LRP2

Chr 2AR

LDL receptor related protein 2

Also known as: DBS, GP330, LRP-2

NCBI Gene: 4036ENSG00000081479UniProt: P98164OMIM: 600073

LRP2 encodes megalin, a multiligand endocytic receptor that mediates cellular uptake of diverse molecules including lipoproteins, vitamins, hormones, and morphogens like sonic hedgehog across multiple tissues, particularly absorptive epithelia. Mutations cause Donnai-Barrow syndrome, an autosomal recessive disorder affecting craniofacial development, hearing, vision, and intellectual development. The gene is highly constrained against loss-of-function variants (pLI >0.99), reflecting its critical role in development and cellular homeostasis.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismARLOEUF 0.251 OMIM phenotype
Clinical Summary— LRP2
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Gene-Disease Validity (ClinGen)
congenital heart disease · ARNo Known Disease Relationship

No known disease relationship

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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.
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ClinVar Variants
16 unique Pathogenic / Likely Pathogenic· 141 VUS of 400 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
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GeneReview available — LRP2
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
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
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
LoF OE0.20 (0.15–0.25)
0≤0.351.4
Missense OE0.88 (0.85–0.92)
0≤0.61.4
Synonymous OE1.03
0≤1.21.6
LoF obs/exp: 47 / 240.7Missense obs/exp: 2242 / 2534.9Syn Z: -0.78
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
limitedLRP2-related intellectual disabilityLOFAD
definitiveLRP2-related Donnai-Barrow syndromeLOFAR
DN
0.4487th %ile
GOF
0.5563th %ile
LOF
0.66top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 88% of P/LP variants are LoF · LOEUF 0.25

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

400 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9
Likely Pathogenic7
VUS141
Likely Benign206
Benign2
9
Pathogenic
7
Likely Pathogenic
141
VUS
206
Likely Benign
2
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
9
0
0
0
9
Likely Pathogenic
5
1
1
0
7
VUS
0
137
3
1
141
Likely Benign
0
3
95
108
206
Benign
0
0
2
0
2
Total14141101109365

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.

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients