LRP2

Summary

LRP2 (LDL receptor related protein 2, HGNC:6694) is a protein-coding gene on chromosome 2q31.1, encoding Low-density lipoprotein receptor-related protein 2 (P98164). Multiligand endocytic receptor.

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).

Source: NCBI Gene 4036 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Donnai-Barrow syndrome (Definitive, GenCC) — +3 more curated relationships
• GWAS associations: 39
• Clinical variants (ClinVar): 5,090 total — 101 pathogenic, 96 likely-pathogenic
• Phenotypes (HPO): 44
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_004525

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6694
Approved symbol	LRP2
Name	LDL receptor related protein 2
Location	2q31.1
Locus type	gene with protein product
Status	Approved
Aliases	gp330, DBS
Ensembl gene	ENSG00000081479
Ensembl biotype	protein_coding
OMIM	600073
Entrez	4036

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 2 protein_coding, 2 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000443831, ENST00000461418, ENST00000491228, ENST00000493501, ENST00000649046, ENST00000649153, ENST00000650252

RefSeq mRNA: 1 — MANE Select: NM_004525 NM_004525

CCDS: CCDS2232

Canonical transcript exons

ENST00000649046 — 79 exons

Exon	Start	End
ENSE00000495477	169247378	169247515
ENSE00000523587	169242956	169243072
ENSE00000523592	169226422	169226588
ENSE00000523602	169196911	169197030
ENSE00000523623	169142674	169142793
ENSE00000523628	169318762	169318884
ENSE00000779036	169320777	169320884
ENSE00000779048	169307281	169307397
ENSE00000779078	169294600	169294710
ENSE00000779081	169294148	169294261
ENSE00000779086	169292253	169292369
ENSE00000779087	169290845	169290997
ENSE00000779088	169289026	169289145
ENSE00000779089	169282873	169283001
ENSE00000779090	169280350	169280519
ENSE00000779091	169279372	169279595
ENSE00000779093	169277745	169277951
ENSE00000779094	169275036	169275238
ENSE00000779096	169270904	169271107
ENSE00000779100	169257124	169257249
ENSE00000779104	169256106	169256236
ENSE00000779109	169246705	169246986
ENSE00000779110	169244693	169244932
ENSE00000779111	169243403	169243522
ENSE00000779116	169240988	169241365
ENSE00000779117	169239527	169239775
ENSE00000779118	169238091	169238302
ENSE00000779119	169237103	169237287
ENSE00000779120	169235840	169236068
ENSE00000779121	169233411	169233588
ENSE00000779122	169231714	169231842
ENSE00000779146	169225310	169225453
ENSE00000779148	169220454	169220563
ENSE00000779150	169216253	169216430
ENSE00000779152	169213657	169213870
ENSE00000779154	169211968	169212207
ENSE00000779156	169209453	169209641
ENSE00000779158	169206330	169207250
ENSE00000779160	169206023	169206188
ENSE00000779162	169205479	169205637
ENSE00000779164	169203982	169204271
ENSE00000779167	169202756	169202959
ENSE00000779170	169198786	169198911
ENSE00000779173	169193761	169193892
ENSE00000779175	169191832	169192033
ENSE00000779176	169187970	169188265
ENSE00000779177	169185503	169186019
ENSE00000779181	169177803	169178026
ENSE00000779182	169176411	169176588
ENSE00000779184	169173919	169174164
ENSE00000779185	169173096	169173224
ENSE00000779186	169172015	169172134
ENSE00000779187	169170551	169170667
ENSE00000779188	169169702	169169818
ENSE00000779200	169146739	169146959
ENSE00000779201	169145747	169145923
ENSE00000779244	169140455	169140545
ENSE00000779245	169139543	169139610
ENSE00000779249	169132574	169132681
ENSE00000779250	169129013	169129084
ENSE00001131243	169259025	169259217
ENSE00001187237	169127109	169128830
ENSE00001301493	169201628	169201870
ENSE00001312980	169175193	169175389
ENSE00001733691	169362321	169362534
ENSE00002436751	169154460	169154603
ENSE00002448352	169150898	169151026
ENSE00002473051	169152799	169152964
ENSE00002481570	169165932	169166054
ENSE00002486593	169168539	169168676
ENSE00002508898	169157371	169157502
ENSE00002529445	169156274	169156405
ENSE00002531114	169162472	169162600
ENSE00003460770	169181448	169181618
ENSE00003532352	169182167	169182319
ENSE00003581739	169138577	169138706
ENSE00003596112	169139251	169139371
ENSE00003598232	169272927	169273067
ENSE00003641699	169137392	169137493

Expression profiles

Bgee: expression breadth ubiquitous, 169 present calls, max score 94.71.

FANTOM5 (CAGE): breadth broad, TPM avg 3.3507 / max 289.5386, expressed in 271 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
31730	2.7075	257
31729	0.4017	154
31731	0.1433	80
31732	0.0982	56

Top tissues by expression

271 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
adult organism	UBERON:0007023	94.71	gold quality
adult mammalian kidney	UBERON:0000082	94.44	gold quality
corpus callosum	UBERON:0002336	94.02	gold quality
buccal mucosa cell	CL:0002336	93.19	gold quality
nephron tubule	UBERON:0001231	93.19	gold quality
inferior vagus X ganglion	UBERON:0005363	92.19	gold quality
kidney	UBERON:0002113	92.08	gold quality
thyroid gland	UBERON:0002046	91.72	gold quality
kidney epithelium	UBERON:0004819	91.66	gold quality
pigmented layer of retina	UBERON:0001782	91.59	gold quality
germinal epithelium of ovary	UBERON:0001304	91.33	gold quality
left lobe of thyroid gland	UBERON:0001120	91.29	gold quality
right lobe of thyroid gland	UBERON:0001119	91.10	gold quality
renal medulla	UBERON:0000362	90.55	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	89.85	gold quality
spinal cord	UBERON:0002240	88.51	gold quality
parietal pleura	UBERON:0002400	88.51	gold quality
subthalamic nucleus	UBERON:0001906	88.06	gold quality
mammary duct	UBERON:0001765	87.75	gold quality
medial globus pallidus	UBERON:0002477	87.69	gold quality
renal glomerulus	UBERON:0000074	87.12	gold quality
metanephric glomerulus	UBERON:0004736	87.08	gold quality
epithelium of mammary gland	UBERON:0003244	86.15	gold quality
caput epididymis	UBERON:0004358	85.87	gold quality
globus pallidus	UBERON:0001875	85.76	gold quality
cortex of kidney	UBERON:0001225	85.61	gold quality
placenta	UBERON:0001987	85.53	gold quality
pons	UBERON:0000988	85.14	gold quality
metanephros	UBERON:0000081	83.06	gold quality
parotid gland	UBERON:0001831	82.63	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	3206.00
E-GEOD-131882	yes	2960.32
E-GEOD-93593	yes	599.65
E-MTAB-10018	yes	267.32
E-GEOD-75140	yes	252.58
E-HCAD-10	yes	38.55
E-ANND-3	yes	14.98
E-CURD-135	no	1393.70
E-MTAB-6911	no	169.13

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PPARA, PPARG, SP1, TBP, YBX3

miRNA regulators (miRDB)

212 targeting LRP2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4262	100.00	73.26	3931
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-507	99.97	70.11	1915

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Megalin and cubilin: multifunctional endocytic receptors. A review. (PMID:11994745)
• This study reveals that LRP2 is a major autoantigen in rheumatoid arthritis and probably drives the production of anti-LRP2 autoantibodies, which may play pathological roles by inhibiting the reabsorbing function of LRP2. (PMID:12723989)
• megalin has a role in thyroid homeostasis with possible implications in thyroid diseases (PMID:14657389)
• a binding affinity of disabled homolog 2 mitogen-responsive phosphoprotein interaction domain for megalin CT of K(D) = 2.6 x 10(-7) +/- 5.3 x 10(-8) (PMID:15134832)
• megalin endocytosed NGAL by a mechanism completely blocked by an antibody against megalin (PMID:15670845)
• Further studies on the intracellular molecular signalling associated with megalin-mediated metabolic pathways may lead to the development of novel strategies for the treatment of nephropathies related to diabetes and metabolic syndrome. (Review) (PMID:16174284)
• This review focuses on the involvement of megalin during embryonic development and its interactions with the developmental morphogen sonic hedgehog. (PMID:16828734)
• Results show that the PPPSP motif and GSK3 activity are critical to allow megalin phosphorylation and also negatively regulate the receptor’s recycling. (PMID:17555532)
• Study mapped Donnai-Barrow syndrome to chromosome 2q23.3-31.1 and identified LRP2 mutations in six families with Donnai-Barrow syndrome and one family with facio-oculo-acoustico-renal syndrome. (PMID:17632512)
• This review summarizes recent data on the biological function of megalin and focuses on its implication in embryonic nutrition and central nervous system malformations. (PMID:17979745)
• These results suggest that Dab2 is a ligand dependent bi-directional regulator of ERK1,2 activity. (PMID:18070591)
• confirm the association between LRP2 and levels of T-Cho and LDL-C in human plasma (PMID:18174661)
• light chain endocytosis is predominantly mediated by the megalin-cubilin tandem endocytic receptor and identify endocytosis as a key step in light chain cytotoxicity. (PMID:18448595)
• Polymorphisms within the megalin gene for associations with prostate cancer risk and outcomes. (PMID:18559602)
• Interaction of the A2 domain of F8 with LRP2 follows the general mode, requires dissociation of factor VIII from von Willebrand factor, and is activation sensitive. (PMID:18685438)
• results show different expression patterns of megalin and cubulin in calculous gallbladders and acalculous gallbladders suggesting an association with gallstone formation and implying a putative role of the two proteins in cholesterol endocytosis (PMID:18791690)
• No defect in the trafficking or function of megalin upon OCRL1 knockdown. (PMID:19940034)
• Data show that MT-I + II and megalin are significantly altered in CNS lymphoma relative to controls. (PMID:20038220)
• allele (A) of the rs3755166 polymorphism within LRP2 gene may contribute to Alzheimer’s disease risk in the Chinese Han Population (PMID:20971101)
• in anagen VI hair follicles megalin was found in all keratinocytes of the distal region (PMID:21104416)
• megalin and cubilin are involved in the metabolism of vitamin D by reabsorbing vitamin D binding protein; dysfunction of these receptors is likely to be associated with the development of vitamin D deficiency in patients with chronic kidney disease (PMID:21595846)
• Sex-specific VDR and Megalin gene variations can modify age-related cognitive decline among US adults. (PMID:22170372)
• A total of 330 Chinese female-offspring nuclear families with 1088 individuals and 400 Chinese male-offspring nuclear families with 1215 individuals were genotyped at six tag single nucleotide polymorphisms of the LRP2 gene. (PMID:22174918)
• Expression of megalin and cubilin is decreased during experimental endotoxemia, which may contribute to an increase in urine levels of albumin during acute renal failure. (PMID:22437417)
• This study confirmed that LRP2 rs2544390 C/T at intron 1 was associated with serum uric acid levels among Japanese males with SLC22A12 258WW, SLC2A9 rs11722228C allele, ABCG2 126QQ and 141Q allele. (PMID:22565184)
• analysis of rare disease variants in LRP2, a gene linked and associated with autism spectrum disorders (PMID:22578327)
• results suggested that GSTT1 wild genotype and C-allele of megalin gene rs2228171 SNPs might be risk factors for cisplatin-induced ototoxicity (PMID:23274376)
• Using NMR titration data in HADDOCK, we have generated a three-dimensional model describing the complex between megalin and gentamicin. (PMID:23275343)
• The hypothalamic clusterin-low-density lipoprotein receptor-related protein-2 axis is a novel anorexigenic signalling pathway. (PMID:23673647)
• Megalin and Dab2 were expressed in prostate and colon epithelial cells, which was markedly enhanced following treatment with retinoic acid (PMID:23909735)
• Data suggest that endodermal layer of yolk sac and syncytiotrophoblast/cytotrophoblast cells of placental villi express megalin mRNA/protein; expression of megalin protein (but not mRNA) is up-regulated as gestation/placentation progresses. (PMID:23978537)
• A new mutation in LRP2 causes a predominantly ocular phenotype suggestive of Stickler syndrome. (PMID:23992033)
• LOS treatment decreased microalbuminuria induced by Cd apparently through a cubilin receptor-dependent mechanism but independent of megalin. (PMID:24093454)
• This review explores current evidence linking megalin expression and function to the development, diagnosis, and progression of acute kidney injury –{REVIEW} (PMID:24197071)
• Transgenic/knock-out megalin-deficient mice develop anxiety behavior and impaired learning, as described in Alzheimer’s disease. (PMID:24254699)
• Association of the T-allele of a single nucleotide polymorphism in LRP2 with gout risk in the Maori and Pacific subjects was consistent with this allele increasing serum urate in Japanese individuals (PMID:24286387)
• Serum uric acid-related gene LRP2 is not involved in gout susceptibility. (PMID:24366390)
• LRP2 sequencing reveals multiple rare variants associated with urinary trefoil factor-3 (PMID:24876117)
• The megalin expression appears to vary inversely with gestational age with the greatest expression noted in the most premature samples. Age-dependent differences in placental megalin may therefore influence fetal exposure. (PMID:25304941)
• levels of urinary C-megalin are associated with histological abnormalities in adult IgAN patients (PMID:25502002)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	lrp2a	ENSDARG00000102506
mus_musculus	Lrp2	ENSMUSG00000027070
rattus_norvegicus	Lrp2	ENSRNOG00000056184
drosophila_melanogaster	arr	FBGN0000119

Paralogs (14): LRP6 (ENSG00000070018), NID2 (ENSG00000087303), NID1 (ENSG00000116962), LRP1 (ENSG00000123384), LDLR (ENSG00000130164), LRP3 (ENSG00000130881), LRP4 (ENSG00000134569), EGF (ENSG00000138798), LRP12 (ENSG00000147650), VLDLR (ENSG00000147852), LRP8 (ENSG00000157193), LRP5 (ENSG00000162337), LRP1B (ENSG00000168702), LRP10 (ENSG00000197324)

Protein

Protein identifiers

Low-density lipoprotein receptor-related protein 2 — P98164 (reviewed: P98164)

Alternative names: Glycoprotein 330, Megalin

All UniProt accessions (4): P98164, A0A3B3IRR0, A0A3B3IT64, E9PC35

UniProt curated annotations — full annotation on UniProt →

Function. Multiligand endocytic receptor. Acts together with CUBN to mediate endocytosis of high-density lipoproteins. Mediates receptor-mediated uptake of polybasic drugs such as aprotinin, aminoglycosides and polymyxin B. In the kidney, mediates the tubular uptake and clearance of leptin. Also mediates transport of leptin across the blood-brain barrier through endocytosis at the choroid plexus epithelium. Endocytosis of leptin in neuronal cells is required for hypothalamic leptin signaling and leptin-mediated regulation of feeding and body weight. Mediates endocytosis and subsequent lysosomal degradation of CST3 in kidney proximal tubule cells. Mediates renal uptake of 25-hydroxyvitamin D3 in complex with the vitamin D3 transporter GC/DBP. Mediates renal uptake of metallothionein-bound heavy metals. Together with CUBN, mediates renal reabsorption of myoglobin. Mediates renal uptake and subsequent lysosomal degradation of APOM. Plays a role in kidney selenium homeostasis by mediating renal endocytosis of selenoprotein SEPP1. Mediates renal uptake of the antiapoptotic protein BIRC5/survivin which may be important for functional integrity of the kidney. Mediates renal uptake of matrix metalloproteinase MMP2 in complex with metalloproteinase inhibitor TIMP1. Mediates endocytosis of Sonic hedgehog protein N-product (ShhN), the active product of SHH. Also mediates ShhN transcytosis. In the embryonic neuroepithelium, mediates endocytic uptake and degradation of BMP4, is required for correct SHH localization in the ventral neural tube and plays a role in patterning of the ventral telencephalon. Required at the onset of neurulation to sequester SHH on the apical surface of neuroepithelial cells of the rostral diencephalon ventral midline and to control PTCH1-dependent uptake and intracellular trafficking of SHH. During neurulation, required in neuroepithelial cells for uptake of folate bound to the folate receptor FOLR1 which is necessary for neural tube closure. In the adult brain, negatively regulates BMP signaling in the subependymal zone which enables neurogenesis to proceed. In astrocytes, mediates endocytosis of ALB which is required for the synthesis of the neurotrophic factor oleic acid. Involved in neurite branching. During optic nerve development, required for SHH-mediated migration and proliferation of oligodendrocyte precursor cells. Mediates endocytic uptake and clearance of SHH in the retinal margin which protects retinal progenitor cells from mitogenic stimuli and keeps them quiescent. Plays a role in reproductive organ development by mediating uptake in reproductive tissues of androgen and estrogen bound to the sex hormone binding protein SHBG. Mediates endocytosis of angiotensin-2. Also mediates endocytosis of angiotensis 1-7. Binds to the complex composed of beta-amyloid protein 40 and CLU/APOJ and mediates its endocytosis and lysosomal degradation. Required for embryonic heart development. Required for normal hearing, possibly through interaction with estrogen in the inner ear.

Subunit / interactions. Binds plasminogen, extracellular matrix components, plasminogen activator-plasminogen activator inhibitor type I complex, apolipoprotein E-enriched beta-VLDL, lipoprotein lipase, lactoferrin, CLU/clusterin and calcium. Forms a multimeric complex together with LRPAP1. Interacts (via PxLPxI/L motif) with ANKRA2 (via ankyrin repeats). Interacts with LRP2BP. Interacts (via NPXY motif) with DAB2; the interaction is not affected by tyrosine phosphorylation of the NPXY motif. Interacts with MB. Interacts with BMP4. Interacts with the Sonic hedgehog protein N-product which is the active product of SHH. Interacts with CST3 in a calcium-dependent manner. Interacts with the vitamin-D binding protein GC/DBP. Interacts with sex hormone-binding protein SHBG. Interacts with angiotensin-2. Also interacts with angiotensin 1-7. Interacts with APOM. Interacts with selenoprotein SEPP1. Interacts with LEP. Interacts with ALB. Interacts with the antiapoptotic protein BIRC5/survivin. Interacts with matrix metalloproteinase MMP2 in complex with metalloproteinase inhibitor TIMP1. In neurons, forms a trimeric complex with APP and APPB1/FE65. Interacts with LDLRAP1/ARH; mediates trafficking of LRP2 to the endocytic recycling compartment. Does not interact with beta-amyloid protein 40 alone but interacts with the complex composed of beta-amyloid protein 40 and CLU/APOJ. Interacts with MDK.

Subcellular location. Apical cell membrane. Endosome lumen. Membrane. Coated pit. Cell projection. Dendrite. Axon.

Tissue specificity. Expressed in first and third trimester cytotrophoblasts in the placenta (at protein level). Absorptive epithelia, including renal proximal tubules.

Post-translational modifications. A fraction undergoes proteolytic cleavage of the extracellular domain at the cell membrane to generate a cytoplasmic tail fragment. This is internalized into the early endosome from where it trafficks in an LDLRAP1/ARH-dependent manner to the endocytic recycling compartment (ERC). In the ERC, it is further cleaved by gamma-secretase to release a fragment which translocates to the nucleus and mediates transcriptional repression. N-glycosylation is required for ligand binding.

Disease relevance. Donnai-Barrow syndrome (DBS) [MIM:222448] An autosomal recessive syndrome characterized by complete or partial agenesis of the corpus callosum, congenital diaphragmatic hernia, facial dysmorphology, ocular anomalies, sensorineural hearing loss, developmental delay, and proteinuria. There is variability in the expression of some features, such as diaphragmatic hernia, corpus callosum anomalies and proteinuria. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Two overlapping PxLPxI/L motifs mediate interaction with ankyrin repeats of ANKRA2. The cytoplasmic domain is required for sorting to the apical cell membrane.

Similarity. Belongs to the LDLR family.

RefSeq proteins (1): NP_004516* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000033	LDLR_classB_rpt	Repeat
IPR000152	EGF-type_Asp/Asn_hydroxyl_site	PTM
IPR000742	EGF	Domain
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR002172	LDrepeatLR_classA_rpt	Repeat
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR011042	6-blade_b-propeller_TolB-like	Homologous_superfamily
IPR018097	EGF_Ca-bd_CS	Conserved_site
IPR019825	Lectin_legB_Mn/Ca_BS	Binding_site
IPR023415	LDLR_class-A_CS	Conserved_site
IPR026823	cEGF	Domain
IPR036055	LDL_receptor-like_sf	Homologous_superfamily
IPR049883	NOTCH1_EGF-like	Domain
IPR051221	LDLR-related	Family
IPR056588	EGF_LRP2	Domain

Pfam: PF00057, PF00058, PF07645, PF12662, PF14670, PF24468

UniProt features (318 total): disulfide bond 126, domain 42, glycosylation site 40, repeat 35, sequence variant 20, sequence conflict 16, binding site 11, short sequence motif 7, modified residue 6, strand 4, region of interest 3, topological domain 2, compositionally biased region 2, signal peptide 1, chain 1, transmembrane region 1, helix 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
9CWM	ELECTRON MICROSCOPY	3.3
9QAW	ELECTRON MICROSCOPY	3.34
9I3V	ELECTRON MICROSCOPY	3.51
2M0P	SOLUTION NMR

Predicted structure (AlphaFold)

No AlphaFold model available for P98164 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (11): 1208; 1210; 1212; 1218; 1219; 1126; 1129; 1131; 1133; 1139; 1140

Post-translational modifications (6): 4463, 4466, 4569, 4616, 4632, 4653

Disulfide bonds (126): 28–40, 35–53, 47–62, 67–80, 74–93, 87–103, 108–120, 115–133, 127–142, 147–157, 152–170, 164–179, 183–195, 190–208, 202–217, 222–234, 229–247, 241–256, 266–279, 273–292 …

Glycosylation sites (40): 159, 178, 299, 300, 341, 388, 463, 866, 1064, 1144, 1186, 1327, 1340, 1383, 1464, 1496, 1550, 1675, 1810, 2055 …

Function

Pathways and Gene Ontology

Reactome pathways

16 pathways

ID	Pathway
R-HSA-196791	Vitamin D (calciferol) metabolism
R-HSA-8856825	Cargo recognition for clathrin-mediated endocytosis
R-HSA-8856828	Clathrin-mediated endocytosis
R-HSA-975634	Retinoid metabolism and transport
R-HSA-9758890	Transport of RCbl within the body
R-HSA-1430728	Metabolism
R-HSA-196741	Cobalamin (Cbl, vitamin B12) transport and metabolism
R-HSA-196849	Metabolism of water-soluble vitamins and cofactors
R-HSA-196854	Metabolism of vitamins and cofactors
R-HSA-199991	Membrane Trafficking
R-HSA-2187338	Visual phototransduction
R-HSA-556833	Metabolism of lipids
R-HSA-5653656	Vesicle-mediated transport
R-HSA-6806667	Metabolism of fat-soluble vitamins
R-HSA-8957322	Metabolism of steroids
R-HSA-9709957	Sensory Perception

MSigDB gene sets: 535 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, GSE45365_NK_CELL_VS_BCELL_DN, GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, RNGTGGGC_UNKNOWN, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, GOBP_OUTFLOW_TRACT_SEPTUM_MORPHOGENESIS, PAX4_01, GOBP_CORONARY_VASCULATURE_DEVELOPMENT

GO Biological Process (44): retinoid metabolic process (GO:0001523), kidney development (GO:0001822), neural tube closure (GO:0001843), secondary heart field specification (GO:0003139), outflow tract septum morphogenesis (GO:0003148), ventricular compact myocardium morphogenesis (GO:0003223), ventricular septum development (GO:0003281), lipid metabolic process (GO:0006629), endocytosis (GO:0006897), receptor-mediated endocytosis (GO:0006898), sensory perception of sound (GO:0007605), cell population proliferation (GO:0008283), male gonad development (GO:0008584), gene expression (GO:0010467), protein transport (GO:0015031), cobalamin transport (GO:0015889), metal ion transport (GO:0030001), negative regulation of BMP signaling pathway (GO:0030514), forebrain development (GO:0030900), diol metabolic process (GO:0034311), aorta development (GO:0035904), vitamin D metabolic process (GO:0042359), negative regulation of apoptotic process (GO:0043066), phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0043491), response to leptin (GO:0044321), transcytosis (GO:0045056), positive regulation of neurogenesis (GO:0050769), vagina development (GO:0060068), coronary artery morphogenesis (GO:0060982), pulmonary artery morphogenesis (GO:0061156), positive regulation of oligodendrocyte progenitor proliferation (GO:0070447), cellular response to growth factor stimulus (GO:0071363), amyloid-beta clearance (GO:0097242), neuron projection arborization (GO:0140058), transport across blood-brain barrier (GO:0150104), folate import across plasma membrane (GO:1904447), cranial skeletal system development (GO:1904888), positive regulation of lysosomal protein catabolic process (GO:1905167), outflow tract morphogenesis (GO:0003151), nervous system development (GO:0007399)

