CORIN

Summary

CORIN (corin, serine peptidase, HGNC:19012) is a protein-coding gene on chromosome 4p12, encoding Atrial natriuretic peptide-converting enzyme (Q9Y5Q5). Serine-type endopeptidase involved in atrial natriuretic peptide (NPPA) and brain natriuretic peptide (NPPB) processing.

This gene encodes a member of the type II transmembrane serine protease class of the trypsin superfamily. Members of this family are composed of multiple structurally distinct domains. The encoded protein converts pro-atrial natriuretic peptide to biologically active atrial natriuretic peptide, a cardiac hormone that regulates blood volume and pressure. This protein may also function as a pro-brain-type natriuretic peptide convertase. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 10699 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Cenani-Lenz syndactyly syndrome (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 22
• Clinical variants (ClinVar): 1,726 total — 23 pathogenic, 26 likely-pathogenic
• Phenotypes (HPO): 155
• MANE Select transcript: NM_006587

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19012
Approved symbol	CORIN
Name	corin, serine peptidase
Location	4p12
Locus type	gene with protein product
Status	Approved
Aliases	PRSC, CRN, ATC2, Lrp4, TMPRSS10
Ensembl gene	ENSG00000145244
Ensembl biotype	protein_coding
OMIM	605236
Entrez	10699

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 27 protein_coding, 3 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000273857, ENST00000502252, ENST00000502726, ENST00000503821, ENST00000504584, ENST00000505754, ENST00000505909, ENST00000508498, ENST00000510974, ENST00000515827, ENST00000610355, ENST00000891632, ENST00000891633, ENST00000891634, ENST00000891635, ENST00000891636, ENST00000961980, ENST00000961981, ENST00000961982, ENST00000961983, ENST00000961984, ENST00000961985, ENST00000961986, ENST00000961987, ENST00000961988, ENST00000961989, ENST00000961990, ENST00000961991, ENST00000961992, ENST00000961993, ENST00000961994, ENST00000961995

RefSeq mRNA: 3 — MANE Select: NM_006587 NM_001278585, NM_001278586, NM_006587

CCDS: CCDS3477, CCDS63958, CCDS75122

Canonical transcript exons

ENST00000273857 — 22 exons

Exon	Start	End
ENSE00000969558	47680141	47680251
ENSE00000969562	47661711	47661856
ENSE00000969563	47653553	47653660
ENSE00000969565	47643146	47643256
ENSE00000969566	47641920	47642049
ENSE00000969567	47626405	47626521
ENSE00000969569	47623571	47623745
ENSE00000969570	47603397	47603668
ENSE00000969571	47600214	47600347
ENSE00001127007	47594001	47595903
ENSE00003550176	47674393	47674500
ENSE00003571743	47677938	47678054
ENSE00003580771	47806903	47807047
ENSE00003594525	47744402	47744583
ENSE00003598886	47623899	47623948
ENSE00003626604	47692970	47693083
ENSE00003639537	47645081	47645194
ENSE00003643003	47683731	47683838
ENSE00003654972	47763379	47763586
ENSE00003671461	47665032	47665263
ENSE00003694280	47786725	47786925
ENSE00003842088	47837887	47838067

Expression profiles

Bgee: expression breadth ubiquitous, 176 present calls, max score 97.52.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.0018 / max 145.5769, expressed in 175 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
52039	0.7828	142
52040	0.2096	81
52038	0.0094	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cardiac muscle of right atrium	UBERON:0003379	97.52	gold quality
heart right ventricle	UBERON:0002080	96.25	gold quality
myocardium	UBERON:0002349	95.17	gold quality
cardiac atrium	UBERON:0002081	94.68	gold quality
right atrium auricular region	UBERON:0006631	94.28	gold quality
left ventricle myocardium	UBERON:0006566	93.74	gold quality
cardiac ventricle	UBERON:0002082	90.31	gold quality
heart left ventricle	UBERON:0002084	90.30	gold quality
apex of heart	UBERON:0002098	89.98	gold quality
heart	UBERON:0000948	89.15	gold quality
decidua	UBERON:0002450	88.03	gold quality
upper leg skin	UBERON:0004262	84.87	gold quality
penis	UBERON:0000989	82.75	gold quality
upper arm skin	UBERON:0004263	82.08	gold quality
stromal cell of endometrium	CL:0002255	81.34	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	77.54	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.53	gold quality
urethra	UBERON:0000057	75.65	gold quality
nipple	UBERON:0002030	75.45	gold quality
myometrium	UBERON:0001296	73.40	gold quality
seminal vesicle	UBERON:0000998	73.28	gold quality
gall bladder	UBERON:0002110	73.26	gold quality
skin of leg	UBERON:0001511	73.05	gold quality
vagina	UBERON:0000996	72.99	gold quality
zone of skin	UBERON:0000014	72.24	gold quality
metanephros cortex	UBERON:0010533	71.13	gold quality
cauda epididymis	UBERON:0004360	70.75	gold quality
adenohypophysis	UBERON:0002196	70.48	gold quality
skin of abdomen	UBERON:0001416	70.40	gold quality
body of uterus	UBERON:0009853	70.18	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.24
E-MTAB-5061	no	3.27

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GATA4

miRNA regulators (miRDB)

118 targeting CORIN, 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-3163	100.00	77.23	8605
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-190A-3P	100.00	80.35	5520
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-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-12121	99.99	66.64	255
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-6744-5P	99.93	66.82	748

Literature-anchored findings (GeneRIF, showing 40)

• Processing of pro-atrial natriuretic peptide by corin in cardiac myocytes. (PMID:11884416)
• These data indicate that the GATA element and its binding to GATA-4 are essential for cardiac expression of the human and murine corin genes. (PMID:12154094)
• the transmembrane domain is not necessary for the biological activity of corin but may be a mechanism to localize corin at specific sites (PMID:14559895)
• in CORIN, the frizzled 1 domain and LDLR repeats 1-4 are important structural elements for recognition of the physiological substrate, pro-ANP (PMID:15192093)
• The corin I555 (P568) allele is common in blacks and is associated with higher blood pressure and an increased risk for prevalent hypertension. (PMID:16216958)
• Corin I555(P568) allele represents a cardiac hypertrophy-sensitizing genetic locus in systemic hypertension. (PMID:17296875)
• N-linked oligosaccharides play an important role in corin activation (PMID:17660514)
• ANP and corin are expressed at the mRNA level in human adipose tissue and preadipocytes (PMID:17890485)
• corin gene single nucleotide polymorphism associated with hypertension and cardiac hypertrophy impair corin zymogen activation and natriuretic peptide processing activity (PMID:18669922)
• Dysfunctional corin i555(p568) allele is associated with impaired brain natriuretic peptide processing and adverse outcomes in blacks with systolic heart failure: results from the Genetic Risk Assessment in Heart Failure substudy. (PMID:19919978)
• corin might be involved in the salt retention seen in glomerular diseases. (PMID:20613715)
• A modest correlation is demonstrated between plasma corin levels and individual echocardiographic indices of cardiac hypertrophy, but no relationships between plasma corin and myocardial performance are proved in this study. (PMID:20670840)
• Insufficient corin activation is expected to prevent natriuretic peptide processing and may contribute to body fluid retention and impaired cardiac function in patients with heart failure. (PMID:20802129)
• Data suggest that there may be patients for whom low corin levels and impaired pro-ANP cleavage contribute to acute decompensated heart failure. (PMID:21216831)
• Ectodomain shedding and autocleavage of the cardiac membrane protease corin. (PMID:21288900)
• the sequence in the cytoplasmic tail plays an important role in corin cell surface targeting and zymogen activation. (PMID:21518754)
• the function and regulation of corin (PMID:22093942)
• results indicate that corin and ANP are essential for physiological changes at the maternal-fetal interface, suggesting that defects in corin and ANP function may contribute to pre-eclampsia (PMID:22437503)
• Results indicate that corin defects may represent an important mechanism in salt-sensitive hypertension and cardiac hypertrophy in blacks. (PMID:22987923)
• The results indicate that renal tubular corin may be shed into urine and that urinary and renal corin levels were reduced in chronic kidney disease patients. (PMID:23327554)
• human CORIN gene mutations causing impaired corin activity may be an underlying mechanism in hypertension (PMID:23372161)
• CORIN is expressed in non-pregnant late secretory phase endometrium, first trimester human implantation sites and is up-regulated with decidualization ex vivo (PMID:23434834)
• The processing of proBNP1_108 by corin may be controlled by O-linked glycosylation of proBNP1-108. A potential impairment of proBNP1lo8 processing in heart failure may be linked to dysregulation of the convertase corin.[Review] (PMID:24015598)
• Corin mediates an essential step in the cascade of natriuretic peptide biosynthesis and eventually their action. Thus, it is postulated that aberrations in the normal activity of corin may contribute to cardiovascular and renal diseases. (PMID:24100222)
• data provide important insights into the molecular basis underlying corin mutations that may contribute to preeclampsia in patients. (PMID:24828501)
• N-glycans at different sites may play distinct roles in regulating the cell membrane targeting, zymogen activation, and ectodomain shedding of corin (PMID:25451932)
• In conclusion, this is the first report of a highly significant association between these two single nucleotide polymorphisms in CORIN gene and preeclampsia. (PMID:25474356)
• the variant altered corin structure and impaired the natriuretic peptide processing activity in vivo. The results highlight corin defects as an important underlying mechanism in hypertension. (PMID:25488193)
• IRE1-dependent corin mRNA decay is a mechanism leading to corin protein deficiency may contribute to the pathophysiology of impaired natriuretic peptide pro-hormone processing in humans processing in humans with advanced systolic heart failure. (PMID:25516437)
• Plasma corin levels decreased significantly from preoperative concentrations after coronary artery bypass graft surgery. (PMID:25649697)
• Hypertensive participants had an increased serum corin level compared to those without hypertension, suggesting that corin may play a role in the pathology of hypertension. (PMID:25663063)
• Circulating corin concentrations are related to infarct size in patients after ST-segment elevation myocardial infarction (PMID:25981578)
• Serum soluble corin was decreased in patients with stroke compared with healthy controls. (PMID:26022632)
• corin may play an important role in the pathology of atrial fibrillation (PMID:26048191)
• Increased serum soluble corin in mid pregnancy was associated with an increased risk for HDP(hypertensive disorders of pregnancy) .–increased serum soluble corin in mid pregnancy could be an indicator for HDP (PMID:26086065)
• identified a PCSK6 mutation that impaired corin activation activity in a hypertensive patient (PMID:26259032)
• Serum soluble corin was significantly and positively associated with dyslipidemia (PMID:26344336)
• Data show that both furin and brain type natriuretic peptide (BNP) were more sensitive than corin in predicting cardiovascular complications in type 2 diabetes mellitus (T2DM) patients. (PMID:26488448)
• serum levels of corin are significantly decreased in acute myocardial infarction patients (PMID:26577631)
• Corin and atrial natriuretic peptide A were most abundant in the proximal convoluted tubules and the medullary connecting ducts. (PMID:27343265)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	corin	ENSDARG00000101281
mus_musculus	Corin	ENSMUSG00000005220
rattus_norvegicus	Corin	ENSRNOG00000002302

