CDH3

Summary

CDH3 (cadherin 3, HGNC:1762) is a protein-coding gene on chromosome 16q22.1, encoding Cadherin-3 (P22223). Cadherins are calcium-dependent cell adhesion proteins.

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. This gene is located in a gene cluster in a region on the long arm of chromosome 16 that is involved in loss of heterozygosity events in breast and prostate cancer. In addition, aberrant expression of this protein is observed in cervical adenocarcinomas. Mutations in this gene are associated with hypotrichosis with juvenile macular dystrophy and ectodermal dysplasia, ectrodactyly, and macular dystrophy syndrome (EEMS).

Source: NCBI Gene 1001 — RefSeq curated summary.

At a glance

• Gene–disease (curated): EEM syndrome (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 8
• Clinical variants (ClinVar): 849 total — 40 pathogenic, 24 likely-pathogenic
• Phenotypes (HPO): 61
• Druggable target: yes
• MANE Select transcript: NM_001793

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1762
Approved symbol	CDH3
Name	cadherin 3
Location	16q22.1
Locus type	gene with protein product
Status	Approved
Aliases	CDHP, PCAD
Ensembl gene	ENSG00000062038
Ensembl biotype	protein_coding
OMIM	114021
Entrez	1001

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 11 protein_coding, 4 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000264012, ENST00000429102, ENST00000542274, ENST00000565453, ENST00000566808, ENST00000567674, ENST00000568292, ENST00000569036, ENST00000569080, ENST00000569117, ENST00000878261, ENST00000878262, ENST00000914962, ENST00000914963, ENST00000914964, ENST00000914965, ENST00000914966

RefSeq mRNA: 3 — MANE Select: NM_001793 NM_001317195, NM_001317196, NM_001793

CCDS: CCDS10868, CCDS82004

Canonical transcript exons

ENST00000264012 — 16 exons

Exon	Start	End
ENSE00001140450	68698191	68700292
ENSE00001204134	68645636	68645750
ENSE00001822923	68645310	68645424
ENSE00003469022	68685205	68685350
ENSE00003470873	68680968	68681096
ENSE00003480193	68678134	68678277
ENSE00003501737	68684583	68684824
ENSE00003545823	68695255	68695385
ENSE00003605993	68687512	68687736
ENSE00003606424	68678762	68678906
ENSE00003608769	68679799	68679974
ENSE00003616620	68678501	68678656
ENSE00003644721	68682302	68682487
ENSE00003657976	68691720	68691926
ENSE00003684875	68695777	68695923
ENSE00003690701	68676385	68676470

Expression profiles

Bgee: expression breadth ubiquitous, 213 present calls, max score 98.08.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0163 / max 2.7299, expressed in 6 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
154761	21.3554	540
154760	0.9119	348
154762	0.3176	141
154754	0.2399	88
154758	0.1865	62
154759	0.1605	52
154753	0.1535	75
154757	0.0219	5
154755	0.0163	6
154756	0.0133	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	98.08	gold quality
oocyte	CL:0000023	97.90	gold quality
mammary duct	UBERON:0001765	95.86	gold quality
gingival epithelium	UBERON:0001949	95.70	gold quality
gingiva	UBERON:0001828	95.54	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	94.46	gold quality
left ovary	UBERON:0002119	94.39	gold quality
epithelium of mammary gland	UBERON:0003244	94.37	gold quality
pigmented layer of retina	UBERON:0001782	93.87	gold quality
retina	UBERON:0000966	93.84	gold quality
nasal cavity epithelium	UBERON:0005384	93.13	gold quality
periodontal ligament	UBERON:0008266	92.58	gold quality
ovary	UBERON:0000992	92.56	gold quality
right ovary	UBERON:0002118	91.20	gold quality
hair follicle	UBERON:0002073	91.14	silver quality
left uterine tube	UBERON:0001303	90.40	gold quality
esophagus mucosa	UBERON:0002469	90.30	gold quality
epithelium of nasopharynx	UBERON:0001951	89.65	gold quality
lower esophagus mucosa	UBERON:0035834	89.59	gold quality
upper leg skin	UBERON:0004262	89.08	gold quality
eye	UBERON:0000970	89.04	gold quality
germinal epithelium of ovary	UBERON:0001304	88.95	gold quality
tongue squamous epithelium	UBERON:0006919	88.60	silver quality
nasal cavity mucosa	UBERON:0001826	88.00	gold quality
skin of abdomen	UBERON:0001416	87.84	gold quality
palpebral conjunctiva	UBERON:0001812	87.73	gold quality
endometrium epithelium	UBERON:0004811	87.14	gold quality
zone of skin	UBERON:0000014	86.52	gold quality
minor salivary gland	UBERON:0001830	86.50	gold quality
mouth mucosa	UBERON:0003729	86.33	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ENAD-20	yes	707.37
E-MTAB-8142	yes	431.54
E-MTAB-10596	yes	169.14
E-MTAB-10662	yes	149.46
E-GEOD-81383	yes	80.99
E-MTAB-9388	yes	7.11
E-CURD-10	no	178.37
E-MTAB-6379	no	14.48
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

6 targets.

Target	Regulation
CTNNB1	Activation
KIT	Activation
KITLG	Activation
MITF	Activation
PMEL	Activation
TYR	Activation

Upstream regulators (CollecTRI, top): BRCA1, CEBPB, CTNNB1, DNMT1, ESR1, FOXO1, GATA3, HNF4A, HOXA9, MYC, PAX3, SMAD4, SNAI1, SNAI2, SP1, TFAP2A, TP53, TP63

miRNA regulators (miRDB)

18 targeting CDH3, 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-4668-5P	99.79	70.58	3782
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-520A-5P	99.35	66.72	1632
HSA-MIR-525-5P	99.35	66.85	1615
HSA-MIR-6506-5P	99.04	65.66	1386
HSA-MIR-6829-5P	98.86	65.12	1480
HSA-MIR-619-5P	98.57	64.97	1988
HSA-MIR-204-3P	97.80	66.84	1656
HSA-MIR-4708-5P	97.77	67.82	831
HSA-MIR-4646-5P	97.70	66.84	1692
HSA-MIR-495-5P	97.62	68.28	682
HSA-MIR-4314	97.50	67.30	1369
HSA-MIR-4797-3P	97.48	67.14	989
HSA-MIR-3192-5P	96.98	65.76	1926
HSA-MIR-6777-3P	95.35	64.30	699

Literature-anchored findings (GeneRIF, showing 40)

• high levels of 80 kDa sP-cadherin in human milk. (PMID:11891861)
• results point to the close relationship between the de novo expression of P-cadherin and the disruption of the cadherin/catenins complex with the squamoid phenotype of mucoepidermoid carcinoma of the thyroid (MECT) (PMID:12021924)
• may play a central role in the development of endometriosis by mediating endometrial-peritoneal cell interactions in a homophilic manner (PMID:12112590)
• Regulated expression of P-cadherin/beta-catenin complexes in ovarian tumor cells may represent a key step in disease progression (PMID:12800191)
• Inappropriate PCAD expression in mouse mammary epithelium is compatible with normal mammary gland function. (PMID:12919105)
• An absent P-cadherin expression could constitute a hallmark of aggressive biological behaviour in oral squamous cell carcinoma. (PMID:15375751)
• In summary, we have ascertained a third gene associated with ectrodactyly and have demonstrated a hitherto unrecognised role of CDH3 in shaping the human hand (PMID:15805154)
• A short truncated 50 kDa form of the N-terminal part of P-cadherin expresses in melanoma cell lines compared to melanocytes and keratinocytes. (PMID:15817166)
• P-cadherin may have a role in progression of oral squamous cell carcinoma (PMID:15967043)
• P-cadherin expression was strongly associated with tumor aggressiveness, being a good indicator of clinical outcome, and the aberrant expression of P-cadherin in breast cancer might be regulated by gene promoter hypomethylation. (PMID:16115928)
• Novel heterozygous CDH3 mutations in hypotrichosis with juvenile macular dystrophy in two nonconsaguineous families. (PMID:17342797)
• P-cadherin may be regarded as an additional immunohistochemical marker of basal-like breast carcinomas. (PMID:18074863)
• P-cadherin is a newly defined transcriptional target gene of p63, with a crucial role in hair follicle morphogenesis as well as the apical ectodermal ridge during limb bud outgrowth in humans. (PMID:18199584)
• Tunisian IBCs are characterized by frequent basal and ERBB2 phenotypes. Surprisingly, luminal inflammatory breast cancer also express the basal marker P-cadherin. (PMID:18230143)
• This preliminary study provides evidence that the CK19/EpCAM2 and/or CK19/P-cadherin ratio(s) may be a simple and accurate prognostic indicator of clinical outcome in early-stage adenocarcinoma of the lung. (PMID:18329483)
• P-cadherin expression in adenomas suggest that this molecule might have role in adenoma formation though not necessarily be involved in neoplastic progression. (PMID:18330089)
• Results suggest that generation of truncated P-cadherin during the progression of oral squamous carcinoma attenuates tissue integrity, facilitates cellular separation, and leads to the acquisition of a more migratory phenotype. (PMID:18637117)
• The expression of P-cadherin (a marker of proliferating keratinocytes) was regulated by all of the examined PKCs, also in an antagonistic manner (inhibited by cPKCalpha/nPKCdelta and stimulated by cPKCbeta/nPKCepsilon). (PMID:18637128)
• High levels of the soluble fragment of P-cadherin in Cancer Nipple aspirate fluid suggest its possible release via proteolytic processing (PMID:18811693)
• Induced P-cadherin expression, especially in mucosal damage, leads to an increased rate of crypt fission, a common feature of clonal expansion in gastrointestinal dysplasia. (PMID:18829530)
• Up-regulation of CDH3 is associated with pancreatic, gastric, and colorectal cancers. (PMID:18927288)
• Expression of CD24, P-cadherin and S100A4 in tumors of the ampulla of Vater. (PMID:19043399)
• The identified mutation IVS10-1 G–>T is very likely to result in skipping of exon 11, leading either to synthesis of truncated protein or to an absence of CDH3 expression, possibly due to mRNA decay. (PMID:19076794)
• EGFR, fibrillin-2, P-cadherin and AP2beta as biomarkers for rhabdomyosarcoma diagnostics. (PMID:19469909)
• Aberrant demethylation of CDH3 is associated with colorectal carcinomas. (PMID:19528483)
• Demethylation of the CDH3 gene was detected in 25 out of the 36 (69%) primary gastric carcinomas, suggesting that the aberrant demethylation of CDH3 is a frequent event in gastric carcinomas. (PMID:19846933)
• Overexpression of CDH3 is associated with basal-like phenotype in breast cancer. (PMID:19882246)
• Data show that P-cadherin overexpression in breast cancer cells with wild-type E-cadherin promotes cell invasion, motility, and induces the secretion of MMP-1 and MMP-2, which then lead to P-cadherin ectodomain cleavage. (PMID:19901964)
• cadherin switching and p120(ctn) signaling as important targets of GnRH function and as novel mediators of invasiveness and tumor progression in ovarian cancer. (PMID:20118984)
• a novel splice site mutation (c.IVS10-1 G –> A) in intron 10, which leads to skipping of exon 11 in CDH3 gene in family with hypotrichosis with juvenile macular dystrophy (PMID:20140736)
• 2 splice site mutations (one novel and one recurrent mutation) were in the CDH3 gene leading to hypotrichosis with juvenile macular dystrophy. (PMID:20203473)
• P-cadherin gene expression proved to be a significant independent prognostic factor for both cancer-specific and recurrence-free survival in bladder cancer (PMID:20204300)
• We investigated methylation patterns in the promoter regions of ABCB1, ATM, BRCA1, CDH3, CDKN2A, CXCR4, ESR1, FBXW7, FOXC1, GSTP1, IGF2, HMLH1, PPP2R2B, and PTEN75 in well-described pre-treatment samples from locally advanced breast cancer (PMID:20338046)
• C/EBPbeta is able to up-regulate CDH3 promoter activity in breast cancer cells; the expression of P-cadherin linked with a worse prognosis of breast cancer patients (PMID:20385540)
• Stable knockdown of P-cadherin in RT-112 cells diminished invasion and migration, and promoted intercellular adhesion (PMID:20473917)
• P-cadherin and CD24 are expressed in carcinomas of the biliary tract with high frequency and at an early stage of carcinogenesis. (PMID:20621328)
• Data indicate that P-cadherin but not E-cadherin is important for maintaining adherens junctions in DU145 and MCF10A cells. (PMID:20668551)
• P-cadherin positivity is associated with high-grade breast cancer subtypes and well-established markers of poor prognosis. (PMID:20852590)
• Data conclude that P-cadherin counteracts the expression and function of myosin II-B, resulting in the suppression of the invasive and migratory behaviour of BLM melanoma cells. (PMID:20860798)
• P-cadherin cooperates with insulin-like growth factor-1 receptor to promote metastatic signaling of gonadotropin-releasing hormone in ovarian cancer via p120 catenin. (PMID:21317933)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	cdh31	ENSDARG00000035796
danio_rerio	cdh29	ENSDARG00000100131
danio_rerio	cdh1	ENSDARG00000102750
danio_rerio	cdh28	ENSDARG00000104332
danio_rerio	cdh30	ENSDARG00000104440
mus_musculus	Cdh3	ENSMUSG00000061048
rattus_norvegicus	Cdh3	ENSRNOG00000020129

Paralogs (33): CDH1 (ENSG00000039068), CDH10 (ENSG00000040731), 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-3 — P22223 (reviewed: P22223)

Alternative names: Placental cadherin

All UniProt accessions (7): P22223, J3KRQ1, J3QKW6, J3QL41, J3QL75, J3QR34, J3QR60

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.

Subunit / interactions. Interacts with CDCP1 and CTNNB1.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in some normal epithelial tissues and in some carcinoma cell lines.

Disease relevance. Hypotrichosis congenital with juvenile macular dystrophy (HJMD) [MIM:601553] A disorder characterized by congenital hypotrichosis, early hair loss, and severe degenerative changes of the retinal macula that culminate in blindness during the second to third decade of life. The disease is caused by variants affecting the gene represented in this entry. Ectodermal dysplasia, ectrodactyly, and macular dystrophy syndrome (EEMS) [MIM:225280] A form of ectodermal dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. It is an autosomal recessive condition characterized by features of ectodermal dysplasia such as sparse eyebrows and scalp hair, and selective tooth agenesis associated with macular dystrophy and ectrodactyly. 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 rigidify the connections, imparting a strong curvature to the full-length ectodomain.

Isoforms (2)

UniProt ID	Names	Canonical?
P22223-1	1	yes
P22223-2	2

RefSeq proteins (3): NP_001304124, NP_001304125, NP_001784* (*=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

UniProt features (46 total): strand 20, domain 5, sequence variant 5, turn 5, glycosylation site 2, helix 2, topological domain 2, signal peptide 1, propeptide 1, splice variant 1, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

19 structures.

PDB	Method	Resolution (Å)
6ZTB	X-RAY DIFFRACTION	1.4
4ZMY	X-RAY DIFFRACTION	1.5
4OY9	X-RAY DIFFRACTION	1.62
4ZML	X-RAY DIFFRACTION	1.85
4ZMZ	X-RAY DIFFRACTION	2.05
6ZTR	X-RAY DIFFRACTION	2.1
4ZMP	X-RAY DIFFRACTION	2.15
4ZMQ	X-RAY DIFFRACTION	2.2
4ZMW	X-RAY DIFFRACTION	2.3
7CMF	X-RAY DIFFRACTION	2.3
4ZMV	X-RAY DIFFRACTION	2.4
5JYM	X-RAY DIFFRACTION	2.45
7CME	X-RAY DIFFRACTION	2.45
4ZMO	X-RAY DIFFRACTION	2.48
5JYL	X-RAY DIFFRACTION	2.55
4ZMN	X-RAY DIFFRACTION	2.6
4ZMT	X-RAY DIFFRACTION	2.7
8HYI	X-RAY DIFFRACTION	2.85
4ZMX	X-RAY DIFFRACTION	3.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P22223-F1	76.71	0.46

Antibody-complex structures (SAbDab): 3 — 5JYL, 5JYM, 6ZTR

Functional residue map

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

Glycosylation sites (2): 200, 566

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-418990	Adherens junctions interactions
R-HSA-1500931	Cell-Cell communication
R-HSA-421270	Cell-cell junction organization
R-HSA-446728	Cell junction organization

