CDH1

Chr 16AD

cadherin 1

Also known as: Arc-1, BCDS1, CD324, CDHE, ECAD, LCAM, UVO

NCBI Gene: 999ENSG00000039068UniProt: P12830

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. [provided by RefSeq, Nov 2015]

Primary Disease Associations & Inheritance

Blepharocheilodontic syndrome 1MIM #119580
AD
Breast cancer, lobular, somaticMIM #114480
Diffuse gastric and lobular breast cancer syndrome with or without cleft lip and/or palateMIM #137215
AD
Endometrial carcinoma, somaticMIM #608089
Ovarian cancer, somaticMIM #167000
UniProtEndometrial cancer
10
Active trials
44
Pathogenic / LP
470
ClinVar variants
6
Pubs (1 yr)
0.7
Missense Z
0.43
LOEUF
Clinical Summary— CDH1
🧬
Gene-Disease Validity (ClinGen)
familial ovarian cancer · ADNo Known Disease Relationship

No known disease relationship

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.25) despite low pLI — interpret in context.
📋
ClinVar Variants
44 Pathogenic / Likely Pathogenic· 302 VUS of 470 total submissions
💊
Clinical Trials
10 active or recruiting trials — potential therapeutic options may be available
📖
GeneReview available — CDH1
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.43LOEUF
pLI 0.146
Z-score 4.22
OE 0.25 (0.15–0.43)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.71Z-score
OE missense 0.91 (0.84–0.98)
448 obs / 492.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.25 (0.15–0.43)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.91 (0.84–0.98)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.99
0≤1.21.6
LoF obs/exp: 9 / 36.5Missense obs/exp: 448 / 492.1Syn Z: 0.09
DN
0.78top 25%
GOF
0.80top 10%
LOF
0.3357th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative, loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports dominant-negative. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation
LOF1 literature citation · 59% of P/LP variants are LoF · LOEUF 0.43
GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNFunctional experiments in zebrafish and human cells showed that the CDH1 variants impair the cell adhesion function of the cadherin-catenin complex in a dominant-negative manner.PMID:29348693
LOFHereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and BeyondPMID:26182300

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

ClinVar Variant Classifications

470 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic29
Likely Pathogenic15
VUS302
Likely Benign107
Conflicting17
29
Pathogenic
15
Likely Pathogenic
302
VUS
107
Likely Benign
17
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
17
0
12
0
29
Likely Pathogenic
9
1
5
0
15
VUS
3
265
31
3
302
Likely Benign
0
7
49
51
107
Benign
0
0
0
0
0
Conflicting
—17
Total292739754470

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

CDH1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

CDH1-related blepharo-cheiro-dontic syndrome

definitive
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

CDH1-related gastric cancer, familial diffuse, with or without cleft lip and/or palate

definitive
ADLoss Of FunctionAbsent Gene Product
Cancer
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Polycythemia VeraEssential ThrombocythaemiaMyelofibrosis

Prevalence Of Germline Gene Mutations In Patients With Myeloproliferative Neoplasms With Family History

NOT YET RECRUITING
NCT06923670Phase NAFondazione Policlinico Universitario Agostino Gemelli IRCCSStarted 2025-05-21
NGS testingNGS analysis for mutations in genes involved in familial predisposition to hematological malignancies
Renal Allograft Fibrosis

Renal Allograft Fibrosis Study

ENROLLING BY INVITATION
NCT05058170Icahn School of Medicine at Mount SinaiStarted 2022-02-04
Giant Cell ArteritisTemporal ArteritisClonal Hematopoiesis of Indeterminate Potential

Clonal Hematopoiesis in Giant Cell Arteritis

NOT YET RECRUITING
NCT06244069ASST Fatebenefratelli SaccoStarted 2024-03
Temporal arterial biopsyWhole exome sequencingSingle cell transcriptomics
BRCA MutationPALB2 Gene MutationDuctal Carcinoma in Situ

Low Dose TamOxifen and LifestylE Changes for bReast cANcer prevenTion

ACTIVE NOT RECRUITING
NCT06033092Phase PHASE2European Institute of OncologyStarted 2024-06-21
Tamoxifen 10 mg TabletIntermittent caloric restrictionStep counter Device
Peri-implantitis

Expression of Epithelial-Mesenchymal Transition Associated Markers in Peri-implant Tissues

RECRUITING
NCT05832541University of BaghdadStarted 2022-08-18
Non-Small Cell Carcinoma of Lung, TNM Stage 4Non-Small Cell Lung CancerEGFR Gene Mutation

Early Rebiopsy to Identify Biomarkers of Tumor Cell Survival Following EGFR, ALK, ROS1 or BRAF TKI Therapy

RECRUITING
NCT03042221University of Colorado, DenverStarted 2016-05-10
Gastric Cancer

The Gastric Cancer Foundation: A Gastric Cancer Registry

RECRUITING
NCT01514045Stanford UniversityStarted 2011-04
Lobular Breast CarcinomaLobular in Situ Breast CarcinomaBRCA1 Mutation

LobularCard Trial: Searching for Novel Germline Mutations in Lobular Breast Cancer Patients

ACTIVE NOT RECRUITING
NCT05410951European Institute of OncologyStarted 2022-05-16
Illumina panel
Lynch SyndromeLi Fraumeni SyndromePTEN Hamartoma Syndrome

Video Capsule Examination in Patients With Lynch Syndrome

RECRUITING
NCT06712095Phase NARoyal Marsden NHS Foundation TrustStarted 2024-03-04
Video capsule investigation
Breast Cancer Surgery

Long-term Safety of Nipple Sparing Mastectomy in Women With High Penetrance Breast Cancer Susceptibility Genes in Breast Cancer

RECRUITING
NCT06888388Sir Mortimer B. Davis - Jewish General HospitalStarted 2025-02-01
Nipple Sparing Mastectomy (NSM)Skin-Sparing Mastectomy (SSM)Total (Simple) Mastectomy
Clinical Literature
Landmark / reviewRecent case evidence
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
The Identification of Large Rearrangements Involving Intron 2 of the CDH1 Gene in BRCA1/2 Negative and Breast Cancer Susceptibility
Ben Aissa-Haj J et al.·Genes (Basel)
2022
The upregulation of circFNDC3B aggravates the recurrence after endoscopic submucosal dissection (ESD) in early gastric cancer (EGC) patients
Zhang J et al.·Sci Rep
2022Cohort
Comprehensive Bioinformatic Analysis of Epithelial-Mesenchymal Transition (EMT) Network-Related microRNAs As Candidate Signatures in Prostate Adenocarcinoma
Prasad G et al.·Cureus
2025
A comprehensive analysis of different types of databases reveals that CDH1 mRNA and E-cadherin protein are not downregulated in most carcinoma tissues and carcinoma cell lines
Sicairos B et al.·BMC Cancer
2023
A Novel CDH1 Variant Identified in a Chinese Family with Blepharocheilodontic Syndrome
Lin B et al.·Diagnostics (Basel)
2022
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

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