Protein

Protein identifiers

Atrial natriuretic peptide-converting enzyme — Q9Y5Q5 (reviewed: Q9Y5Q5)

Alternative names: Corin, Heart-specific serine proteinase ATC2, Pro-ANP-converting enzyme, Transmembrane protease serine 10

All UniProt accessions (6): A0A087X1D5, E7EQE7, Q9Y5Q5, J3KR83, J3KR88, J3KR90

UniProt curated annotations — full annotation on UniProt →

Function. Serine-type endopeptidase involved in atrial natriuretic peptide (NPPA) and brain natriuretic peptide (NPPB) processing. Converts through proteolytic cleavage the non-functional propeptides NPPA and NPPB into their active hormones, ANP and BNP(1-32) respectively, thereby regulating blood pressure in the heart and promoting natriuresis, diuresis and vasodilation. Proteolytic cleavage of pro-NPPA also plays a role in female pregnancy by promoting trophoblast invasion and spiral artery remodeling in uterus. Also acts as a regulator of sodium reabsorption in kidney. Has weaker endopeptidase activity compared to isoform 1.

Subcellular location. Cell membrane Cell membrane Secreted Secreted Secreted.

Tissue specificity. Highly expressed in heart. Expressed in heart myocytes. Also expressed in pregnant uterus. Detected in blood, in plasma as well as in serum (at protein level).

Post-translational modifications. N-glycosylated; required for processing and activation. Activated through proteolytic processing by a trypsin-like protease; cleaved into a N-terminal propeptide and an activated corin protease fragment. Different soluble forms are produced by cleavage and autocatalytic cleavage: Atrial natriuretic peptide-converting enzyme, 180 kDa soluble fragment is produced by cleavage by ADAM10, while 160 kDa and 100 kDa soluble fragments are produced by autocatalytic cleavage. Cleavage by ADAM10 to produce soluble 180 kDa soluble fragment takes place after the transmembrane region and before FZ 1. A disulfide bond links the activated corin protease fragment and the N-terminal propeptide. The disulfide bond also links the activated corin protease fragment with soluble fragments (100 kDa, 160 kDa and 180 kDa fragments).