MSigDB gene sets: 357 (showing top): GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EPITHELIUM_DEVELOPMENT, MYOGENIN_Q6, GOBP_PHENOL_CONTAINING_COMPOUND_BIOSYNTHETIC_PROCESS, GU_PDEF_TARGETS_DN, chr16q22, JAEGER_METASTASIS_DN, GOBP_KERATINOCYTE_PROLIFERATION, SP3_Q3, AREB6_03, GAUSSMANN_MLL_AF4_FUSION_TARGETS_E_UP, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, GOBP_REGULATION_OF_HAIR_CYCLE, CAGCTG_AP4_Q5

GO Biological Process (24): cell morphogenesis (GO:0000902), retina homeostasis (GO:0001895), cell-cell junction assembly (GO:0007043), cell adhesion (GO:0007155), homophilic cell-cell adhesion (GO:0007156), visual perception (GO:0007601), positive regulation of keratinocyte proliferation (GO:0010838), calcium-dependent cell-cell adhesion (GO:0016339), cell migration (GO:0016477), hair cycle process (GO:0022405), negative regulation of transforming growth factor beta receptor signaling pathway (GO:0030512), keratinization (GO:0031424), adherens junction organization (GO:0034332), positive regulation of insulin-like growth factor receptor signaling pathway (GO:0043568), cell-cell adhesion mediated by cadherin (GO:0044331), positive regulation of melanin biosynthetic process (GO:0048023), hair follicle maturation (GO:0048820), regulation of transport (GO:0051049), negative regulation of timing of catagen (GO:0051796), positive regulation of canonical Wnt signaling pathway (GO:0090263), positive regulation of gene expression (GO:0010628), obsolete positive regulation of tyrosinase activity (GO:0032773), cell-cell adhesion (GO:0098609), positive regulation of melanosome transport (GO:1902910)

GO Molecular Function (4): calcium ion binding (GO:0005509), beta-catenin binding (GO:0008013), cadherin binding (GO:0045296), metal ion binding (GO:0046872)

GO Cellular Component (6): cytoplasm (GO:0005737), plasma membrane (GO:0005886), adherens junction (GO:0005912), catenin complex (GO:0016342), cell junction (GO:0030054), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Cell-cell junction organization	1
Cell junction organization	1
Cell-Cell communication	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell-cell adhesion	3
cellular anatomical structure	3
cell-cell junction organization	2
anatomical structure morphogenesis	1
tissue homeostasis	1
cell junction assembly	1
cellular process	1
sensory perception of light stimulus	1
regulation of keratinocyte proliferation	1
keratinocyte proliferation	1
positive regulation of epithelial cell proliferation	1
cell motility	1
molting cycle process	1
hair cycle	1
transforming growth factor beta receptor signaling pathway	1
regulation of transforming growth factor beta receptor signaling pathway	1
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
keratinocyte differentiation	1
multicellular organismal process	1
positive regulation of signal transduction	1
regulation of insulin-like growth factor receptor signaling pathway	1
insulin-like growth factor receptor signaling pathway	1
melanin biosynthetic process	1
regulation of melanin biosynthetic process	1
positive regulation of secondary metabolite biosynthetic process	1
hair follicle development	1
hair cycle process	1
anatomical structure maturation	1
transport	1
regulation of localization	1
catagen	1
negative regulation of hair follicle maturation	1
regulation of timing of catagen	1
positive regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
metal ion binding	1
protein binding	1
cell adhesion molecule binding	1
cation binding	1

Protein interactions and networks

STRING

1686 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CDH3	NPHS1	O60500	985
CDH3	NPHS2	Q9NP85	961
CDH3	TJP1	Q07157	948
CDH3	CTNNB1	P35222	947
CDH3	CTNND1	O60716	888
CDH3	CDH1	P12830	879
CDH3	CD2AP	Q9Y5K6	841
CDH3	KIRREL1	Q96J84	775
CDH3	CDH2	P19022	756
CDH3	CTNNA1	P35221	692
CDH3	EGFR	P00533	669
CDH3	KRT5	P13647	648
CDH3	RHOA	P06749	630
CDH3	KRT14	P02533	611
CDH3	VCL	P18206	604

