CDH1

Summary

CDH1 (cadherin 1, HGNC:1748) is a protein-coding gene on chromosome 16q22.1, encoding Cadherin-1 (P12830). Cadherins are calcium-dependent cell adhesion proteins. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a classical cadherin of the cadherin superfamily. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature glycoprotein. This calcium-dependent cell-cell adhesion protein is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid and ovarian cancer. Loss of function of this gene is thought to contribute to cancer progression by increasing proliferation, invasion, and/or metastasis. The ectodomain of this protein mediates bacterial adhesion to mammalian cells and the cytoplasmic domain is required for internalization. This gene is present in a gene cluster with other members of the cadherin family on chromosome 16.

Source: NCBI Gene 999 — RefSeq curated summary.

At a glance

• Gene–disease (curated): CDH1-related diffuse gastric and lobular breast cancer syndrome (Definitive, ClinGen) — +7 more curated relationships
• GWAS associations: 23
• Clinical variants (ClinVar): 5,210 total — 523 pathogenic, 132 likely-pathogenic
• Phenotypes (HPO): 57
• Druggable target: yes
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 6 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_004360

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1748
Approved symbol	CDH1
Name	cadherin 1
Location	16q22.1
Locus type	gene with protein product
Status	Approved
Aliases	uvomorulin, CD324
Ensembl gene	ENSG00000039068
Ensembl biotype	protein_coding
OMIM	192090
Entrez	999

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 4 protein_coding, 3 nonsense_mediated_decay, 3 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000261769, ENST00000422392, ENST00000561751, ENST00000562118, ENST00000562836, ENST00000564676, ENST00000564745, ENST00000565810, ENST00000566510, ENST00000566612, ENST00000567320, ENST00000884375, ENST00000931199

RefSeq mRNA: 4 — MANE Select: NM_004360 NM_001317184, NM_001317185, NM_001317186, NM_004360

CCDS: CCDS10869, CCDS82005

Canonical transcript exons

ENST00000261769 — 16 exons

Exon	Start	End
ENSE00000844392	68738297	68738411
ENSE00001930498	68833290	68835537
ENSE00003463070	68822001	68822225
ENSE00003470877	68813313	68813495
ENSE00003478164	68810197	68810341
ENSE00003480911	68823399	68823626
ENSE00003524722	68828174	68828304
ENSE00003530746	68811684	68811859
ENSE00003536040	68829654	68829797
ENSE00003583378	68808424	68808567
ENSE00003598752	68801670	68801893
ENSE00003610169	68812135	68812263
ENSE00003650604	68819280	68819425
ENSE00003666145	68808693	68808848
ENSE00003688123	68815515	68815759
ENSE00003713181	68737292	68737463

Expression profiles

Bgee: expression breadth ubiquitous, 245 present calls, max score 99.72.

FANTOM5 (CAGE): breadth broad, TPM avg 75.5786 / max 1390.8897, expressed in 693 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
154769	75.5116	685
154774	0.0434	12
154776	0.0236	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	99.72	gold quality
esophagus squamous epithelium	UBERON:0006920	99.51	gold quality
gingival epithelium	UBERON:0001949	99.47	gold quality
colonic mucosa	UBERON:0000317	99.46	gold quality
mucosa of sigmoid colon	UBERON:0004993	99.46	gold quality
gingiva	UBERON:0001828	99.39	gold quality
endometrium epithelium	UBERON:0004811	99.35	gold quality
upper leg skin	UBERON:0004262	99.14	gold quality
palpebral conjunctiva	UBERON:0001812	99.08	gold quality
skin of hip	UBERON:0001554	99.07	gold quality
bronchial epithelial cell	CL:0002328	99.06	gold quality
squamous epithelium	UBERON:0006914	99.05	gold quality
duodenum	UBERON:0002114	98.93	gold quality
ileal mucosa	UBERON:0000331	98.85	gold quality
epithelium of nasopharynx	UBERON:0001951	98.82	gold quality
mammalian vulva	UBERON:0000997	98.80	gold quality
nasopharynx	UBERON:0001728	98.80	gold quality
epithelium of bronchus	UBERON:0002031	98.76	gold quality
penis	UBERON:0000989	98.74	gold quality
hair follicle	UBERON:0002073	98.74	gold quality
islet of Langerhans	UBERON:0000006	98.72	gold quality
oral cavity	UBERON:0000167	98.72	gold quality
bronchus	UBERON:0002185	98.69	gold quality
epithelium of esophagus	UBERON:0001976	98.66	gold quality
nasal cavity epithelium	UBERON:0005384	98.64	gold quality
upper arm skin	UBERON:0004263	98.60	gold quality
pharyngeal mucosa	UBERON:0000355	98.44	gold quality
tongue squamous epithelium	UBERON:0006919	98.38	gold quality
rectum	UBERON:0001052	98.23	gold quality
corpus epididymis	UBERON:0004359	98.20	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-MTAB-10662	yes	236.82
E-MTAB-8205	yes	178.65
E-MTAB-8498	yes	59.10
E-MTAB-10287	yes	45.60
E-MTAB-8410	yes	45.13
E-GEOD-125970	yes	22.67
E-HCAD-10	yes	13.69
E-MTAB-9388	yes	7.39
E-CURD-53	no	224.18
E-GEOD-100618	no	17.35
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

100 targeting CDH1, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-219A-5P	99.91	73.36	735
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-4782-3P	99.88	73.31	735
HSA-MIR-6766-3P	99.88	73.38	732
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-4728-5P	99.85	69.39	4718

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Products of the c-myc gene activate or repress the activity of the E-cadherin promoter (PMID:10523846)
• Both expression of E-cadherin and its membranous localization are required for well-differentiated-type morphogenesis in gallbladder cancer cells. (PMID:11683173)
• Mutations and polymorphisms in E-cadherin gene CDH1, such as S270A, may contribute to the onset of prostate cancer (PCA) and warrant further investigations in other populations. (PMID:11705864)
• The E-cadherin gene was potentially inactivated in a significant number of synovial sarcomas. (PMID:11733362)
• Loss of E-cadherin may result in the disruption of the function of the cell-cell adhesion complex, which may cause weak cell-cell adhesion and confer invasive properties on a tumor. (PMID:11747475)
• Cadherin-mediated cell sorting not determined by binding or adhesion specificity (PMID:11790800)
• restoration of E-cadherin dependent adhsion in human protate carcinoma cells by expression of receptor protein-tyrosine phosphatase, PTPmu (PMID:11801604)
• E-cadherin might be used as additional cell markers of Schwann cell-derived tumors. (PMID:11813884)
• distinct methylation pattern in bladder cancer with frequent methylation of RARbeta, DAPK, E-cadherin, and p16. (PMID:11839665)
• D257A & D370A mutations result in abnormal protein localization, changes in the actin cytoskeleton, reduced homophilic cell adhesion, and altered cell morphology; tumor-associated D370A mutation, but not the D257A mutation, induced increased cell motility (PMID:11846558)
• biological function of Cys(9) within the first repeat (the E-cadherin-derived N-terminal repeat) (PMID:11856755)
• These results demonstrate that integrin-dependent cell to extracellular matrix adhesion reinforces E-cadherin-dependent cell-cell adhesion in Caco-2 cells. (PMID:11861761)
• E-cadherin play important roles in esophageal carcinogenesis. (PMID:11870667)
• The SLUG zinc-finger protein represses E-cadherin in breast cancer. (PMID:11912130)
• Lateral dimerization of the E-cadherin extracellular domain is necessary but not sufficient for adhesive activity (PMID:11916976)
• results suggest that the inadequate trophoblastic invasion, induced by antiphospholipid antibodies, can be the result of decreased alpha1 integrin and VE-cadherin and increased alpha5 integrin and E-cadherin expression in the trophoblast (PMID:11937138)
• characterization of DNA polymorphism in promoter regions (PMID:11996968)
• mucoepidermoid carcinoma of the thyroid (MECT)displays consistent neoexpression of P-cadherin and major alterations in the expression of E-cadherin and the three catenins (PMID:12021924)
• Tumor-associated mutations of E-cadherin enhanced random cell movement of transfected MDA-MB-435S mammary carcinoma cells as compared to wild-type (wt) E-cadherin-expressing cells. (PMID:12027444)
• restoration of cell adhesion by overexpression of nectin in HSC-39 cells (PMID:12037667)
• Differential expression in human brain tumors (PMID:12049819)
• E-cadherin expression in dental epithelium followed an apical-coronal gradient that was opposite to that observed for N-cadherin. (PMID:12057916)
• CAS/CSE 1 stimulates E-cadhrin-dependent cell polarity in HT-29 human colon epithelial cells. (PMID:12061792)
• promoter methylation studied in 80 patients with head and neck squamous cell carcinoma (HNSCC) (PMID:12082610)
• role in regulating expression of the leucocyte common antigen-related tyrosine phosphatase (PMID:12095414)
• Recovery of cellular E-cadherin precedes replenishment of estrogen receptor and estrogen-dependent proliferation of breast cancer cells rescued from a death stimulus. (PMID:12115723)
• aberrant methylation preferentially occurs in invasive ductal breast cancer associated with poor prognosis and is one of the mechanisms of expression silence in breast cancers (PMID:12127160)
• Src-induced disruption of E-cadherin localization requires specific integrin signalling. (PMID:12134161)
• Data suggest that E-cadherin-mediated signaling through PI3-kinase can regulate the invasive behavior of cells by modulating proteinase secretion. (PMID:12138162)
• Defected E-cadherin expression might play a role in the development of malignant phenotype in NSCLC (PMID:12140137)
• ZEB1 plays a role in repressing E-cadherin and MUC1 in epithelial cells [ZEB-1] (PMID:12161443)
• oxidative stress induces tyrosine phosphorylation and cellular redistribution of occludin-ZO-1 and E-cadherin-beta-catenin complexes by a tyrosine-kinase-dependent mechanism (PMID:12169098)
• Downregulation of E-cadherin in melanocytes and melanoma cells by endothelin-1 (PMID:12189238)
• Altered expression of E-cadherin in hepatocellular carcinoma (PMID:12198663)
• CpG hypermethylation was an important mechanism of E-cadherin gene inactivation in bladder cancer and also that specific CpG sites consistently presented higher methylation levels than others. (PMID:12203370)
• E-cadherin promoter is subject to epigenetic control in colorectal ulceration and plays a role in the progression from chronic inflammation to colorectal cancer. (PMID:12203775)
• E-cadherin polymorphism in prostate neoplasms (PMID:12209606)
• CDH1 c-160a promotor polymorphism is not associated with risk of stomach cancer. (PMID:12209998)
• germline E-cadherin mutations responsible for the predisposition to diffuse gastric cancer (DGC) among the Japanese (PMID:12216071)
• Restoration of E-cadherin/beta-catenin expression in pancreatic cancer cells inhibits growth by induction of apoptosis. (PMID:12219004)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	si:dkey-30c15.12	ENSDARG00000058546
mus_musculus	Cdh1	ENSMUSG00000000303
rattus_norvegicus	Cdh1	ENSRNOG00000020151

Paralogs (33): CDH10 (ENSG00000040731), CDH3 (ENSG00000062038), CDH19 (ENSG00000071991), CDHR2 (ENSG00000074276), CDH17 (ENSG00000079112), CDH7 (ENSG00000081138), PCDH11Y (ENSG00000099715), CDHR5 (ENSG00000099834), CDH20 (ENSG00000101542), PCDH11X (ENSG00000102290), CDH23 (ENSG00000107736), CDH9 (ENSG00000113100), CDH6 (ENSG00000113361), CDH26 (ENSG00000124215), CDHR3 (ENSG00000128536), CDH15 (ENSG00000129910), CDH24 (ENSG00000139880), CDH11 (ENSG00000140937), CDH13 (ENSG00000140945), CDH18 (ENSG00000145526), CDHR1 (ENSG00000148600), CDH22 (ENSG00000149654), CDH8 (ENSG00000150394), CDH12 (ENSG00000154162), PCDH1 (ENSG00000156453), DCHS1 (ENSG00000166341), PCDH7 (ENSG00000169851), CDH2 (ENSG00000170558), CDH4 (ENSG00000179242), CDH5 (ENSG00000179776), PCDH9 (ENSG00000184226), DCHS2 (ENSG00000197410), PCDH20 (ENSG00000280165)

Protein

Protein identifiers

Cadherin-1 — P12830 (reviewed: P12830)

Alternative names: CAM 120/80, Epithelial cadherin, Uvomorulin

All UniProt accessions (5): A0A0U2ZQU7, P12830, H3BNC6, H3BVI7, J3QKP1

UniProt curated annotations — full annotation on UniProt →

Function. Cadherins are calcium-dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner in connecting cells; cadherins may thus contribute to the sorting of heterogeneous cell types. CDH1 is involved in mechanisms regulating cell-cell adhesions, mobility and proliferation of epithelial cells. Promotes organization of radial actin fiber structure and cellular response to contractile forces, via its interaction with AMOTL2 which facilitates anchoring of radial actin fibers to CDH1 junction complexes at the cell membrane. Plays a role in the early stages of desmosome cell-cell junction formation via facilitating the recruitment of DSG2 and DSP to desmosome plaques. Has a potent invasive suppressor role. It is a ligand for integrin alpha-E/beta-7. E-Cad/CTF2 promotes non-amyloidogenic degradation of Abeta precursors. Has a strong inhibitory effect on APP C99 and C83 production. (Microbial infection) Serves as a receptor for Listeria monocytogenes; internalin A (InlA) binds to this protein and promotes uptake of the bacteria.

Subunit / interactions. Homodimer; disulfide-linked. Component of an E-cadherin/ catenin adhesion complex composed of at least E-cadherin/CDH1, beta-catenin/CTNNB1 or gamma-catenin/JUP, and potentially alpha-catenin/CTNNA1; the complex is located to adherens junctions. Found in a complex composed of CDH1, RAP1A and PKP3; PKP3 acts as a scaffold protein within the complex, the complex is required for CDH1 localization to mature desmosome cell junctions. Interacts with the TRPV4 and CTNNB1 complex. Interacts with CTNND1. The stable association of CTNNA1 is controversial as CTNNA1 was shown not to bind to F-actin when assembled in the complex. Alternatively, the CTNNA1-containing complex may be linked to F-actin by other proteins such as LIMA1. Interaction with PSEN1, cleaves CDH1 resulting in the disassociation of cadherin-based adherens junctions (CAJs). Interacts with AJAP1 and DLGAP5. Interacts with TBC1D2. Interacts with LIMA1. Interacts with CAV1. Interacts with PIP5K1C. Interacts with RAB8B. Interacts with RAPGEF2. Interacts with DDR1; this stabilizes CDH1 at the cell surface and inhibits its internalization. Interacts with KLRG1. Forms a ternary complex composed of ADAM10, CADH1 and EPHA4; within the complex, CADH1 is cleaved by ADAM10 which disrupts adherens junctions. Interacts with SPEF1. Interacts with CTNNB1 and PKP2. Interacts with AMOTL2; the interaction may facilitate binding of radial actin fibers to cell junction complexes. Interacts with DSG3; the interaction is required for CDH1 localization to developing adherens junctions. (Microbial infection) Interacts with L.monocytogenes InlA. The formation of the complex between InlA and cadherin-1 is calcium-dependent.

Subcellular location. Cell junction. Adherens junction. Cell membrane. Endosome. Golgi apparatus. trans-Golgi network. Cytoplasm. Desmosome.

Tissue specificity. Expressed in granuloma macrophages (at protein level). Expressed in the skin (at protein level). Expressed in the liver.

Post-translational modifications. During apoptosis or with calcium influx, cleaved by a membrane-bound metalloproteinase (ADAM10), PS1/gamma-secretase and caspase-3. Processing by the metalloproteinase, induced by calcium influx, causes disruption of cell-cell adhesion and the subsequent release of beta-catenin into the cytoplasm. The residual membrane-tethered cleavage product is rapidly degraded via an intracellular proteolytic pathway. Cleavage by caspase-3 releases the cytoplasmic tail resulting in disintegration of the actin microfilament system. The gamma-secretase-mediated cleavage promotes disassembly of adherens junctions. During development of the cochlear organ of Corti, cleavage by ADAM10 at adherens junctions promotes pillar cell separation. N-glycosylation at Asn-637 is essential for expression, folding and trafficking. Addition of bisecting N-acetylglucosamine by MGAT3 modulates its cell membrane location. Ubiquitinated by a SCF complex containing SKP2, which requires prior phosphorylation by CK1/CSNK1A1. Ubiquitinated by CBLL1/HAKAI, requires prior phosphorylation at Tyr-754. O-glycosylated. O-manosylated by TMTC1, TMTC2, TMTC3 or TMTC4. Thr-285 and Thr-509 are O-mannosylated by TMTC2 or TMTC4 but not TMTC1 or TMTC3. (Microbial infection) Cleaved by S.pyogenes SpeB protease; leading to its degradation. Degradation by SpeB promotes bacterial translocation across the host epithelial barrier.

Disease relevance. Diffuse gastric and lobular breast cancer syndrome (DGLBC) [MIM:137215] A cancer predisposition syndrome with increased susceptibility to diffuse gastric cancer. Diffuse gastric cancer is a malignant disease characterized by poorly differentiated infiltrating lesions resulting in thickening of the stomach. Malignant tumors start in the stomach, can spread to the esophagus or the small intestine, and can extend through the stomach wall to nearby lymph nodes and organs. It also can metastasize to other parts of the body. In addition to gastric cancer, most female mutation carriers develop lobular carcinoma of the breast. Disease susceptibility is associated with variants affecting the gene represented in this entry. Heterozygous CDH1 germline mutations are responsible for familial cases of diffuse gastric cancer. Somatic mutations has also been found in patients with sporadic diffuse gastric cancer and lobular breast cancer. Endometrial cancer (ENDMC) [MIM:608089] A malignancy of endometrium, the mucous lining of the uterus. Most endometrial cancers are adenocarcinomas, cancers that begin in cells that make and release mucus and other fluids. Disease susceptibility is associated with variants affecting the gene represented in this entry. Ovarian cancer (OC) [MIM:167000] The term ovarian cancer defines malignancies originating from ovarian tissue. Although many histologic types of ovarian tumors have been described, epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients are diagnosed with advanced disease. Disease susceptibility is associated with variants affecting the gene represented in this entry. Breast cancer, lobular (LBC) [MIM:137215] A type of breast cancer that begins in the milk-producing glands (lobules) of the breast. The gene represented in this entry may be involved in disease pathogenesis. Blepharocheilodontic syndrome 1 (BCDS1) [MIM:119580] A form of blepharocheilodontic syndrome, a rare autosomal dominant disorder. It is characterized by lower eyelid ectropion, upper eyelid distichiasis, euryblepharon, bilateral cleft lip and palate, and features of ectodermal dysplasia, including hair anomalies, conical teeth and tooth agenesis. An additional rare manifestation is imperforate anus. There is considerable phenotypic variability among affected individuals. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Three calcium ions are usually bound at the interface of each cadherin domain and strengthen the connections, imparting a strong curvature to the full-length ectodomain.

Induction. Induced in the hours following cyclic mechanical strain in keratinocytes. Expression is repressed by MACROD1.

Miscellaneous. May play a role in blister formation in Pemphigus vulgaris patients, expression is lost at sites of cell-cell contact between the basal and suprabasal layers in blisters and immediately adjacent to blisters.

Isoforms (2)

UniProt ID	Names	Canonical?
P12830-1	1	yes
P12830-2	2

RefSeq proteins (4): NP_001304113, NP_001304114, NP_001304115, NP_004351* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000233	Cadherin_Y-type_LIR	Domain
IPR002126	Cadherin-like_dom	Domain
IPR014868	Cadherin_pro_dom	Domain
IPR015919	Cadherin-like_sf	Homologous_superfamily
IPR020894	Cadherin_CS	Conserved_site
IPR027397	Catenin-bd_sf	Homologous_superfamily
IPR039808	Cadherin	Family

Pfam: PF00028, PF01049, PF08758

UniProt features (157 total): strand 41, sequence variant 34, glycosylation site 13, turn 12, sequence conflict 11, modified residue 8, mutagenesis site 8, domain 5, chain 4, site 4, helix 3, region of interest 3, binding site 3, topological domain 2, signal peptide 1, propeptide 1, compositionally biased region 1, disulfide bond 1, splice variant 1, transmembrane region 1

Structure

Experimental structures (PDB)

22 structures.

PDB	Method	Resolution (Å)
2OMZ	X-RAY DIFFRACTION	1.6
2OMX	X-RAY DIFFRACTION	1.7
2OMY	X-RAY DIFFRACTION	1.7
1O6S	X-RAY DIFFRACTION	1.8
2OMU	X-RAY DIFFRACTION	1.8
3FF7	X-RAY DIFFRACTION	1.8
2OMV	X-RAY DIFFRACTION	1.9
8H62	X-RAY DIFFRACTION	1.91
4ZT1	X-RAY DIFFRACTION	1.92
2O72	X-RAY DIFFRACTION	2
2OMT	X-RAY DIFFRACTION	2
3FF8	X-RAY DIFFRACTION	2
4ZTE	X-RAY DIFFRACTION	2.13
6CXY	X-RAY DIFFRACTION	2.2
3L6X	X-RAY DIFFRACTION	2.4
6VEL	X-RAY DIFFRACTION	2.65
7STZ	X-RAY DIFFRACTION	2.95
3L6Y	X-RAY DIFFRACTION	3
6OLE	ELECTRON MICROSCOPY	3.1
9P99	ELECTRON MICROSCOPY	3.37
6OLG	ELECTRON MICROSCOPY	3.4
6OLF	ELECTRON MICROSCOPY	3.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P12830-F1	79.13	0.46

Antibody-complex structures (SAbDab): 3 — 6CXY, 6VEL, 7STZ

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 (4): 364–365 (cleavage; by s.pyogenes speb); 700–701 (cleavage; by a metalloproteinase); 731–732 (cleavage; by gamma-secretase/ps1); 750–751 (cleavage; by caspase-3)

Ligand- & substrate-binding residues (3): 257; 257; 288

Post-translational modifications (8): 753, 754, 755, 770, 793, 838, 840, 846

Disulfide bonds (1): 163

Glycosylation sites (13): 280, 285, 358, 470, 472, 509, 558, 570, 576, 578, 580, 622, 637

Mutagenesis-validated functional residues (8):

Position	Phenotype
156	no longer binds l.monocytogenes inla.
156	protein is partially unfolded, no longer binds l.monocytogenes inla.
170	no longer binds l.monocytogenes inla.
170	no longer adheres to l.monocytogenes inla coated beads, nor do cells take up inla coated beads.
175	reduces localization to desmosome cell-cell junctions. also reduces the localization of dsg2 and dsp to desmosome cell-c
637	cdh1 becomes a substrate for erad and is retro-translocated from er to cytoplasm.
754	abolishes binding to cbll1.
759–761	binds to ctnnb1 but abolishes interaction of ctnnb1 with psen1. abolishes gamma-secretase cleavage.

Function

Pathways and Gene Ontology

Reactome pathways

44 pathways

ID	Pathway
R-HSA-1474228	Degradation of the extracellular matrix
R-HSA-198933	Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell
R-HSA-216083	Integrin cell surface interactions
R-HSA-351906	Apoptotic cleavage of cell adhesion proteins
R-HSA-418990	Adherens junctions interactions
R-HSA-5626467	RHO GTPases activate IQGAPs
R-HSA-8876493	InlA-mediated entry of Listeria monocytogenes into host cells
R-HSA-9764561	Regulation of CDH1 Function
R-HSA-9764562	Regulation of CDH1 mRNA translation by microRNAs
R-HSA-9766229	Degradation of CDH1
R-HSA-9768727	Regulation of CDH1 posttranslational processing and trafficking to plasma membrane
R-HSA-9823730	Formation of definitive endoderm
R-HSA-9856649	Transcriptional and post-translational regulation of MITF-M expression and activity
R-HSA-9926550	Regulation of MITF-M-dependent genes involved in extracellular matrix, focal adhesion and epithelial-to-mesenchymal transition
R-HSA-9927418	Developmental Lineage of Mammary Gland Luminal Epithelial Cells
R-HSA-9927432	Developmental Lineage of Mammary Gland Myoepithelial Cells
R-HSA-9938206	Developmental Lineage of Mammary Stem Cells
R-HSA-9958810	SRC activates STAT3 in a quantitative manner, through Cadherin-11 (CDH11), RAC1 and gp130 (IL6ST)
R-HSA-9958825	Activation of STAT3 by cadherin engagement
R-HSA-9758919	Epithelial-Mesenchymal Transition (EMT) during gastrulation
R-HSA-9764725	Negative Regulation of CDH1 Gene Transcription
R-HSA-9764790	Positive Regulation of CDH1 Gene Transcription
R-HSA-109581	Apoptosis
R-HSA-111465	Apoptotic cleavage of cellular proteins
R-HSA-1266738	Developmental Biology
R-HSA-1280218	Adaptive Immune System
R-HSA-1474244	Extracellular matrix organization
R-HSA-1500931	Cell-Cell communication
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease

MSigDB gene sets: 694 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, FARMER_BREAST_CANCER_CLUSTER_7, GU_PDEF_TARGETS_DN, chr16q22, GOBP_NEURON_PROJECTION_EXTENSION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_NEGATIVE_REGULATION_OF_AXON_EXTENSION, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_SYNAPSE_ASSEMBLY, GOCC_VACUOLAR_MEMBRANE, JAEGER_METASTASIS_DN, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, ZHAN_MULTIPLE_MYELOMA_MF_UP

GO Biological Process (30): cell morphogenesis (GO:0000902), desmosome assembly (GO:0002159), cell-cell junction assembly (GO:0007043), homophilic cell-cell adhesion (GO:0007156), synapse assembly (GO:0007416), response to xenobiotic stimulus (GO:0009410), response to toxic substance (GO:0009636), regulation of gene expression (GO:0010468), calcium-dependent cell-cell adhesion (GO:0016339), cell migration (GO:0016477), pituitary gland development (GO:0021983), negative regulation of cell-cell adhesion (GO:0022408), negative regulation of cell migration (GO:0030336), negative regulation of axon extension (GO:0030517), neuron projection development (GO:0031175), adherens junction organization (GO:0034332), positive regulation of protein import into nucleus (GO:0042307), cell-cell adhesion mediated by cadherin (GO:0044331), positive regulation of DNA-templated transcription (GO:0045893), cellular response to lithium ion (GO:0071285), response to heparin (GO:0071503), cellular response to indole-3-methanol (GO:0071681), protein localization to plasma membrane (GO:0072659), cell-cell adhesion (GO:0098609), regulation of protein catabolic process at postsynapse, modulating synaptic transmission (GO:0099576), response to Gram-positive bacterium (GO:0140459), positive regulation of protein localization (GO:1903829), cell adhesion (GO:0007155), cell junction assembly (GO:0034329), regulation of transport (GO:0051049)

GO Molecular Function (13): calcium ion binding (GO:0005509), beta-catenin binding (GO:0008013), ankyrin binding (GO:0030506), GTPase activating protein binding (GO:0032794), identical protein binding (GO:0042802), gamma-catenin binding (GO:0045295), cadherin binding (GO:0045296), cell adhesion molecule binding (GO:0050839), cell adhesion mediator activity (GO:0098631), protein tyrosine kinase binding (GO:1990782), protein binding (GO:0005515), metal ion binding (GO:0046872), cell-cell adhesion mediator activity (GO:0098632)

GO Cellular Component (29): Golgi membrane (GO:0000139), extracellular region (GO:0005576), cytoplasm (GO:0005737), lysosomal membrane (GO:0005765), endoplasmic reticulum lumen (GO:0005788), endoplasmic reticulum membrane (GO:0005789), Golgi lumen (GO:0005796), trans-Golgi network (GO:0005802), plasma membrane (GO:0005886), adherens junction (GO:0005912), cytoplasmic side of plasma membrane (GO:0009898), actin cytoskeleton (GO:0015629), membrane (GO:0016020), lateral plasma membrane (GO:0016328), catenin complex (GO:0016342), flotillin complex (GO:0016600), lamellipodium (GO:0030027), cell junction (GO:0030054), desmosome (GO:0030057), early endosome membrane (GO:0031901), apical junction complex (GO:0043296), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062), postsynapse (GO:0098794), glutamatergic synapse (GO:0098978), endosome (GO:0005768), Golgi apparatus (GO:0005794), cortical actin cytoskeleton (GO:0030864), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
Regulation of CDH1 Expression and Function	3
Developmental Lineages of the Mammary Gland	3
Extracellular matrix organization	2
Gastrulation	2
Adaptive Immune System	1
Apoptotic cleavage of cellular proteins	1
Cell-cell junction organization	1
RHO GTPase Effectors	1
Listeria monocytogenes entry into host cells	1
Regulation of CDH1 Function	1
MITF-M-regulated melanocyte development	1
MITF-M-dependent gene expression	1
Activation of STAT3 by cadherin engagement	1
Adherens junctions interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell-cell adhesion	5
protein binding	5
cellular anatomical structure	5
cell junction assembly	2
cell-cell junction organization	2
response to chemical	2
cell adhesion molecule binding	2
Golgi apparatus	2
intracellular organelle lumen	2
cell-cell junction	2
plasma membrane	2
plasma membrane protein complex	2
anatomical structure morphogenesis	1
desmosome organization	1
cell-cell junction assembly	1
nervous system development	1
synapse organization	1
gene expression	1
regulation of macromolecule biosynthetic process	1
cell motility	1
diencephalon development	1
endocrine system development	1
gland development	1
negative regulation of cell adhesion	1
regulation of cell-cell adhesion	1
cell migration	1
regulation of cell migration	1
negative regulation of cell motility	1
negative regulation of cell growth	1
regulation of axon extension	1
negative regulation of developmental growth	1
axon extension	1
negative regulation of axonogenesis	1
neuron development	1
plasma membrane bounded cell projection organization	1
protein import into nucleus	1
regulation of protein import into nucleus	1
positive regulation of nucleocytoplasmic transport	1
positive regulation of intracellular protein transport	1
positive regulation of protein localization to nucleus	1

Protein interactions and networks

STRING

7460 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CDH1	CTNNB1	P35222	999
CDH1	CTNND1	O60716	998
CDH1	EGFR	P00533	995
CDH1	ITGAE	P38570	993
CDH1	IQGAP1	P46940	993
CDH1	OCLN	Q16625	992
CDH1	KLRG1	Q96E93	992
CDH1	VCL	P18206	991
CDH1	SLCO6A1	Q86UG4	987
CDH1	TJP1	Q07157	986
CDH1	CDH2	P19022	983
CDH1	CTNNA1	P35221	979
CDH1	CDH5	P33151	969
CDH1	ERBB2	P04626	964
CDH1	SNAI1	O95863	962

IntAct

276 interactions, top by confidence:

A	B	Type	Score
CDH1	CTNNB1	psi-mi:“MI:0914”(association)	0.960
CTNNB1	CDH1	psi-mi:“MI:0914”(association)	0.960
CTNNB1	CDH1	psi-mi:“MI:0915”(physical association)	0.960
CDH1	CTNNB1	psi-mi:“MI:0915”(physical association)	0.960
CDH1	CDH1	psi-mi:“MI:0407”(direct interaction)	0.910
CDH1	CDH1	psi-mi:“MI:0915”(physical association)	0.910
CDH1	CTNNA1	psi-mi:“MI:0914”(association)	0.800
CDH1	CTNNA1	psi-mi:“MI:0915”(physical association)	0.800
CTNNA1	CDH1	psi-mi:“MI:0914”(association)	0.800
EGFR	CDH1	psi-mi:“MI:0915”(physical association)	0.740
CDH1	CTNND1	psi-mi:“MI:0914”(association)	0.730
CDH1	CTNND1	psi-mi:“MI:0915”(physical association)	0.730
CTNND1	CDH1	psi-mi:“MI:0915”(physical association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710

BioGRID (1002): CTNND1 (Affinity Capture-Western), CTNNB1 (Affinity Capture-Western), CTNNB1 (Affinity Capture-Western), CTNND1 (Affinity Capture-Western), CDH1 (Affinity Capture-Western), PIP5K1C (Affinity Capture-Western), CTNNB1 (Affinity Capture-Western), JUP (Affinity Capture-Western), CDH1 (Affinity Capture-MS), CDH1 (Two-hybrid), ECT2 (Affinity Capture-Western), CDH1 (Affinity Capture-Western), KLF4 (Affinity Capture-Western), E2F1 (Affinity Capture-Western), CDH1 (Reconstituted Complex)

ESM2 similar proteins: B0KW95, B2KI42, B4USZ0, F1PAA9, O02840, O60330, P08641, P09803, P10287, P10288, P12830, P15116, P19022, P19534, P19535, P20310, P22223, P24503, P26009, P33145, P33147, P33148, P33150, P33151, P33152, P39038, P53708, P55283, P55284, P79883, Q08174, Q5DRB7, Q5DRB8, Q5DRC0, Q5DRC2, Q5R9X1, Q5RAX1, Q6R8F2, Q6URK6, Q90275

Diamond homologs: A0A8M2BIB6, B0KW95, B2KI42, B4USZ0, F1PAA9, H2EQR6, O18926, O35902, O55075, O55111, O88277, P08641, P09803, P10287, P10288, P12830, P15116, P19022, P19534, P19535, P20310, P22223, P24503, P30944, P32926, P33145, P33146, P33147, P33148, P33150, P33152, P33545, P39038, P55283, P55290, P55291, P55292, P55849, P55850, P79883

SIGNOR signaling

71 interactions.

A	Effect	B	Mechanism
PRKD1	up-regulates	CDH1	phosphorylation
CDH1	up-regulates	LRP6	binding
CDH1	up-regulates	CTNNA1	binding
TBX3	“down-regulates quantity by repression”	CDH1	“transcriptional regulation”
Cell-Cell_contact	up-regulates	CDH1
CTNND1	“up-regulates quantity by stabilization”	CDH1	binding
ARVCF	“up-regulates quantity by stabilization”	CDH1	binding
CTNND2	“up-regulates quantity by stabilization”	CDH1	binding
SNAI1	“down-regulates quantity”	CDH1	“transcriptional regulation”
CBX7	“up-regulates quantity by expression”	CDH1	“transcriptional regulation”
MTA1	“down-regulates quantity by repression”	CDH1	“transcriptional regulation”
SALL4	“down-regulates quantity by repression”	CDH1	“transcriptional regulation”
SNAI2	“down-regulates quantity by repression”	CDH1	“transcriptional regulation”
SNAI1	“down-regulates quantity by repression”	CDH1	“transcriptional regulation”
TWIST1	“down-regulates quantity by repression”	CDH1	“transcriptional regulation”
ZEB1	“down-regulates quantity by repression”	CDH1	“transcriptional regulation”
ZEB2	“down-regulates quantity by repression”	CDH1	“transcriptional regulation”
TWIST2	“down-regulates quantity by repression”	CDH1	“transcriptional regulation”
YBX1	“up-regulates quantity by expression”	CDH1	“transcriptional regulation”
CTBP1	“down-regulates quantity by repression”	CDH1	“transcriptional regulation”
ADAM10	“up-regulates activity”	CDH1	cleavage
ATXN1	“up-regulates quantity by expression”	CDH1	“transcriptional regulation”
CTBP2	“down-regulates quantity by repression”	CDH1	“transcriptional regulation”
CTNNA3	“up-regulates quantity”	CDH1	relocalization
α-Catenin	“up-regulates quantity”	CDH1	relocalization
CDH1	“up-regulates activity”	α-Catenin	binding
calcium(2+)	“up-regulates activity”	CDH1	“chemical activation”
CDH1	“up-regulates activity”	CTNNB1	binding
ANK3	“up-regulates activity”	CDH1	binding
PBX1	“up-regulates quantity by expression”	CDH1	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 96 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
SRC activates STAT3 in a quantitative manner, through Cadherin-11 (CDH11), RAC1 and gp130 (IL6ST)	5	36.5×	3e-05
Degradation of CDH1	7	20.3×	2e-05
VEGFA-VEGFR2 Pathway	5	10.2×	5e-03
Constitutive Signaling by Aberrant PI3K in Cancer	5	9.3×	7e-03
RHOA GTPase cycle	6	6.6×	9e-03
RAF/MAP kinase cascade	7	6.3×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
integrin-mediated signaling pathway	6	11.3×	5e-03
cell morphogenesis	6	11.1×	5e-03
cell-cell adhesion	8	9.6×	1e-03
positive regulation of canonical NF-kappaB signal transduction	10	8.6×	3e-04
cell migration	8	5.8×	8e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 6 cancer types — BLCA, BRCA, CSCC, DLBCLNOS, ESCA, STAD.

Clinical variants and AI predictions

ClinVar

5210 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	523
Likely pathogenic	132
Uncertain significance	2255
Likely benign	1027
Benign	207

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1050193	NC_000016.10:g.68828174_68828304del	Pathogenic
1050280	NM_004360.5(CDH1):c.2440-2_*1del	Pathogenic
1068969	NM_004360.5(CDH1):c.1569T>G (p.Tyr523Ter)	Pathogenic
1069664	NC_000016.10:g.68829654del	Pathogenic
1069750	NM_004360.5(CDH1):c.1641del (p.Glu547fs)	Pathogenic
1069973	NM_004360.5(CDH1):c.1920dup (p.Gln641fs)	Pathogenic
1070687	NM_004360.5(CDH1):c.1616del (p.Thr539fs)	Pathogenic
1071176	NC_000016.9:g.(?68835563)(68863710_?)del	Pathogenic
1071177	NC_000016.9:g.(?68820946)(68842761_?)del	Pathogenic
1071833	NM_004360.5(CDH1):c.150_151dup (p.Val51fs)	Pathogenic
1072150	NM_004360.5(CDH1):c.555del (p.Gly186fs)	Pathogenic
1072773	NM_004360.5(CDH1):c.1356_1362del (p.His453fs)	Pathogenic
1072979	NC_000016.9:g.(?68771319)(68835806_?)del	Pathogenic
1072980	NC_000016.9:g.(?_68857535)_68864666del	Pathogenic
1072981	NC_000016.9:g.(?68863547)(68867402_?)del	Pathogenic
1072982	NC_000016.9:g.(?68772190)(68849672_?)del	Pathogenic
1074240	NM_004360.5(CDH1):c.1695_1696insTT (p.Ile566fs)	Pathogenic
1074394	NM_004360.5(CDH1):c.1878_1885del (p.Phe626fs)	Pathogenic
1075278	NC_000016.10:g.68815516del	Pathogenic
1076986	NC_000016.9:g.(?68867183)(68867402_?)del	Pathogenic
1170987	NM_004360.5(CDH1):c.1307del (p.Ile435_Leu436insTer)	Pathogenic
1196343	NM_004360.5(CDH1):c.1577G>A (p.Trp526Ter)	Pathogenic
12234	NM_004360.5(CDH1):c.781G>T (p.Glu261Ter)	Pathogenic
12237	NM_004360.5(CDH1):c.2095C>T (p.Gln699Ter)	Pathogenic
12239	NM_004360.5(CDH1):c.59G>A (p.Trp20Ter)	Pathogenic
12240	NM_004360.5(CDH1):c.70G>T (p.Glu24Ter)	Pathogenic
12241	NM_004360.5(CDH1):c.1792C>T (p.Arg598Ter)	Pathogenic
12248	NM_004360.5(CDH1):c.531+2T>A	Pathogenic
12251	NC_000016.10:g.68602418_68796011del	Pathogenic
12252	NM_004360.5(CDH1):c.2440-396_*224delinsGGA	Pathogenic