GO Molecular Function (10): low-density lipoprotein particle receptor activity (GO:0005041), calcium ion binding (GO:0005509), SH3 domain binding (GO:0017124), insulin-like growth factor I binding (GO:0031994), cargo receptor activity (GO:0038024), hormone binding (GO:0042562), protein-folding chaperone binding (GO:0051087), protein transporter activity (GO:0140318), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (23): lysosome (GO:0005764), lysosomal membrane (GO:0005765), endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), clathrin-coated pit (GO:0005905), external side of plasma membrane (GO:0009897), apical plasma membrane (GO:0016324), axon (GO:0030424), dendrite (GO:0030425), clathrin-coated endocytic vesicle membrane (GO:0030669), brush border membrane (GO:0031526), endosome lumen (GO:0031904), signaling receptor complex (GO:0043235), extracellular exosome (GO:0070062), endosome (GO:0005768), brush border (GO:0005903), endomembrane system (GO:0012505), membrane (GO:0016020), endocytic vesicle (GO:0030139), cell projection (GO:0042995), organelle (GO:0043226), apical part of cell (GO:0045177)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Metabolism of vitamins and cofactors	2
Metabolism	2
Metabolism of steroids	1
Clathrin-mediated endocytosis	1
Membrane Trafficking	1
Visual phototransduction	1
Metabolism of fat-soluble vitamins	1
Cobalamin (Cbl, vitamin B12) transport and metabolism	1
Metabolism of water-soluble vitamins and cofactors	1
Vesicle-mediated transport	1
Sensory Perception	1
Metabolism of lipids	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
endomembrane system	4
vesicle-mediated transport	2
binding	2
cytoplasm	2
intracellular membrane-bounded organelle	2
membrane	2
plasma membrane	2
apical part of cell	2
neuron projection	2
cytoplasmic vesicle	2
cellular anatomical structure	2
diterpenoid metabolic process	1
animal organ development	1
renal system development	1
primary neural tube formation	1
tube closure	1
heart field specification	1
outflow tract morphogenesis	1
cardiac septum morphogenesis	1
ventricular cardiac muscle tissue morphogenesis	1
cardiac ventricle development	1
cardiac septum development	1
primary metabolic process	1
vesicle budding from membrane	1
membrane invagination	1
import into cell	1
endocytosis	1
sensory perception of mechanical stimulus	1
cellular process	1
gonad development	1
development of primary male sexual characteristics	1
macromolecule biosynthetic process	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
vitamin transport	1
nitrogen compound transport	1
monoatomic cation transport	1
BMP signaling pathway	1
regulation of BMP signaling pathway	1

Protein interactions and networks

STRING

2184 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LRP2	CUBN	O60494	999
LRP2	AMN	Q9BXJ7	998
LRP2	ALB	P02768	994
LRP2	APOE	P02649	988
LRP2	GC	P02774	988
LRP2	CLU	P10909	987
LRP2	LCN2	P30150	984
LRP2	LTF	P02788	968
LRP2	ANKRA2	Q9H9E1	936
LRP2	CLCN5	P51795	933
LRP2	SHH	Q15465	925
LRP2	DAB2	P98082	916
LRP2	TTR	P02766	904
LRP2	GIPC1	O14908	902
LRP2	PTH	P01270	884

IntAct

117 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
SNW1	AQR	psi-mi:“MI:0914”(association)	0.650
LRP2	DLG4	psi-mi:“MI:0915”(physical association)	0.610
DLG4	LRP2	psi-mi:“MI:0915”(physical association)	0.610
LRP2	DLG4	psi-mi:“MI:0403”(colocalization)	0.610
DLG4	LRP2	psi-mi:“MI:0407”(direct interaction)	0.610
RIBC2	LRP2	psi-mi:“MI:0915”(physical association)	0.590
MANSC1	KLRG2	psi-mi:“MI:0914”(association)	0.530
INSL6	POTEF	psi-mi:“MI:0914”(association)	0.530
SOST	KPNA4	psi-mi:“MI:0914”(association)	0.530
TAFA4	NRP1	psi-mi:“MI:0914”(association)	0.530
ZBTB48	ZBTB24	psi-mi:“MI:0914”(association)	0.530
LRPAP1	LRP4	psi-mi:“MI:0914”(association)	0.530
ZNF224	LRP4	psi-mi:“MI:0914”(association)	0.530
SYT1	PGK2	psi-mi:“MI:0914”(association)	0.530
CCN2	LRP2	psi-mi:“MI:0914”(association)	0.530
LRP2	DLG2	psi-mi:“MI:0407”(direct interaction)	0.530
DCLK1	DCX	psi-mi:“MI:0914”(association)	0.530
CBX5	KPNA3	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
PDGFD	DCTN6	psi-mi:“MI:0914”(association)	0.530
LGALS1	PODXL	psi-mi:“MI:0914”(association)	0.530
CCDC59	GAPDHS	psi-mi:“MI:0914”(association)	0.530
GREM2	ZZEF1	psi-mi:“MI:0914”(association)	0.530

BioGRID (200): LRP2 (Affinity Capture-MS), LRP2 (Affinity Capture-MS), LRP2 (Affinity Capture-MS), LRP2 (Affinity Capture-MS), LRP2 (Proximity Label-MS), DLG3 (Two-hybrid), MAGI1 (Two-hybrid), LRP2 (Two-hybrid), LRP2BP (Two-hybrid), DAB2 (Two-hybrid), DLG2 (Two-hybrid), LRP2 (Affinity Capture-MS), LRP2 (Affinity Capture-MS), LRP2 (Affinity Capture-MS), LRP2 (Affinity Capture-MS)

ESM2 similar proteins: A2ARV4, C0HL13, F1RWC3, G3V928, O57409, O60494, O70244, P01130, P01131, P01132, P07522, P20063, P35950, P35951, P35952, P35953, P41413, P46023, P56677, P78504, P98155, P98156, P98157, P98158, P98163, P98164, P98165, P98166, Q04592, Q04833, Q07954, Q0IIH7, Q20176, Q28832, Q63722, Q6X0I2, Q90Y57, Q91ZX7, Q92673, Q92824

Diamond homologs: A2AR95, A2ARV4, A4IHY6, C0HL13, E9Q6D8, G3V928, O75074, O75197, O75581, O88204, O88307, O88572, P0DSP1, P13671, P35953, P56677, P61134, P61135, P86091, P98153, P98154, P98155, P98156, P98157, P98158, P98160, P98163, P98164, P98165, P98166, P98167, Q04833, Q06561, Q07954, Q0IIH7, Q14114, Q28832, Q29RU4, Q5HZW5, Q5R662

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
LRP2	“up-regulates quantity”	PTCH1	binding
CLU	“up-regulates quantity”	LRP2	binding
TIMP2	“up-regulates quantity”	LRP2	binding
MMP2	“up-regulates quantity”	LRP2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

5090 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	101
Likely pathogenic	96
Uncertain significance	1923
Likely benign	2315
Benign	275