IntAct

24 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
TAX1BP3	ARVCF	psi-mi:“MI:0914”(association)	0.690
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
PCDHGB1	FAM171A2	psi-mi:“MI:0914”(association)	0.530
SMURF2	CDH3	psi-mi:“MI:0407”(direct interaction)	0.440
CDH3	IGF1R	psi-mi:“MI:0915”(physical association)	0.400
PCDHGB1	FAM171A2	psi-mi:“MI:0914”(association)	0.350
CTNNA3	ARVCF	psi-mi:“MI:0914”(association)	0.350
ELK1	TPP1	psi-mi:“MI:0914”(association)	0.350
GRB10	POLRMT	psi-mi:“MI:0914”(association)	0.350
ELK1	PPP6C	psi-mi:“MI:0914”(association)	0.350
RHOA	PPP6C	psi-mi:“MI:0914”(association)	0.350
YAP1	CTNND1	psi-mi:“MI:0914”(association)	0.350
CTNNB1	IGLL5	psi-mi:“MI:0914”(association)	0.350
CTNNB1	ARVCF	psi-mi:“MI:0914”(association)	0.350
AP2M1	CTNND1	psi-mi:“MI:0914”(association)	0.350
	CDH3	psi-mi:“MI:0915”(physical association)	0.000
CDH3		psi-mi:“MI:0915”(physical association)	0.000

BioGRID (39): CTNND1 (Affinity Capture-Western), CTNNB1 (Affinity Capture-Western), CDH3 (Affinity Capture-MS), CDH3 (Affinity Capture-MS), CDH3 (Affinity Capture-MS), CDH1 (Affinity Capture-Western), CDH3 (Affinity Capture-Western), CDH3 (Co-purification), CDH3 (Co-purification), CDH3 (Affinity Capture-Western), CTNNA1 (Co-purification), CTNNA1 (Affinity Capture-Western), CTNNB1 (Co-purification), CTNNB1 (Affinity Capture-Western), JUP (Affinity Capture-Western)

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

5 interactions.

A	Effect	B	Mechanism
CTNND1	“up-regulates quantity by stabilization”	CDH3	binding
ARVCF	“up-regulates quantity by stabilization”	CDH3	binding
CTNND2	“up-regulates quantity by stabilization”	CDH3	binding
calcium(2+)	“up-regulates activity”	CDH3	“chemical activation”
CDH3	“up-regulates activity”	CTNNB1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	40
Likely pathogenic	24
Uncertain significance	389
Likely benign	294
Benign	40

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1071354	NM_001793.6(CDH3):c.1519C>T (p.Gln507Ter)	Pathogenic
1075911	NC_000016.9:g.(?68710288)(68729826_?)del	Pathogenic
1076843	NM_001793.6(CDH3):c.1831_1832del (p.Lys611fs)	Pathogenic
1322049	NM_001793.6(CDH3):c.160+1G>A	Pathogenic
1437434	NM_001793.6(CDH3):c.1837dup (p.Asp613fs)	Pathogenic
1454138	NM_001793.6(CDH3):c.661C>T (p.Arg221Ter)	Pathogenic
1457451	NM_001793.6(CDH3):c.118dup (p.Ala40fs)	Pathogenic
1457861	NM_001793.6(CDH3):c.1850_1851del (p.Val617fs)	Pathogenic
1459147	NM_001793.6(CDH3):c.1086G>A (p.Trp362Ter)	Pathogenic
1460035	NC_000016.9:g.(?68679283)(68679673_?)del	Pathogenic
1687039	NM_001793.6(CDH3):c.665_666dup (p.Ser223fs)	Pathogenic
17638	NM_001793.6(CDH3):c.981del (p.Met327fs)	Pathogenic
17640	NM_001793.6(CDH3):c.965A>T (p.Asn322Ile)	Pathogenic
17641	NM_001793.6(CDH3):c.830del (p.Gly277fs)	Pathogenic
1966382	NM_001793.6(CDH3):c.401_403delinsTT (p.Asn134fs)	Pathogenic
2028530	NM_001793.6(CDH3):c.1114del (p.Asp372fs)	Pathogenic
2050951	NM_001793.6(CDH3):c.927dup (p.Thr310fs)	Pathogenic
2055956	NM_001793.6(CDH3):c.222del (p.Val75fs)	Pathogenic
2118830	NM_001793.6(CDH3):c.978dup (p.Met327fs)	Pathogenic
2137840	NM_001793.6(CDH3):c.316_317del (p.Lys106fs)	Pathogenic
2137842	NM_001793.6(CDH3):c.1796-2A>G	Pathogenic
2424241	NC_000016.9:g.(?68349883)(68732303_?)del	Pathogenic
2424243	NC_000016.9:g.(?68718466)(68721659_?)del	Pathogenic
2424247	NC_000016.9:g.(?68710268)(68716410_?)del	Pathogenic
291181	NM_001793.6(CDH3):c.1085G>A (p.Trp362Ter)	Pathogenic
2989730	NM_001793.6(CDH3):c.1202_1205del (p.Lys401fs)	Pathogenic
3010459	NM_001793.6(CDH3):c.719_720insA (p.Asp241fs)	Pathogenic
3248980	NC_000016.10:g.(?68645368)(68645750_68676385)del	Pathogenic
3249648	NM_001793.6(CDH3):c.692-1G>T	Pathogenic
3250013	NM_001793.6(CDH3):c.1183-2A>G	Pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

5458 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:68679916:T:C	F270S	0.997
16:68678583:T:C	F158S	0.996
16:68678604:G:A	G165D	0.995
16:68678583:T:G	F158C	0.994
16:68678634:G:C	R175P	0.994
16:68680987:T:C	L296P	0.994
16:68678537:T:G	Y143D	0.992
16:68678582:T:C	F158L	0.992
16:68678584:C:A	F158L	0.992
16:68678584:C:G	F158L	0.992
16:68678853:C:A	P213H	0.992
16:68678859:T:C	F215S	0.992
16:68679823:C:A	A239D	0.992
16:68679915:T:C	F270L	0.992
16:68679917:C:A	F270L	0.992
16:68679917:C:G	F270L	0.992
16:68678604:G:T	G165V	0.991
16:68678610:T:C	L167S	0.991
16:68678775:C:A	A187D	0.991
16:68678858:T:C	F215L	0.991
16:68678860:T:A	F215L	0.991
16:68678860:T:G	F215L	0.991
16:68679834:G:C	D243H	0.991
16:68679870:T:G	Y255D	0.991
16:68679916:T:G	F270C	0.991
16:68679943:T:A	I279N	0.991
16:68680998:G:C	A300P	0.991
16:68678829:T:A	V205E	0.990
16:68679822:G:C	A239P	0.990
16:68680999:C:A	A300D	0.990

dbSNP variants (sampled 300 via entrez): RS1000005881 (16:68732161 C>A), RS1000029042 (16:68710552 A>C,G), RS1000037012 (16:68731907 T>G), RS1000071013 (16:68652592 T>C,G), RS1000084626 (16:68679675 A>G), RS1000138049 (16:68674331 C>T), RS1000151483 (16:68692332 C>G,T), RS1000169526 (16:68670093 G>A), RS1000185060 (16:68707285 C>T), RS1000188798 (16:68729752 C>T), RS1000199470 (16:68678688 C>A,G,T), RS1000204769 (16:68650770 A>G), RS1000219942 (16:68729561 T>C,G), RS1000251282 (16:68713660 T>C), RS1000348284 (16:68726112 T>C)

Disease associations

OMIM: gene MIM:114021 | disease phenotypes: MIM:225280, MIM:601553, MIM:605389, MIM:268000

GenCC curated gene-disease

Disease	Classification	Inheritance
EEM syndrome	Definitive	Autosomal recessive
congenital hypotrichosis with juvenile macular dystrophy	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
EEM syndrome	Definitive	AR

Mondo (8): EEM syndrome (MONDO:0009155), inherited retinal dystrophy (MONDO:0019118), congenital hypotrichosis with juvenile macular dystrophy (MONDO:0011107), prostate cancer (MONDO:0008315), hypotrichosis simplex (MONDO:0018914), retinal disorder (MONDO:0005283), hypotrichosis (MONDO:0003037), retinitis pigmentosa (MONDO:0019200)

Orphanet (6): EEM syndrome (Orphanet:1897), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Hypotrichosis with juvenile macular degeneration (Orphanet:1573), Familial prostate cancer (Orphanet:1331), Hypotrichosis simplex (Orphanet:55654), Retinitis pigmentosa (Orphanet:791)

HPO phenotypes

61 total (30 of 61 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000164	Abnormality of the dentition
HP:0000478	Abnormality of the eye
HP:0000486	Strabismus
HP:0000488	Retinopathy
HP:0000504	Abnormality of vision
HP:0000608	Macular degeneration
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000653	Sparse eyelashes
HP:0000670	Carious teeth
HP:0000687	Widely spaced teeth
HP:0000691	Microdontia
HP:0000962	Hyperkeratosis
HP:0000968	Ectodermal dysplasia
HP:0000975	Hyperhidrosis
HP:0000980	Pallor
HP:0000995	Melanocytic nevus
HP:0001155	Abnormality of the hand
HP:0001171	Split hand
HP:0001233	2-3 finger cutaneous syndactyly
HP:0001480	Freckling
HP:0001592	Selective tooth agenesis
HP:0001597	Abnormal nail morphology
HP:0001760	Abnormal foot morphology
HP:0002209	Sparse scalp hair
HP:0002213	Fine hair
HP:0002223	Absent eyebrow
HP:0002231	Sparse body hair
HP:0002299	Brittle hair

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST004133_66	Ulcerative colitis	4.000000e-08
GCST004621_185	Red cell distribution width	3.000000e-20
GCST005531_12	Multiple sclerosis	1.000000e-08
GCST007954_20	Glycated hemoglobin levels	2.000000e-07
GCST009597_89	Multiple sclerosis	8.000000e-07
GCST010302_15	Cutaneous melanoma or hair colour	1.000000e-08
GCST90002396_594	Mean reticulocyte volume	1.000000e-09
GCST90002402_461	Platelet count	3.000000e-09

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0009188	Red cell distribution width
EFO:0004541	HbA1c measurement
EFO:0003924	hair color
EFO:0010701	mean reticulocyte volume
EFO:0004309	platelet count

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D007039	Hypotrichosis	C17.800.329.937
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
D012164	Retinal Diseases	C11.768
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684
C536190	Ectodermal dysplasia, ectrodactyly, and macular dystrophy (supp.)
C537160	Hypotrichosis simplex (supp.)
C537698	Juvenile macular degeneration and hypotrichosis (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3989384 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	5
Tobacco Smoke Pollution	affects expression, increases expression	4
trichostatin A	affects cotreatment, increases expression	3
sodium arsenite	increases expression, decreases expression	2
mercuric bromide	increases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	2
belinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Smoke	decreases expression, decreases reaction	2
sotorasib	affects cotreatment, decreases expression	1
methylmercuric chloride	decreases expression	1
bisphenol A	increases expression, increases reaction	1
lead acetate	decreases expression	1
arsenite	increases methylation	1
benzo(e)pyrene	increases methylation	1
4-hydroxy-2-nonenal	decreases expression	1
aflatoxin B2	increases methylation	1
cupric chloride	decreases expression	1
nickel sulfate	decreases expression	1
1-nitropyrene	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
isobutyl alcohol	increases expression, affects cotreatment, increases abundance	1
4-hydroxy-equilenin	increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
chloropicrin	affects expression	1
deguelin	increases expression	1
rofecoxib	increases expression	1

Cellosaurus cell lines

6 cell lines: 4 cancer cell line, 1 spontaneously immortalized cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E6PT	Genomeditech CHO-K1 H_CDH3	Spontaneously immortalized cell line	Female
CVCL_E6TI	Genomeditech HEK-293 H_CDH3	Transformed cell line	Female
CVCL_SI15	HAP1 CDH3 (-) 1	Cancer cell line	Male
CVCL_SI16	HAP1 CDH3 (-) 2	Cancer cell line	Male
CVCL_SI17	HAP1 CDH3 (-) 3	Cancer cell line	Male
CVCL_SI18	HAP1 CDH3 (-) 4	Cancer cell line	Male

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