disease Validity (ClinGen)
congenital heart disease · ARNo Known Disease Relationship

No known disease relationship

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
36 Pathogenic / Likely Pathogenic· 95 VUS of 500 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.25LOEUF
pLI 1.000
Z-score 11.57
OE 0.20 (0.15–0.25)
Highly constrained

Highly LoF-intolerant (top ~10% 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.
2.07Z-score
OE missense 0.88 (0.85–0.92)
2242 obs / 2534.9 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.0.20 (0.15–0.25)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.88 (0.85–0.92)
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.1.03
0≤1.21.6
LoF obs/exp: 47 / 240.7Missense obs/exp: 2242 / 2534.9Syn Z: -0.78

ClinVar Variant Classifications

500 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic21
Likely Pathogenic15
VUS95
Likely Benign363
Benign3
Conflicting3
21
Pathogenic
15
Likely Pathogenic
95
VUS
363
Likely Benign
3
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
13
0
8
0
21
Likely Pathogenic
11
0
4
0
15
VUS
1
86
8
0
95
Likely Benign
0
0
162
201
363
Benign
0
0
3
0
3
Conflicting
—3
Total2586185201500

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

View in ClinVar →

Protein Context — Lollipop Plot

LRP2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

LRP2-related intellectual disability

limited
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

LRP2-related Donnai-Barrow syndrome

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersEye
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Donnai-Barrow syndrome

MIM #222448

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — LRP2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Autosomal Recessive Stickler Syndrome.
Nixon TRW et al.·Genes (Basel)
2022Review
Single-Cell Multi-Omics Map of Cell Type-Specific Mechanistic Drivers of Multiple Sclerosis Lesions.
Elkjaer ML et al.·Neurol Neuroimmunol Neuroinflamm
2024
Metabolic effects of RUBCN/Rubicon deficiency in kidney proximal tubular epithelial cells.
Matsuda J et al.·Autophagy
2020
AMPK protects proximal tubular epithelial cells from lysosomal dysfunction and dedifferentiation induced by lipotoxicity.
Pierre L et al.·Autophagy
2025
Association Analysis of the Cubilin (CUBN) and Megalin (LRP2) Genes with ESRD in African Americans.
Ma J et al.·Clin J Am Soc Nephrol
2016Meta-analysis
TRPML-1 Dysfunction and Renal Tubulopathy in Mucolipidosis Type IV.
Grieco G et al.·J Am Soc Nephrol
2025
Biomarkers and immunotherapy in endometrial cancer: mechanisms and clinical applications.
Zhao L et al.·Front Immunol
2025Review
Genotype variability in early-onset Hereditary Spastic Paraplegia: a single-center study.
Colona VL et al.·Eur J Paediatr Neurol
2025
Pharmacogenomics in pediatric oncology patients with solid tumors related to chemotherapy-induced toxicity: A systematic review.
Hansson P et al.·Crit Rev Oncol Hematol
2025Review
Variable expression pattern in Donnai-Barrow syndrome: Report of two novel LRP2 mutations and review of the literature.
Khalifa O et al.·Eur J Med Genet
2015Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Megalin (LRP2) Expression Patterns in Prostate Cancer Stem Cells and Metastatic Subtypes: Implications for Tumor Progression and Metabolism.
Mukhtarova G et al.·Prostate
2026
Independent Mutations in the LRP2 Gene Mediating Telescope Eyes and Celestial Eyes in Goldfish.
Li R et al.·Int J Mol Sci
2025🔓 Open Access
AIBP-LRP2-mediated HDL uptake restricts CXCR4+ stemlike capillary expansion and collateral circulation.
Zhu L et al.·Sci Adv
2025🔓 Open Access
LRP2 Expression in Melanoma Is Associated With a Transitory Cell State, Increased T Cell Infiltration, and Is Upregulated by IFNy Signaling.
Rasmussen MQ et al.·Pigment Cell Melanoma Res
2025🔓 Open Access
Spatial transcriptomics reveals Inhba/Smad2/E2f4 axis in Lrp2high thecal cell proliferation in androgen-induced PCOS mice.
Luo M et al.·Front Cell Dev Biol
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Physiological AdaptationsSport PerformanceAerobic Capacity

Molecular Hydrogen Inhalation: Effects on Health, Exercise Capacity and Inflammatory Response - in Vivo/in Vitro Studies

NOT YET RECRUITING
NCT07130942Phase NAGdansk University of Physical Education and SportStarted 2025-10-01
Inhalation using a molecular hydrogen generator

External Resources

Links to major genomics databases and tools