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1071842	NM_004525.3(LRP2):c.11530dup (p.Ala3844fs)	Pathogenic
1338230	NM_004525.3(LRP2):c.11276del (p.Cys3759fs)	Pathogenic
1352478	NM_004525.3(LRP2):c.4572C>G (p.Tyr1524Ter)	Pathogenic
1353323	NM_004525.3(LRP2):c.2894dup (p.Asn966fs)	Pathogenic
1384479	NM_004525.3(LRP2):c.8530G>T (p.Gly2844Ter)	Pathogenic
1446088	NM_004525.3(LRP2):c.12187C>T (p.Arg4063Ter)	Pathogenic
1452044	NM_004525.3(LRP2):c.10575C>A (p.Cys3525Ter)	Pathogenic
1454324	NM_004525.3(LRP2):c.13660del (p.Ser4554fs)	Pathogenic
1454326	NM_004525.3(LRP2):c.13200-2A>G	Pathogenic
1454370	NM_004525.3(LRP2):c.12689G>A (p.Trp4230Ter)	Pathogenic
1455766	NM_004525.3(LRP2):c.12556C>T (p.Gln4186Ter)	Pathogenic
1457995	NM_004525.3(LRP2):c.5243_5244insTTTTTTTTTTTTTTTTTTTTNNNNNNNNNNGGGGTTTCACCGTTTTAGCCGGGATGGTCTCGATCTCCTGACCTCGTGATCCGCCCGCCTCGGCCTCCCCAACCTTTCTT (p.Leu1748delinsPhePhePhePhePhePhePheXaaXaaXaaXaaGlyPheHisArgPheSerArgAspGlyLeuAspLeuLeuThrSerTer)	Pathogenic
1526144	NM_004525.3(LRP2):c.8244T>A (p.Cys2748Ter)	Pathogenic
1710508	NM_004525.3(LRP2):c.8452_8452+1del	Pathogenic
2001708	NM_004525.3(LRP2):c.345C>A (p.Cys115Ter)	Pathogenic
2003271	NM_004525.3(LRP2):c.12585_12588del (p.Leu4196fs)	Pathogenic
2008657	NM_004525.3(LRP2):c.5326_5336del (p.Gly1776fs)	Pathogenic
2087187	NM_004525.3(LRP2):c.12000dup (p.Asp4001Ter)	Pathogenic
2088234	NM_004525.3(LRP2):c.2397T>G (p.Tyr799Ter)	Pathogenic
2088878	NM_004525.3(LRP2):c.3104del (p.Asn1035fs)	Pathogenic
2105013	NM_004525.3(LRP2):c.709C>T (p.Gln237Ter)	Pathogenic
2127309	NM_004525.3(LRP2):c.2757del (p.Ala920fs)	Pathogenic
2135955	NM_004525.3(LRP2):c.10010G>A (p.Trp3337Ter)	Pathogenic
21418	NM_004525.3(LRP2):c.11469_11472del (p.Cys3823fs)	Pathogenic
2188892	NM_004525.3(LRP2):c.427C>T (p.Gln143Ter)	Pathogenic
2257773	NM_004525.3(LRP2):c.7401del (p.Ala2468fs)	Pathogenic
2425147	NC_000002.11:g.(?169999164)(170038849_?)dup	Pathogenic
2695836	NM_004525.3(LRP2):c.11343C>A (p.Tyr3781Ter)	Pathogenic
2697382	NM_004525.3(LRP2):c.9651T>G (p.Tyr3217Ter)	Pathogenic
2698959	NM_004525.3(LRP2):c.2564G>A (p.Trp855Ter)	Pathogenic

SpliceAI

12369 predictions. Top by Δscore:

Variant	Effect	Δscore
2:169128831:C:CC	acceptor_gain	1.0000
2:169129008:ATTAC:A	donor_loss	1.0000
2:169129009:TTAC:T	donor_loss	1.0000
2:169129010:TAC:T	donor_loss	1.0000
2:169129011:ACC:A	donor_loss	1.0000
2:169129012:CCTGT:C	donor_loss	1.0000
2:169129082:CAC:C	acceptor_gain	1.0000
2:169129084:CCTAA:C	acceptor_loss	1.0000
2:169129085:C:A	acceptor_loss	1.0000
2:169129086:T:G	acceptor_loss	1.0000
2:169137490:CACT:C	acceptor_gain	1.0000
2:169137491:ACT:A	acceptor_gain	1.0000
2:169137492:CT:C	acceptor_gain	1.0000
2:169137492:CTC:C	acceptor_gain	1.0000
2:169137492:CTCT:C	acceptor_loss	1.0000
2:169137493:TCTG:T	acceptor_gain	1.0000
2:169137494:C:CC	acceptor_gain	1.0000
2:169137494:C:G	acceptor_gain	1.0000
2:169137501:C:CT	acceptor_gain	1.0000
2:169137507:C:CT	acceptor_gain	1.0000
2:169137508:A:T	acceptor_gain	1.0000
2:169138575:A:AC	donor_gain	1.0000
2:169138575:AC:A	donor_gain	1.0000
2:169138576:C:CT	donor_gain	1.0000
2:169138576:CC:C	donor_gain	1.0000
2:169138576:CCA:C	donor_gain	1.0000
2:169138702:TTAAG:T	acceptor_gain	1.0000
2:169138703:TAAG:T	acceptor_gain	1.0000
2:169138704:AAG:A	acceptor_gain	1.0000
2:169138705:AG:A	acceptor_gain	1.0000

AlphaMissense

31224 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:169150983:C:G	A4169P	0.998
2:169166018:C:G	C3891S	0.998
2:169166019:A:T	C3891S	0.998
2:169168574:C:G	C3867S	0.998
2:169168575:A:T	C3867S	0.998
2:169168628:C:G	C3849S	0.998
2:169168629:A:T	C3849S	0.998
2:169172098:C:G	C3727S	0.998
2:169172099:A:T	C3727S	0.998
2:169173125:C:G	C3705S	0.998
2:169173126:A:T	C3705S	0.998
2:169201663:C:G	C2806S	0.998
2:169201664:A:T	C2806S	0.998
2:169162501:C:G	C3953S	0.997
2:169162502:A:T	C3953S	0.997
2:169168573:A:C	C3867W	0.997
2:169168592:C:G	C3861S	0.997
2:169168593:A:T	C3861S	0.997
2:169169731:C:G	C3823S	0.997
2:169169732:A:T	C3823S	0.997
2:169170580:C:G	C3784S	0.997
2:169170581:A:T	C3784S	0.997
2:169172044:C:G	C3745S	0.997
2:169172045:A:T	C3745S	0.997
2:169173124:G:C	C3705W	0.997
2:169174136:C:A	W3599C	0.997
2:169174136:C:G	W3599C	0.997
2:169175282:C:G	C3560S	0.997
2:169175283:A:T	C3560S	0.997
2:169175348:C:G	C3538S	0.997

dbSNP variants (sampled 300 via entrez): RS1000002148 (2:169235159 A>G), RS1000006684 (2:169363455 G>T), RS1000011974 (2:169305388 T>C), RS1000014403 (2:169157262 A>C,G), RS1000041130 (2:169260823 G>C), RS1000053225 (2:169319891 T>C), RS1000068269 (2:169333913 C>T), RS1000073359 (2:169361909 G>A), RS1000073486 (2:169191006 T>C), RS1000086578 (2:169144235 C>T), RS1000098987 (2:169194626 C>T), RS1000099857 (2:169354494 G>A), RS1000101418 (2:169188462 T>A,C), RS1000102020 (2:169212298 A>T), RS1000121098 (2:169255341 G>A,C)

Disease associations

OMIM: gene MIM:600073 | disease phenotypes: MIM:222448, MIM:600634, MIM:108300, MIM:618164

GenCC curated gene-disease

Disease	Classification	Inheritance
Donnai-Barrow syndrome	Definitive	Autosomal recessive
Stickler syndrome	Moderate	Autosomal dominant
intellectual disability	Limited	Autosomal dominant
congenital heart disease	No Known Disease Relationship	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
congenital heart disease	No Known Disease Relationship	AR

Mondo (11): Donnai-Barrow syndrome (MONDO:0009104), congenital heart disease (MONDO:0005453), intellectual disability (MONDO:0001071), hearing loss disorder (MONDO:0005365), non-syndromic syndactyly (MONDO:0019530), breast ductal adenocarcinoma (MONDO:0005590), primary ovarian failure (MONDO:0005387), prolactin-producing pituitary gland adenoma (MONDO:0010911), Stickler syndrome (MONDO:0019354), cardiac, facial, and digital anomalies with developmental delay (MONDO:0032572), inherited retinal dystrophy (MONDO:0019118)

Orphanet (8): Donnai-Barrow syndrome (Orphanet:2143), Non-syndromic syndactyly (Orphanet:90025), Prolactinoma (Orphanet:2965), Stickler syndrome (Orphanet:828), TRAF7-associated heart defect-digital anomalies-facial dysmorphism-motor and speech delay syndrome (Orphanet:592570), OBSOLETE: Inherited retinal disorder (Orphanet:71862), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

44 total (30 of 44 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000093	Proteinuria
HP:0000130	Abnormality of the uterus
HP:0000256	Macrocephaly
HP:0000260	Wide anterior fontanel
HP:0000272	Malar flattening
HP:0000316	Hypertelorism
HP:0000337	Broad forehead
HP:0000349	Widow’s peak
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000407	Sensorineural hearing impairment
HP:0000455	Broad nasal tip
HP:0000494	Downslanted palpebral fissures
HP:0000518	Cataract
HP:0000520	Proptosis
HP:0000529	Progressive visual loss
HP:0000541	Retinal detachment
HP:0000545	Myopia
HP:0000556	Retinal dystrophy
HP:0000612	Iris coloboma
HP:0000776	Congenital diaphragmatic hernia
HP:0000813	Bicornuate uterus
HP:0000879	Short sternum
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001274	Agenesis of corpus callosum
HP:0001338	Partial agenesis of the corpus callosum

GWAS associations

39 associations (top):

Study	Trait	p-value
GCST000581_4	Urate levels	4.000000e-08
GCST000873_1	Anorexia nervosa	9.000000e-06
GCST002587_3	Blood pressure (smoking interaction)	5.000000e-08
GCST003372_28	Glomerular filtration rate (creatinine)	4.000000e-08
GCST003790_20	Glomerular filtration rate	6.000000e-10
GCST003790_34	Glomerular filtration rate	4.000000e-06
GCST004292_50	Glomerular filtration rate (creatinine)	4.000000e-06
GCST004752_1	Relapse in multiple sclerosis	3.000000e-08
GCST005983_43	Serum uric acid levels	1.000000e-13
GCST005984_25	Glomerular filtration rate	5.000000e-22
GCST005985_62	Creatinine levels	3.000000e-25
GCST006392_1	Estimated glomerular filtration rate	5.000000e-07
GCST006393_1	Serum creatinine levels	5.000000e-07
GCST006976_118	Macular thickness	4.000000e-11
GCST007344_134	Estimated glomerular filtration rate	9.000000e-24
GCST007344_51	Estimated glomerular filtration rate	1.000000e-06
GCST007344_90	Estimated glomerular filtration rate	6.000000e-08
GCST007725_15	Serum uric acid levels	7.000000e-14
GCST007733_49	Serum uric acid levels	1.000000e-13
GCST007876_7	Estimated glomerular filtration rate	3.000000e-22
GCST007916_16	Hyperuricemia	2.000000e-16
GCST007917_20	Estimated glomerular filtration rate	2.000000e-16
GCST007918_27	Serum uric acid levels	2.000000e-16
GCST007919_9	Creatinine levels	2.000000e-16
GCST007920_4	Chronic kidney disease	2.000000e-16
GCST008058_69	Estimated glomerular filtration rate	2.000000e-25
GCST008059_57	Estimated glomerular filtration rate	5.000000e-25
GCST008610_1	Proteinuria	1.000000e-11
GCST008611_1	Proteinuria (moderate to severe)	4.000000e-06
GCST008612_1	Proteinuria (mild)	3.000000e-10

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement
EFO:0006335	systolic blood pressure
EFO:0006526	pack-years measurement
EFO:0004952	disease recurrence
EFO:0004761	uric acid measurement
EFO:0009104	hyperuricemia
EFO:0007874	gut microbiome measurement

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750
D015175	Prolactinoma	C04.557.470.035.625; C04.588.322.609.792; C10.228.140.617.738.675.800; C19.344.609.792; C19.700.734.792
D058499	Retinal Dystrophies	C11.768.585.658
C536390	Donnai-Barrow syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3883310 (PROTEIN-PROTEIN INTERACTION)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2075252	Toxicity	4	cisplatin	Neoplasms
rs2228171	Toxicity	3	cisplatin	Neoplasms

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2075252	LRP2	4	-1.00	1	cisplatin
rs2228171	LRP2	3	2.25	1	cisplatin

CTD chemical–gene interactions

32 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases methylation, increases expression, affects expression, decreases expression	8
trichostatin A	affects cotreatment, decreases expression	3
sodium arsenite	decreases expression, increases expression, affects methylation	3
Ethinyl Estradiol	affects expression, decreases expression	3
bisphenol A	affects expression, decreases expression	2
entinostat	increases expression, affects cotreatment, decreases expression	2
Vorinostat	affects cotreatment, decreases expression, increases expression	2
Panobinostat	affects cotreatment, decreases expression	2
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	2
2,4,6-tribromophenol	increases expression	1
methylmercuric chloride	decreases expression	1
methyleugenol	decreases expression	1
2-tert-butylhydroquinone	decreases expression	1
tetrabromobisphenol A	increases expression	1
aflatoxin B2	decreases methylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
pentabrominated diphenyl ether 100	increases expression	1
Cadmium	decreases expression	1
Carbamazepine	affects expression	1
Cisplatin	decreases expression	1
Hydrogen Peroxide	affects expression	1
Methimazole	increases expression	1
Methotrexate	increases expression	1
Propylthiouracil	decreases expression	1
Tetrachlorodibenzodioxin	affects expression	1
Tobacco Smoke Pollution	increases expression	1
Triclosan	increases expression	1
Cyclosporine	decreases expression	1
Okadaic Acid	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1268507	Binding	Effect on interaction between Axin1-GFP and Lrp2 in HEK293 cells transfected with LRP6-myc and Axin2-myc cDNAs at 10 uM by Western blot analysis	Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. — Nat Chem Biol

Cellosaurus cell lines

4 cell lines: 1 embryonic stem cell, 1 finite cell line, 1 induced pluripotent stem cell, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A5EQ	WAe009-A-56	Embryonic stem cell	Female
CVCL_B4GJ	WG4066	Finite cell line	Female
CVCL_VN07	WTSIi227-A-1	Induced pluripotent stem cell	Female
CVCL_VN85	293-M7	Transformed cell line	Female

Clinical trials (associated diseases)

301 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00668824	PHASE4	UNKNOWN	Improved Diagnosis of Congenital Heart Disease by Magnetic Resonance Imaging Using Vasovist
NCT01368705	PHASE4	COMPLETED	Nitrogen Balance in Infants After Post Cardiothoracic Surgery
NCT01619982	PHASE4	COMPLETED	Pre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients
NCT02122679	PHASE4	WITHDRAWN	Tranexamic Acid Effect on Platelet Aggregation Following Infant Cardiopulmonary Bypass
NCT02527811	PHASE4	UNKNOWN	Ulinastatin Injection in in Pediatric Patients Undergoing Open Heart Surgery
NCT03014700	PHASE4	COMPLETED	Fibrinogen Concentrate vs Cryoprecipitate
NCT03408340	PHASE4	TERMINATED	Paravertebral Nerve Blocks in Neonates
NCT03630796	PHASE4	UNKNOWN	Effect of Sevoflurane in Postoperative Troponin I Levels in Children Undergoing Congenital Heart Defects Surgery
NCT03667703	PHASE4	COMPLETED	Stress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease
NCT04453761	PHASE4	UNKNOWN	Thiamine Influenced on Substrate Energy Effectiveness in Indonesian Children Undergoing Cardiopulmonary Bypass
NCT06668389	PHASE4	RECRUITING	Sodium-Glucose Cotransporter 2 Inhibitors for Repaired Tetralogy of Fallot Patients for Enhancement of Cardio-Pulmonary Status Trial
NCT07499154	PHASE4	NOT_YET_RECRUITING	Perioperative Lidocaine for Lung Protection in Infants Undergoing Cardiac Surgery
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00000494	PHASE3	COMPLETED	Management of Patent Ductus in Premature Infants
NCT01134302	PHASE3	UNKNOWN	Hybrid Versus Norwood Management Strategies in Infants Undergoing Single Ventricle Palliation
NCT01607983	PHASE3	WITHDRAWN	Effects of Pulmonary Vasodilation Upon VA Coupling in Fontan Patients
NCT01662011	PHASE3	UNKNOWN	Application of Neurally Adjusted Ventilatory Assist to Children After Congenital Cardiac Surgery
NCT02320669	PHASE3	COMPLETED	Phase 3 Triiodothyronine Supplementation for Infants After Cardiopulmonary Bypass
NCT02615262	PHASE3	COMPLETED	Intraoperative Dexamethasone in Pediatric Cardiac Surgery
NCT03153137	PHASE3	COMPLETED	Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects
NCT03154476	PHASE3	COMPLETED	Role of Sildenafil for Fontan Associated Liver Disease (SiFALD) Study
NCT04536194	PHASE3	COMPLETED	Dopamine Versus Norepinephrine Under General Anesthesia
NCT04702373	PHASE3	ACTIVE_NOT_RECRUITING	Training in Exercise Activities and Motion for Growth (TEAM 4 Growth) RCT
NCT05049590	PHASE3	COMPLETED	Acute Normovolemic Hemodilution in Complex Cardiac Surgery
NCT06406517	PHASE3	UNKNOWN	Comparative Effectiveness of Gadopiclenol for Evaluation of Adult Congenital Heart Anatomy and Hemodynamics
NCT06693674	PHASE3	RECRUITING	Effect of Sacubitril-Valsartan on Cardiac Structure and Function
NCT06955260	PHASE3	NOT_YET_RECRUITING	SGLT2 Inhibition With Empagliflozin in Fontan Circulatory Failure
NCT00115375	PHASE2	COMPLETED	Platelet Aggregation Inhibition in Children on Clopidogrel (PICOLO)
NCT00350220	PHASE2	COMPLETED	Transfusion Strategies in Pediatric Cardiothoracic Surgery
NCT00374088	PHASE2	COMPLETED	N-Acetylcysteine in Neonatal Congenital Heart Surgery (INACT Study)
NCT00538785	PHASE2	COMPLETED	A Study to Evaluate MEDI-524 In Children With Hemodynamically Significant Congenital Heart Disease
NCT00770705	PHASE2	WITHDRAWN	Parenteral Phenoxybenzamine During Congenital Heart Disease Surgery
NCT00919945	PHASE2	TERMINATED	Impact of Early Enteral Feeding on Splanchnic Blood Flow After Surgery for Critical Heart Disease in the Newborn
NCT01063712	PHASE2	COMPLETED	Safety and Effectiveness of the Device Nit-Occlud® PDA-R
NCT01069510	PHASE2	COMPLETED	Spironolactone in Adult Congenital Heart Disease
NCT01189981	PHASE2	COMPLETED	Effect of eHealth Encouragements to Intensive Exercise in Adolescents With Congenital Heart Disease
NCT01330433	PHASE2	COMPLETED	Effects of CoSeal on Bleeding & Adhesions in Pediatric Heart Surgery
NCT01662037	PHASE2	COMPLETED	Bosentan Therapy in Children With Functional Single Ventricle
NCT01668264	PHASE2	UNKNOWN	Imaging Assessment of Diastolic Function
NCT01827059	PHASE2	UNKNOWN	Bosentan In Exercise Induced Pulmonary Arterial Hypertension in CongenitaL Heart diseasE