SpliceAI

2896 predictions. Top by Δscore:

Variant	Effect	Δscore
16:68737635:G:GT	donor_gain	1.0000
16:68738409:GAG:G	donor_gain	1.0000
16:68738409:GAGGT:G	donor_loss	1.0000
16:68738412:G:A	donor_loss	1.0000
16:68738413:T:A	donor_loss	1.0000
16:68771091:GC:G	donor_gain	1.0000
16:68801666:GCA:G	acceptor_loss	1.0000
16:68801667:CA:C	acceptor_loss	1.0000
16:68801668:A:AG	acceptor_gain	1.0000
16:68801668:AGT:A	acceptor_gain	1.0000
16:68801669:G:GC	acceptor_gain	1.0000
16:68801669:GT:G	acceptor_gain	1.0000
16:68801669:GTG:G	acceptor_gain	1.0000
16:68801669:GTGA:G	acceptor_gain	1.0000
16:68801669:GTGAA:G	acceptor_gain	1.0000
16:68801890:TCAGG:T	donor_loss	1.0000
16:68801892:AGG:A	donor_loss	1.0000
16:68801894:G:GA	donor_loss	1.0000
16:68801895:T:G	donor_loss	1.0000
16:68808563:TTC:T	donor_gain	1.0000
16:68808563:TTCAG:T	donor_loss	1.0000
16:68808564:TCAGG:T	donor_loss	1.0000
16:68808565:CAGG:C	donor_loss	1.0000
16:68808566:AGGTA:A	donor_loss	1.0000
16:68808567:GGTAG:G	donor_loss	1.0000
16:68808568:G:T	donor_loss	1.0000
16:68808569:T:G	donor_loss	1.0000
16:68808577:G:GT	donor_gain	1.0000
16:68808680:A:AG	acceptor_gain	1.0000
16:68808680:ATTTT:A	acceptor_gain	1.0000

AlphaMissense

5795 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:68808502:T:A	W156R	0.999
16:68808502:T:C	W156R	0.999
16:68808504:G:C	W156C	0.999
16:68808504:G:T	W156C	0.999
16:68808775:T:C	F205S	0.999
16:68808774:T:C	F205L	0.998
16:68808776:T:A	F205L	0.998
16:68808776:T:G	F205L	0.998
16:68808796:G:A	G212E	0.998
16:68808802:T:C	L214P	0.998
16:68808826:G:C	R222T	0.998
16:68810279:A:C	D257A	0.998
16:68810288:C:A	P260H	0.998
16:68810293:T:C	F262L	0.998
16:68810294:T:C	F262S	0.998
16:68810295:C:A	F262L	0.998
16:68810295:C:G	F262L	0.998
16:68811801:T:C	F317S	0.998
16:68812208:C:A	A361D	0.998
16:68823462:T:C	L667P	0.998
16:68823468:T:C	L669P	0.998
16:68808498:A:C	R154S	0.997
16:68808498:A:T	R154S	0.997
16:68808530:A:T	E165V	0.997
16:68808531:A:C	E165D	0.997
16:68808531:A:T	E165D	0.997
16:68808547:T:C	F171L	0.997
16:68808549:T:A	F171L	0.997
16:68808549:T:G	F171L	0.997
16:68808729:T:G	Y190D	0.997

dbSNP variants (sampled 300 via entrez): RS1000002037 (16:68754292 A>T), RS1000023211 (16:68771588 T>C), RS1000027342 (16:68751659 C>T), RS1000033418 (16:68754002 C>T), RS1000135592 (16:68806208 G>A,C), RS1000147817 (16:68835682 C>A), RS1000189618 (16:68797398 T>C), RS1000211726 (16:68776755 A>C,G), RS1000237293 (16:68810968 G>A), RS1000240000 (16:68771010 C>G,T), RS1000244873 (16:68817917 G>T), RS1000263505 (16:68754516 C>G), RS1000274223 (16:68794015 G>C,T), RS1000286096 (16:68782196 T>G), RS1000294600 (16:68754203 C>T)

Disease associations

OMIM: gene MIM:192090 | disease phenotypes: MIM:114480, MIM:137215, MIM:167000, MIM:119580, MIM:613659, MIM:119530, MIM:176807, MIM:612555, MIM:604370, MIM:617769, MIM:114500

GenCC curated gene-disease

Disease	Classification	Inheritance
blepharocheilodontic syndrome 1	Definitive	Autosomal dominant
hereditary breast carcinoma	Definitive	Autosomal dominant
hereditary diffuse gastric adenocarcinoma	Definitive	Autosomal dominant
CDH1-related diffuse gastric and lobular breast cancer syndrome	Definitive	Autosomal dominant
cleft soft palate	Moderate	Autosomal dominant
orofacial cleft 3	Moderate	Autosomal dominant
blepharocheilodontic syndrome	Supportive	Autosomal dominant
familial ovarian cancer	No Known Disease Relationship	Unknown

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
CDH1-related diffuse gastric and lobular breast cancer syndrome	Definitive	AD
familial ovarian cancer	No Known Disease Relationship	AD

Mondo (31): hereditary diffuse gastric adenocarcinoma (MONDO:0007648), hereditary neoplastic syndrome (MONDO:0015356), hereditary breast carcinoma (MONDO:0016419), CDH1-related diffuse gastric and lobular breast cancer syndrome (MONDO:0100488), hereditary breast ovarian cancer syndrome (MONDO:0003582), breast cancer (MONDO:0007254), colon carcinoma (MONDO:0002032), ovarian cancer (MONDO:0008170), prostate cancer (MONDO:0008315), blepharocheilodontic syndrome 1 (MONDO:0054740), endometrial carcinoma (MONDO:0002447), ovarian neoplasm (MONDO:0021068), breast lobular carcinoma (MONDO:0000552), gastric cancer (MONDO:0001056), gastric adenocarcinoma (MONDO:0005036)

Orphanet (13): Inherited cancer-predisposing syndrome (Orphanet:140162), Hereditary diffuse gastric cancer (Orphanet:26106), Hereditary breast cancer (Orphanet:227535), Hereditary breast and/or ovarian cancer syndrome (Orphanet:145), Rare ovarian cancer (Orphanet:213500), Familial prostate cancer (Orphanet:1331), Blepharo-cheilo-odontic syndrome (Orphanet:1997), Microphthalmia-anophthalmia-coloboma (Orphanet:98555), Spinocerebellar ataxia type 45 (Orphanet:589527), Cleft lip with or without cleft palate (Orphanet:1991), Cleft lip/palate (Orphanet:199306), NON RARE IN EUROPE: Adenocarcinoma of stomach (Orphanet:464463), NON RARE IN EUROPE: Colorectal cancer (Orphanet:466667)