Disease relevance. Pre-eclampsia/eclampsia 5 (PEE5) [MIM:614595] A hypertensive disorder of pregnancy characterized by new hypertension (blood pressure 140/90 or greater) presenting after 20 weeks’ gestation with clinically relevant proteinuria. It impacts 2 individuals, the mother and her child, both of whom can be severely affected. Preeclampsia is one of the causes of maternal mortality and morbidity worldwide. The disease is caused by variants affecting the gene represented in this entry. Cardiomyopathy, familial hypertrophic, 30, atrial (CMH30) [MIM:620734] An autosomal recessive heart disease characterized by enlarged and thickened left atrium, left atrial fibrosis, atrial arrhythmias, and hypertension. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited in a dose-dependent manner by non-specific trypsin-like serine protease inhibitors including benzamidine.

Domain organisation. The DDNN motif is required for targeting to the cell membrane and enzyme activation.

Miscellaneous. Initially named CORIN due to its abundant expression in the heart.

Similarity. Belongs to the peptidase S1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y5Q5-1	1, E1, hE1	yes
Q9Y5Q5-2	2, E1a, hE1a

RefSeq proteins (3): NP_001265514, NP_001265515, NP_006578* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001190	SRCR	Domain
IPR001254	Trypsin_dom	Domain
IPR002172	LDrepeatLR_classA_rpt	Repeat
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR017052	Corin	Family
IPR020067	Frizzled_dom	Domain
IPR023415	LDLR_class-A_CS	Conserved_site
IPR033116	TRYPSIN_SER	Active_site
IPR036055	LDL_receptor-like_sf	Homologous_superfamily
IPR036772	SRCR-like_dom_sf	Homologous_superfamily
IPR036790	Frizzled_dom_sf	Homologous_superfamily
IPR041762	Corin_CRD_1	Domain
IPR041763	Corin_CRD_2	Domain
IPR043504

Pfam: PF00057, PF00089, PF01392, PF15494

UniProt features (102 total): disulfide bond 36, glycosylation site 19, domain 11, mutagenesis site 11, chain 6, sequence variant 5, active site 3, site 3, sequence conflict 2, topological domain 2, region of interest 1, short sequence motif 1, transmembrane region 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y5Q5-F1	70.20	0.07

Functional residue map

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

Catalytic / active sites (6): 843 (charge relay system); 892 (charge relay system); 985 (charge relay system); 164–165 (cleavage; by autolysis); 427–428 (cleavage; by autolysis); 801–802 (cleavage)

Disulfide bonds (36): 139–199, 147–192, 183–223, 212–256, 216–240, 269–282, 277–295, 289–304, 306–318, 313–331, 325–340, 342–355, 350–368, 362–377, 379–392, 387–405, 399–414, 455–518, 463–511, 502–540 …

Glycosylation sites (19): 80, 104, 135, 141, 231, 245, 251, 305, 320, 376, 413, 446, 451, 469, 567, 651, 697, 761, 1022

Mutagenesis-validated functional residues (11):

Position	Phenotype
26	impairs cell membrane targeting; when associated with a-30.
30	impairs cell membrane targeting; when associated with a-26.
134	does not affect autocatalytic cleavage.
164	affects autocatalytic cleavage and production of atrial natriuretic peptide-converting enzyme, 160 kda soluble fragment.
180	does not affect autocatalytic cleavage.
213	does not affect autocatalytic cleavage.
239	does not affect autocatalytic cleavage.
244	does not affect autocatalytic cleavage.
427	affects autocatalytic cleavage and production of atrial natriuretic peptide-converting enzyme, 100 kda soluble fragment.
801	loss of activity towards nppa.
985	loss of activity towards nppa.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5578768	Physiological factors

MSigDB gene sets: 735 (showing top): BIOCARTA_GCR_PATHWAY, GOBP_NEUROMUSCULAR_JUNCTION_DEVELOPMENT, GOBP_DENDRITE_DEVELOPMENT, GOBP_EXCRETION, GCM_MAP4K4, GOBP_EPITHELIUM_DEVELOPMENT, ACTACCT_MIR196A_MIR196B, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_CIRCULATORY_SYSTEM_PROCESS, MODULE_255, GOBP_SYNAPSE_ASSEMBLY, GOBP_MEMBRANE_BIOGENESIS, GOBP_EMBRYONIC_DIGIT_MORPHOGENESIS, ROVERSI_GLIOMA_COPY_NUMBER_UP

GO Biological Process (8): regulation of systemic arterial blood pressure by atrial natriuretic peptide (GO:0003050), female pregnancy (GO:0007565), regulation of blood pressure (GO:0008217), peptide hormone processing (GO:0016486), regulation of renal sodium excretion (GO:0035813), regulation of cardiac conduction (GO:1903779), proteolysis (GO:0006508), regulation of system process (GO:0044057)

GO Molecular Function (6): endopeptidase activity (GO:0004175), serine-type endopeptidase activity (GO:0004252), protein binding (GO:0005515), peptidase activity (GO:0008233), serine-type peptidase activity (GO:0008236), hydrolase activity (GO:0016787)

GO Cellular Component (6): extracellular region (GO:0005576), plasma membrane (GO:0005886), cell surface (GO:0009986), actin cytoskeleton (GO:0015629), nuclear body (GO:0016604), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Cardiac conduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
peptidase activity	2
regulation of systemic arterial blood pressure by hormone	1
multi-organism reproductive process	1
multi-multicellular organism process	1
blood circulation	1
regulation of biological quality	1
hormone metabolic process	1
signaling receptor ligand precursor processing	1
renal sodium excretion	1
regulation of excretion	1
regulation of renal system process	1
regulation of heart contraction	1
cardiac conduction	1
protein metabolic process	1
system process	1
regulation of multicellular organismal process	1
endopeptidase activity	1
serine-type peptidase activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
serine hydrolase activity	1
catalytic activity	1
membrane	1
cell periphery	1
cytoskeleton	1
nucleoplasm	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1273 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CORIN	NPPA	P01160	871
CORIN	ACADM	P11310	633
CORIN	FURIN	P09958	628
CORIN	NPR1	P16066	624
CORIN	PCSK6	P29122	615
CORIN	LMX1A	Q8TE12	604
CORIN	NPPB	P16860	586
CORIN	NPR3	P17342	585
CORIN	AGRN	O00468	585
CORIN	EN1	Q05925	583
CORIN	NPPC	P23582	528
CORIN	NPR2	P20594	511
CORIN	MME	P08473	499
CORIN	MMEL1	Q495T6	494
CORIN	DVL1	O14640	493

IntAct

12 interactions, top by confidence:

A	B	Type	Score
EMP1	CORIN	psi-mi:“MI:0915”(physical association)	0.560
GPX8	CORIN	psi-mi:“MI:0915”(physical association)	0.560
AQP6	CORIN	psi-mi:“MI:0915”(physical association)	0.560
CLDN5	CORIN	psi-mi:“MI:0915”(physical association)	0.560
CORIN	AQP6	psi-mi:“MI:0915”(physical association)	0.000
CORIN	CLDN5	psi-mi:“MI:0915”(physical association)	0.000
CORIN	EMP1	psi-mi:“MI:0915”(physical association)	0.000
CORIN	GPX8	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (6): CORIN (Two-hybrid), CORIN (Two-hybrid), GPX8 (Two-hybrid), CLDN5 (Two-hybrid), CORIN (Cross-Linking-MS (XL-MS)), CORIN (Proximity Label-MS)

ESM2 similar proteins: A0A2K5V015, A1YIY0, A8MUZ8, A8MWA4, B8JI71, O08569, P01133, P0DJ43, P14370, P14585, P17630, P19070, P48357, P82279, P97435, Q07444, Q0D2K5, Q28066, Q28660, Q29RU2, Q4KUS1, Q5G872, Q5R6R1, Q5RCW9, Q5T1H1, Q5UKY4, Q5Z5Q3, Q60736, Q63515, Q63722, Q6DFV8, Q6GMZ9, Q6V0K7, Q6ZN79, Q7TSY4, Q811Q4, Q8N2E2, Q8VHS2, Q90Y54, Q95MI4

Diamond homologs: A0A0K3AWM6, B3DIG4, G5ECQ2, O00144, O19116, O42579, O57328, O57329, O60353, O70421, O75084, O93274, P18537, P58421, P97299, P97401, Q08463, Q08464, Q13467, Q14332, Q24760, Q498S8, Q5BL72, Q5RCN4, Q5RF67, Q5T4F7, Q61086, Q61088, Q61089, Q61090, Q61091, Q6FHJ7, Q7YRN1, Q80YN4, Q863H1, Q8AVJ9, Q8BKG4, Q8C4U3, Q8CHL0, Q8K4C8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1726 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	23
Likely pathogenic	26
Uncertain significance	910
Likely benign	555
Benign	83

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1323250	NM_002334.4(LRP4):c.2830C>T (p.Gln944Ter)	Pathogenic
1393202	NM_002334.4(LRP4):c.2260C>T (p.Arg754Ter)	Pathogenic
2112258	NM_002334.4(LRP4):c.2498del (p.Thr833fs)	Pathogenic
2504113	NM_006587.4(CORIN):c.684dup (p.Met229fs)	Pathogenic
2921833	NM_002334.4(LRP4):c.1850del (p.Ala617fs)	Pathogenic
2945597	NM_002334.4(LRP4):c.4400dup (p.Asn1467fs)	Pathogenic
2950364	NM_002334.4(LRP4):c.1123_1126dup (p.Val376fs)	Pathogenic
30450	NM_006587.4(CORIN):c.949A>G (p.Lys317Glu)	Pathogenic
30451	NM_006587.4(CORIN):c.1414A>G (p.Ser472Gly)	Pathogenic
3756432	NM_002334.4(LRP4):c.5215del (p.Val1739fs)	Pathogenic
3756686	NM_002334.4(LRP4):c.3898C>T (p.Gln1300Ter)	Pathogenic
3764559	NM_002334.4(LRP4):c.2613-2A>T	Pathogenic
428601	NM_002334.4(LRP4):c.316+1G>A	Pathogenic
4783116	NM_002334.4(LRP4):c.2656C>T (p.Arg886Ter)	Pathogenic
4785456	NM_002334.4(LRP4):c.3549G>A (p.Trp1183Ter)	Pathogenic
4794477	NM_002334.4(LRP4):c.5308C>T (p.Arg1770Ter)	Pathogenic
5686	NM_002334.4(LRP4):c.1585G>A (p.Asp529Asn)	Pathogenic
5688	NM_002334.4(LRP4):c.4959C>G (p.Gly1653=)	Pathogenic
5690	NM_002334.4(LRP4):c.479G>A (p.Cys160Tyr)	Pathogenic
5691	NM_002334.4(LRP4):c.1345G>A (p.Asp449Asn)	Pathogenic
5692	NM_002334.4(LRP4):c.1381A>C (p.Thr461Pro)	Pathogenic
5693	NM_002334.4(LRP4):c.200-9G>A	Pathogenic
576661	NM_002334.4(LRP4):c.2866G>T (p.Glu956Ter)	Pathogenic
1179057	NM_002334.4(LRP4):c.1560G>A (p.Trp520Ter)	Likely pathogenic
1179202	NM_002334.4(LRP4):c.1184-1G>A	Likely pathogenic
2119457	NM_002334.4(LRP4):c.3699+1G>A	Likely pathogenic
2687873	NM_002334.4(LRP4):c.2814+1G>A	Likely pathogenic
2690639	NM_002334.4(LRP4):c.4225_4226insC (p.Ile1409fs)	Likely pathogenic
2925899	NM_002334.4(LRP4):c.1184-2A>G	Likely pathogenic
2937965	NM_002334.4(LRP4):c.898G>A (p.Asp300Asn)	Likely pathogenic

SpliceAI

10825 predictions. Top by Δscore:

Variant	Effect	Δscore
11:46859312:CTCC:C	acceptor_gain	1.0000
11:46859313:TCCC:T	acceptor_loss	1.0000
11:46859314:CCCTA:C	acceptor_loss	1.0000
11:46859315:CCTAG:C	acceptor_loss	1.0000
11:46859316:CT:C	acceptor_loss	1.0000
11:46859317:T:G	acceptor_loss	1.0000
11:46862600:TTTTA:T	donor_loss	1.0000
11:46862601:TTTA:T	donor_loss	1.0000
11:46862602:TTA:T	donor_loss	1.0000
11:46862603:TACC:T	donor_loss	1.0000
11:46862605:CCT:C	donor_gain	1.0000
11:46862607:T:TA	donor_gain	1.0000
11:46862743:TGTGT:T	acceptor_gain	1.0000
11:46862744:GTGT:G	acceptor_gain	1.0000
11:46862745:TGT:T	acceptor_gain	1.0000
11:46862745:TGTC:T	acceptor_loss	1.0000
11:46862746:GT:G	acceptor_gain	1.0000
11:46862746:GTCT:G	acceptor_loss	1.0000
11:46862748:C:CC	acceptor_gain	1.0000
11:46862748:C:CG	acceptor_loss	1.0000
11:46862749:T:C	acceptor_gain	1.0000
11:46862750:T:C	acceptor_gain	1.0000
11:46862750:T:TC	acceptor_gain	1.0000
11:46868115:C:CC	acceptor_gain	1.0000
11:46868713:CCT:C	acceptor_loss	1.0000
11:46868714:C:CG	acceptor_loss	1.0000
11:46868715:T:A	acceptor_loss	1.0000
11:46869152:C:CT	acceptor_gain	1.0000
11:46871569:G:A	donor_gain	1.0000
11:46871629:AGATC:A	acceptor_gain	1.0000

AlphaMissense

6977 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:47603416:C:A	W931C	1.000
4:47603416:C:G	W931C	1.000
4:47595832:C:A	W1006C	0.999
4:47595832:C:G	W1006C	0.999
4:47595884:A:G	L989P	0.999
4:47595899:T:A	D984V	0.999
4:47595899:T:G	D984A	0.999
4:47595900:C:G	D984H	0.999
4:47600217:G:C	C981W	0.999
4:47600218:C:G	C981S	0.999
4:47600218:C:T	C981Y	0.999
4:47600219:A:G	C981R	0.999
4:47600219:A:T	C981S	0.999
4:47600250:A:C	C970W	0.999
4:47600251:C:T	C970Y	0.999
4:47600252:A:G	C970R	0.999
4:47600295:A:C	C955W	0.999
4:47603418:A:G	W931R	0.999
4:47603418:A:T	W931R	0.999
4:47603431:G:C	C926W	0.999
4:47623579:G:C	C844W	0.999
4:47623666:C:A	W815C	0.999
4:47623666:C:G	W815C	0.999
4:47623668:A:G	W815R	0.999
4:47623668:A:T	W815R	0.999
4:47623672:C:A	W813C	0.999
4:47623672:C:G	W813C	0.999
4:47623674:A:G	W813R	0.999
4:47623674:A:T	W813R	0.999
4:47661793:C:A	W551C	0.999

dbSNP variants (sampled 300 via entrez): RS1000009526 (4:47809292 G>A), RS1000014477 (4:47793239 C>A,G,T), RS1000014755 (4:47641320 A>G), RS1000035868 (4:47656743 C>A), RS1000038359 (4:47739696 T>C), RS10000405 (4:47714864 C>A,T), RS1000047539 (4:47816070 A>C), RS1000053843 (4:47832735 C>A,T), RS10000636 (4:47605279 A>T), RS1000079248 (4:47634483 A>C), RS10001009 (4:47740297 T>C,G), RS1000110333 (4:47654661 C>G,T), RS1000110750 (4:47696750 T>C), RS1000143663 (4:47686641 TG>T), RS1000164522 (4:47614004 T>C)

Disease associations

OMIM: gene MIM:605236 | disease phenotypes: MIM:212780, MIM:614305, MIM:616304, MIM:156000, MIM:614595, MIM:620734, MIM:600334, MIM:603689, MIM:607569, MIM:604145, MIM:608807, MIM:611705, MIM:613765, MIM:123100

GenCC curated gene-disease

Disease	Classification	Inheritance
Cenani-Lenz syndactyly syndrome	Definitive	Autosomal recessive
congenital myasthenic syndrome 17	Strong	Autosomal recessive
sclerosteosis	Supportive	Autosomal recessive
postsynaptic congenital myasthenic syndrome	Supportive	Autosomal recessive
sclerosteosis 2	Limited	Semidominant
preeclampsia/eclampsia 5	Limited	Unknown

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
Cenani-Lenz syndactyly syndrome	Definitive	AR
congenital myasthenic syndrome 17	Limited	AR

Mondo (21): Cenani-Lenz syndactyly syndrome (MONDO:0008931), sclerosteosis 2 (MONDO:0013679), congenital myasthenic syndrome 17 (MONDO:0014578), prostate cancer (MONDO:0008315), epilepsy (MONDO:0005027), Meniere disease (MONDO:0007972), preeclampsia/eclampsia 5 (MONDO:0013817), atrial fibrillation (MONDO:0004981), cardiomyopathy (MONDO:0004994), hypertensive disorder (MONDO:0005044), cardiomyopathy, familial hypertrophic, 30, atrial (MONDO:0958241), intellectual disability (MONDO:0001071), tibial muscular dystrophy (MONDO:0010870), myopathy, myofibrillar, 9, with early respiratory failure (MONDO:0011362), dilated cardiomyopathy 1G (MONDO:0011400)

Orphanet (14): Sclerosteosis (Orphanet:3152), Cenani-Lenz syndrome (Orphanet:3258), Congenital myasthenic syndrome (Orphanet:590), Familial prostate cancer (Orphanet:1331), Rare cardiomyopathy (Orphanet:167848), Titin-related limb-girdle muscular dystrophy R10 (Orphanet:140922), Familial isolated dilated cardiomyopathy (Orphanet:154), Hereditary myopathy with early respiratory failure (Orphanet:178464), Early-onset myopathy with fatal cardiomyopathy (Orphanet:289377), Distal myopathy with early respiratory muscle involvement (Orphanet:34521), Tibial muscular dystrophy (Orphanet:609), Craniosynostosis (Orphanet:1531), NON RARE IN EUROPE: Menière disease (Orphanet:45360), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