HPO phenotypes

57 total (30 of 57 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000175	Cleft palate
HP:0000202	Orofacial cleft
HP:0000204	Cleft upper lip
HP:0000220	Velopharyngeal insufficiency
HP:0000316	Hypertelorism
HP:0000327	Hypoplasia of the maxilla
HP:0000348	High forehead
HP:0000403	Recurrent otitis media
HP:0000405	Conductive hearing impairment
HP:0000453	Choanal atresia
HP:0000478	Abnormality of the eye
HP:0000492	Abnormal eyelid morphology
HP:0000504	Abnormality of vision
HP:0000668	Hypodontia
HP:0000670	Carious teeth
HP:0000689	Dental malocclusion
HP:0000698	Conical tooth
HP:0000750	Delayed speech and language development
HP:0001442	Typified by somatic mosaicism
HP:0001611	Hypernasal speech
HP:0001792	Small nail
HP:0002023	Anal atresia
HP:0002033	Poor suck
HP:0002164	Nail dysplasia
HP:0002582	Atrophic gastritis
HP:0003002	Breast carcinoma
HP:0003581	Adult onset
HP:0004395	Malnutrition
HP:0004471	Aplasia cutis congenita over the scalp vertex

GWAS associations

23 associations (top):

Study	Trait	p-value
GCST000270_3	Colorectal cancer	1.000000e-08
GCST000527_3	Ulcerative colitis	3.000000e-08
GCST003061_15	Cutaneous malignant melanoma	3.000000e-07
GCST003815_48	Late-onset Alzheimer’s disease	1.000000e-06
GCST004602_280	Mean corpuscular volume	2.000000e-11
GCST004611_208	High light scatter reticulocyte count	4.000000e-15
GCST004612_199	High light scatter reticulocyte percentage of red cells	6.000000e-17
GCST004619_170	Reticulocyte fraction of red cells	8.000000e-18
GCST004622_39	Reticulocyte count	2.000000e-14
GCST004630_205	Mean corpuscular hemoglobin	2.000000e-10
GCST007856_91	Colorectal cancer or advanced adenoma	3.000000e-08
GCST010303_22	Nevus count or cutaneous melanoma	6.000000e-15
GCST010304_56	Cutaneous malignant melanoma	8.000000e-14
GCST012484_6	Cerebral amyloid angiopathy x APOEe4 status interaction in Alzheimer’s disease	1.000000e-06
GCST90002385_81	High light scatter reticulocyte count	6.000000e-36
GCST90002386_287	High light scatter reticulocyte percentage of red cells	2.000000e-41
GCST90002387_14	Immature fraction of reticulocytes	1.000000e-12
GCST90002390_94	Mean corpuscular hemoglobin	3.000000e-28
GCST90002391_79	Mean corpuscular hemoglobin concentration	2.000000e-10
GCST90002392_510	Mean corpuscular volume	2.000000e-21
GCST90002404_342	Red cell distribution width	2.000000e-49
GCST90002405_311	Reticulocyte count	3.000000e-38
GCST90002406_436	Reticulocyte fraction of red cells	1.000000e-45

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:1001870	late-onset Alzheimers disease
EFO:0007986	reticulocyte count
EFO:0004527	mean corpuscular hemoglobin
EFO:0004632	nevus count
EFO:0007659	APOE carrier status
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0009188	Red cell distribution width

MeSH disease descriptors (11)

Descriptor	Name	Tree numbers
D001943	Breast Neoplasms	C04.588.180; C17.800.090.500
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
D010051	Ovarian Neoplasms	C04.588.322.455; C12.050.351.500.056.630.705; C12.050.351.937.418.685; C12.100.250.056.630.705; C12.900.418.685; C19.344.410; C19.391.630.705
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
D013274	Stomach Neoplasms	C04.588.274.476.767; C06.301.371.767; C06.405.249.767; C06.405.748.789
C536188	Blepharo-cheilo-dontic syndrome (supp.)
C562840	Breast Cancer, Familial (supp.)
C562950	Cleft Soft Palate (supp.)
C563448	Orofacial Cleft 3 (supp.)
C537243	Prostate cancer, familial (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2321609 (SINGLE PROTEIN), CHEMBL3885533 (PROTEIN-PROTEIN INTERACTION), CHEMBL4888449 (PROTEIN-PROTEIN INTERACTION)

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

Binding affinities (BindingDB)

4 measured of 4 human assays (4 total across all organisms); most potent 4 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
[(2R)-1-[3,10-dihydroxy-12-[(2R)-2-(4-hydroxyphenoxy)carbonyloxypropyl]-2,6,7,11-tetramethoxy-4,9-dioxoperylen-1-yl]propan-2-yl] benzoate	KI	53800 nM	US-9284299: Substituted 1H-indazol-1-ol analogs as inhibitors of beta catenin/Tcf protein-protein interactions
CHEBI:3556	KI	62500 nM	US-9284299: Substituted 1H-indazol-1-ol analogs as inhibitors of beta catenin/Tcf protein-protein interactions
1-hydroxy-5-[2-(2H-tetrazol-5-yl)ethyl]benzotriazole	KI	171000 nM	US-9284299: Substituted 1H-indazol-1-ol analogs as inhibitors of beta catenin/Tcf protein-protein interactions
1,6-dimethylpyrimido[5,4-e][1,2,4]triazine-5,7(1H,6H)-dione	KI	171000 nM	US-9284299: Substituted 1H-indazol-1-ol analogs as inhibitors of beta catenin/Tcf protein-protein interactions

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, decreases reaction, increases expression, affects cotreatment, affects expression (+3 more)	32
Particulate Matter	decreases expression, decreases reaction, increases expression, affects cotreatment, affects reaction (+3 more)	19
bisphenol A	decreases expression, decreases reaction, increases expression, increases reaction, affects reaction (+1 more)	18
Decitabine	increases expression, affects expression, affects methylation, affects acetylation, affects cotreatment (+5 more)	14
Benzo(a)pyrene	decreases expression, decreases reaction, increases expression, increases methylation, affects reaction (+3 more)	14
Arsenic Trioxide	increases expression, increases reaction, affects reaction, decreases expression, decreases methylation (+3 more)	13
Resveratrol	decreases expression, decreases reaction, increases expression	12
Tetrachlorodibenzodioxin	decreases expression, decreases reaction, affects expression, increases expression	11
Tobacco Smoke Pollution	decreases expression, decreases reaction, affects cotreatment, increases phosphorylation, increases reaction (+2 more)	11
Fulvestrant	decreases reaction, increases expression, affects cotreatment, affects localization, decreases expression	10
Silicon Dioxide	decreases expression, decreases reaction, increases reaction, increases secretion, affects reaction	10
Cadmium Chloride	increases secretion, increases reaction, decreases reaction, increases cleavage, increases expression (+3 more)	10
Estradiol	decreases expression, decreases reaction, increases reaction, increases expression	9
Valproic Acid	affects cotreatment, increases expression	9
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	increases abundance, increases reaction, increases expression, decreases expression, decreases reaction	8
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, decreases reaction, increases abundance, affects cotreatment, increases expression	8
Arsenic	decreases expression, decreases reaction, affects methylation, affects expression, affects cotreatment (+4 more)	8
U 0126	increases expression, decreases expression, decreases reaction, increases abundance, increases reaction	7
Acetylcysteine	increases cleavage, increases expression, increases methylation, decreases expression, decreases reaction (+1 more)	7
Cadmium	increases abundance, affects localization, increases degradation, increases cleavage, decreases expression (+1 more)	7
trichostatin A	affects cotreatment, affects expression, increases expression, decreases expression, decreases reaction (+1 more)	6
Folic Acid	affects cotreatment, decreases expression, affects reaction, increases expression	6
Glucose	decreases reaction, affects cotreatment, increases reaction, decreases expression	6
Plant Extracts	decreases expression, decreases reaction, increases abundance, increases expression	6
Tretinoin	affects expression, decreases expression, increases expression, increases reaction	6
bisphenol S	decreases reaction, affects reaction, decreases expression, increases expression, increases methylation	5
Cisplatin	increases reaction, decreases cleavage, decreases expression, affects binding, decreases response to substance (+2 more)	5
Curcumin	affects cotreatment, increases expression, decreases expression, decreases reaction	5
Diethylhexyl Phthalate	decreases expression, increases expression, increases reaction	5
Endosulfan	affects binding, decreases reaction, decreases expression	5

ChEMBL screening assays

18 unique, capped per target: 18 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3822105	Binding	Binding affinity to E-cadherin in human OAW42 cells assessed as effect on PI3K/Akt signalling activation by measuring phosphorylation of Akt at Ser-473 residue at 1 to 2 mM by immunoblot analysis	Crystal Structure of Human E-Cadherin-EC1EC2 in Complex with a Peptidomimetic Competitive Inhibitor of Cadherin Homophilic Interaction. — J Med Chem

Cellosaurus cell lines

59 cell lines: 53 cancer cell line, 4 transformed cell line, 1 induced pluripotent stem cell, 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0033	SK-BR-3	Cancer cell line	Female
CVCL_0418	MDA-MB-453	Cancer cell line	Female
CVCL_0617	MDA-MB-134-VI	Cancer cell line	Female
CVCL_1115	CAMA-1	Cancer cell line	Female
CVCL_1207	Evsa-T	Cancer cell line	Female
CVCL_1661	ZR-75-30	Cancer cell line	Female
CVCL_1781	UACC-812	Cancer cell line	Female
CVCL_1782	UACC-893	Cancer cell line	Female
CVCL_3352	OCUB-F	Cancer cell line	Female
CVCL_3424	SUM44PE	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02562170	PHASE4	COMPLETED	Protexa® Versus TiLoopBra® in Immediate Breast Reconstruction- A Pilot Study
NCT00014638	PHASE4	COMPLETED	Letrozole in Treating Postmenopausal Women With Metastatic Breast Cancer
NCT00022386	PHASE4	COMPLETED	Epoetin Alfa in Treating Chemotherapy-Related Anemia in Women With Stage I, Stage II, or Stage III Breast Cancer
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00030758	PHASE4	UNKNOWN	Filgrastim or Pegfilgrastim in Preventing Neutropenia in Women Receiving Chemotherapy Following Surgery for Breast Cancer
NCT00082277	PHASE4	COMPLETED	Anastrozole Biphosphonate Study in Postmenopausal Women With Hormone-Receptor-Positive Early Breast Cancer
NCT00087620	PHASE4	TERMINATED	A Study of Capecitabine In Combination With Docetaxel vs Capecitabine Followed by Docetaxel As First-Line Treatment For Metastatic Breast Cancer
NCT00121836	PHASE4	COMPLETED	A Study of Xeloda (Capecitabine) in Women With HER2-Negative Metastatic Breast Cancer
NCT00126360	PHASE4	UNKNOWN	STARS Breast Trial (Study of Anastrozole and Radiotherapy Sequencing Pilot)
NCT00127933	PHASE4	COMPLETED	XeNA Study - A Study of Xeloda (Capecitabine) in Patients With Invasive Breast Cancer
NCT00128297	PHASE4	COMPLETED	Pamidronate Administration in Breast Cancer Patients With Bone Metastases
NCT00129597	PHASE4	UNKNOWN	Effect of Ketalar to Prevent Postoperative Chronic Pain After Mastectomy
NCT00131170	PHASE4	COMPLETED	Paravertebral Block for Breast Surgery
NCT00156039	PHASE4	COMPLETED	Randomized Trial of Follow-up Strategies in Breast Cancer
NCT00160901	PHASE4	COMPLETED	Complementary Therapies for the Reduction of Side Effects During Chemotherapy for Breast Cancer
NCT00171847	PHASE4	TERMINATED	Study of the Efficacy and Safety of Letrozole Combined With Trastuzumab in Patients With Metastatic Breast Cancer
NCT00176046	PHASE4	COMPLETED	Mistletoe Extract in Early or Advanced Breast Cancer, A Feasibility Study
NCT00190697	PHASE4	COMPLETED	A Study of LY353381 (Arzoxifene) for Patients Who Benefitted From This Drug in Other Oncology Trials and Wished to Continue Treatment
NCT00234195	PHASE4	COMPLETED	Wellbutrin XL, Major Depressive Disorder and Breast Cancer
NCT00237133	PHASE4	COMPLETED	Treatment of Locally Advanced Breast Cancer With Letrozole in Postmenopausal Women
NCT00237224	PHASE4	COMPLETED	Open Label Study of Postmenopausal Women With ER and /or PgR Positive Breast Cancer Treated With Letrozole
NCT00241046	PHASE4	TERMINATED	Letrozole in the Treatment of 1st and 2nd Line Hormone Receptor Positive Breast Cancer: Pre-therapeutic Risk Assessment
NCT00277160	PHASE4	COMPLETED	A Study of Primary Prophylaxis With Neulasta (Pegfilgrastim) Versus Secondary Prophylaxis After Chemotherapy in Elderly Subjects (>/= 65 Years Old) With Cancer
NCT00323479	PHASE4	COMPLETED	Arthralgia During Anastrozole Therapy for Breast Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00356148	PHASE4	COMPLETED	The Efficacy of Prophylactic Antibiotic Administration During Breast Cancer Surgery in Overweight Patients.
NCT00372476	PHASE4	COMPLETED	Efficacy and Safety of Imatinib and Vinorelbine in Patients With Advanced Breast Cancer
NCT00413491	PHASE4	UNKNOWN	National Screening in Denmark With MR Versus Mammography and Ultrasound of Women With BRCA1 or BRCA2 Mutations
NCT00484614	PHASE4	UNKNOWN	Study the Role of Positron Emission Mammography in Pre-surgical Planning for Breast Cancer
NCT00485953	PHASE4	COMPLETED	Effect of Bisphosphonate on Bone Loss in Postmenopausal Women With Breast Cancer Initiating Aromatase Inhibitor Therapy
NCT00496678	PHASE4	COMPLETED	Trial of Patient Navigation-Activation
NCT00531973	PHASE4	UNKNOWN	A Study of Liposomal Doxorubicin in Women With Breast Cancer Exploiting Tissue Doppler Imaging
NCT00537771	PHASE4	COMPLETED	Liver Safety Under Upfront Arimidex vs Tamoxifen
NCT00544986	PHASE4	COMPLETED	A Prospective,Open-label Study of Anastrozole in Post-menopausal Women With Hormone Sensitive Advanced Breast Cancer
NCT00613275	PHASE4	COMPLETED	Patient Navigation in the Safety Net:CONNECTeDD
NCT00638599	PHASE4	COMPLETED	Comparison of Laryngeal Mask Airway (LMA®) and Tracheal Tube in Modified Radical Mastectomy on Breast Cancer
NCT00647075	PHASE4	UNKNOWN	Yunzhi as Dietary Supplement in Breast Cancer
NCT00688909	PHASE4	COMPLETED	Rheumatological Evaluation of Anastrozole and Letrozole as Adjuvant Treatment in Post-menopausal Women With Breast Cancer
NCT00699101	PHASE4	TERMINATED	Using the Conture® Multi-Lumen Balloon to Deliver Accelerated Partial Breast Brachytherapy
NCT00742222	PHASE4	COMPLETED	Electronic Xoft Intersociety Brachytherapy Trial: Electronic Brachytherapy (EBT) For Treatment of Early Stage Breast Cancer