155 total (30 of 155 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000077	Abnormality of the kidney
HP:0000083	Renal insufficiency
HP:0000086	Ectopic kidney
HP:0000089	Renal hypoplasia
HP:0000093	Proteinuria
HP:0000098	Tall stature
HP:0000104	Renal agenesis
HP:0000147	Polycystic ovaries
HP:0000218	High palate
HP:0000256	Macrocephaly
HP:0000272	Malar flattening
HP:0000303	Mandibular prognathia
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000324	Facial asymmetry
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000366	Abnormality of the nose
HP:0000407	Sensorineural hearing impairment
HP:0000411	Protruding ear
HP:0000444	Convex nasal ridge
HP:0000494	Downslanted palpebral fissures
HP:0000496	Abnormality of eye movement
HP:0000504	Abnormality of vision
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000520	Proptosis
HP:0000597	Ophthalmoparesis

GWAS associations

22 associations (top):

Study	Trait	p-value
GCST000297_2	Bone mineral density (hip)	7.000000e-07
GCST000755_37	HDL cholesterol	3.000000e-18
GCST001049_13	D-dimer levels	8.000000e-06
GCST002223_27	HDL cholesterol	7.000000e-29
GCST004232_8	HDL cholesterol levels	6.000000e-39
GCST004521_122	Autism spectrum disorder or schizophrenia	3.000000e-13
GCST004521_165	Autism spectrum disorder or schizophrenia	3.000000e-08
GCST005580_44	Intraocular pressure	1.000000e-12
GCST006268_467	Reaction time	2.000000e-08
GCST006288_36	Heel bone mineral density	3.000000e-32
GCST006288_494	Heel bone mineral density	2.000000e-20
GCST006288_730	Heel bone mineral density	3.000000e-15
GCST006624_107	Systolic blood pressure	4.000000e-21
GCST006979_790	Heel bone mineral density	3.000000e-63
GCST007325_231	General risk tolerance (MTAG)	4.000000e-09
GCST007825_4	Alzheimer’s disease or fasting glucose levels (pleiotropy)	3.000000e-16
GCST008357_37	Mood instability	9.000000e-14
GCST008758_12	Pre-treatment viral load in HIV-1 infection	1.000000e-17
GCST008972_91	Urate levels	2.000000e-08
GCST009030_16	Venous thromboembolism	1.000000e-31
GCST010396_293	Gut microbiota (bacterial taxa, hurdle binary method)	5.000000e-08
GCST90020026_774	Hip index	5.000000e-10

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004507	D dimer measurement
EFO:0004695	intraocular pressure measurement
EFO:0008393	reaction time measurement
EFO:0009270	heel bone mineral density
EFO:0006335	systolic blood pressure
EFO:0008579	risk-taking behaviour
EFO:0008475	mood instability measurement
EFO:0010125	viral load
EFO:0004531	urate measurement
EFO:0007874	gut microbiome measurement
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (15)

Descriptor	Name	Tree numbers
D001281	Atrial Fibrillation	C14.280.067.198; C23.550.073.198
D009202	Cardiomyopathies	C14.280.238
D003398	Craniosynostoses	C05.116.099.370.894.232; C05.660.207.240; C05.660.906.364; C16.131.621.207.240; C16.131.621.906.364
D004827	Epilepsy	C10.228.140.490
D006973	Hypertension	C14.907.489
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008575	Meniere Disease	C09.218.568.217.500
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750
C565824	Cardiomyopathy, Dilated, 1g (supp.)
C566044	Cardiomyopathy, Familial Hypertrophic, 9 (supp.)
C566343	Hereditary Myopathy with Early Respiratory Failure (supp.)
C563854	Muscular Dystrophy, Limb-Girdle, Type 2J (supp.)
C567129	Myopathy, Early-Onset, with Fatal Cardiomyopathy (supp.)
C537525	Sclerosteosis (supp.)
C538150	Syndactyly Cenani Lenz type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Doxorubicin	decreases expression	3
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	2
Daunorubicin	decreases expression	2
Mitoxantrone	decreases expression	2
Progesterone	increases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
triphenyl phosphate	decreases expression	1
bisphenol A	increases methylation, affects cotreatment, affects methylation	1
testosterone undecanoate	increases expression	1
decabromobiphenyl ether	decreases expression	1
tetrabromobisphenol A	decreases expression	1
benzo(e)pyrene	increases methylation	1
triadimefon	decreases expression	1
tetrachlorodian	decreases expression	1
CGP 52608	affects binding, increases reaction	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	decreases expression	1
Fulvestrant	affects cotreatment, affects methylation	1
Acetaminophen	increases expression	1
Arsenic	affects methylation	1
Methapyrilene	increases methylation	1
Nickel	decreases expression	1
Smoke	decreases expression	1
Tretinoin	increases expression	1
Triclosan	decreases expression	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer