# NM_004360.5(CDH1):c.8C>G (p.Pro3Arg)

https://sugi.bio/variant/cdh1-p-pro3arg

## Summary

**CDH1 p.Pro3Arg (c.8C>G)** is classified **Likely benign** in CDH1 (ClinVar, Expert panel, 21 submitters; last evaluated 2023-08-17). AlphaMissense: likely benign (0.0583); Ultra-rare (popmax 0.012%, nfe); Associated with CDH1-related diffuse gastric and lobular breast cancer syndrome.

**At a glance:** Likely benign · review: Expert panel · rsID rs587782484 · 21 submitters · 7 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.012%, nfe)

## For patients & families {#patients}

This is a change in the CDH1 gene that is classified as likely benign — not considered disease-causing, submitted by 21 submitters, and is linked to CDH1-related diffuse gastric and lobular breast cancer syndrome.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0026244/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CDH1](https://sugi.bio/atlas/gene/CDH1/) |
| Protein change (HGVS p.) | p.Pro3Arg |
| Coding change (HGVS c.) | c.8C>G |
| MANE Select transcript | [NM_004360](https://www.ncbi.nlm.nih.gov/nuccore/NM_004360) |
| dbSNP | [rs587782484](https://www.ncbi.nlm.nih.gov/snp/rs587782484/) |
| Variant type | single nucleotide variant |
| Location | chr16:68737423-68737423 (GRCh38) |
| ClinVar | [VCV142469](https://www.ncbi.nlm.nih.gov/clinvar/variation/142469/) |

**All HGVS expressions:** `LRG_301:g.5132C>G`, `LRG_301t1:c.8C>G`, `NC_000016.10:g.68737423C>G`, `NC_000016.9:g.68771326C>G`, `NG_008021.1:g.5132C>G`, `NM_001317184.2:c.8C>G`, `NM_001317185.2:c.-1608C>G`, `NM_001317186.2:c.-1812C>G`, `NM_004360.5:c.8C>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.0583)
- REVEL 0.085 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.579 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 2.423, GERP -0.915, phastCons 0.18 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 19.71**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 1.05** across the covering region of the MANE Select transcript (68,737,416–68,808,494), spanning 71,078 bp. Chi-square p 0.52. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.012%** (nfe) · FAF95 0.0103% · FAF99 0.00975% · 138/1,146,758 in the highest group · 187/1,534,038 alleles overall — ultra-rare (popmax 0.012%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.0932% | 1,073 |
| European (non-Finnish) (grpmax) | 0.012% | 8,310 |
| Remaining individuals (not grpmax-eligible) | 0.01% | 9,965 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0035% | 28,574 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CDH1** population constraint: LOEUF 0.514, pLI 0.85613, missense-Z 1.9041; ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **CDH1-related diffuse gastric and lobular breast cancer syndrome** — Definitive (AD)
- **familial ovarian cancer** — No Known Disease Relationship (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 79.13, 46% of residues very-high.

**22 experimental structure(s)** (PDB): [1O6S](https://www.rcsb.org/structure/1O6S), [2O72](https://www.rcsb.org/structure/2O72), [2OMT](https://www.rcsb.org/structure/2OMT), [2OMU](https://www.rcsb.org/structure/2OMU), [2OMV](https://www.rcsb.org/structure/2OMV), [2OMX](https://www.rcsb.org/structure/2OMX).

## What this gene does {#gene-function}

*Describes the biological roles of CDH1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** CDH1's established molecular role includes beta-catenin binding. In Reactome, CDH1 is annotated in disease pathway(s) including **InlA-mediated entry of Listeria monocytogenes into host cells**.

**Disease mechanism (Reactome):** CDH1 loss or alteration is curated in [InlA-mediated entry of Listeria monocytogenes into host cells](https://reactome.org/content/detail/R-HSA-8876493).

### Pathways affected {#pathways}

CDH1 participates in **19 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [InlA-mediated entry of Listeria monocytogenes into host cells](https://reactome.org/content/detail/R-HSA-8876493) | curated |
| [Adherens junctions interactions](https://reactome.org/content/detail/R-HSA-418990) | curated |
| [Apoptotic cleavage of cell adhesion  proteins](https://reactome.org/content/detail/R-HSA-351906) | curated |
| [Degradation of CDH1](https://reactome.org/content/detail/R-HSA-9766229) | curated |
| [Developmental Lineage of Mammary Gland Luminal Epithelial Cells](https://reactome.org/content/detail/R-HSA-9927418) | curated |
| [Developmental Lineage of Mammary Gland Myoepithelial Cells](https://reactome.org/content/detail/R-HSA-9927432) | curated |
| [Developmental Lineage of Mammary Stem Cells](https://reactome.org/content/detail/R-HSA-9938206) | curated |
| [Integrin cell surface interactions](https://reactome.org/content/detail/R-HSA-216083) | curated |
| [RHO GTPases activate IQGAPs](https://reactome.org/content/detail/R-HSA-5626467) | curated |
| [Regulation of CDH1 Function](https://reactome.org/content/detail/R-HSA-9764561) | curated |
| [Regulation of CDH1 mRNA translation by microRNAs](https://reactome.org/content/detail/R-HSA-9764562) | curated |
| [Regulation of CDH1 posttranslational processing and trafficking to plasma membrane](https://reactome.org/content/detail/R-HSA-9768727) | curated |
| [Regulation of MITF-M-dependent genes involved in extracellular matrix, focal adhesion and epithelial-to-mesenchymal transition](https://reactome.org/content/detail/R-HSA-9926550) | curated |
| [SRC activates STAT3 in a quantitative manner, through Cadherin-11 (CDH11), RAC1 and gp130 (IL6ST)](https://reactome.org/content/detail/R-HSA-9958810) | curated |
| [Transcriptional and post-translational regulation of MITF-M expression and activity](https://reactome.org/content/detail/R-HSA-9856649) | curated |
| [Activation of STAT3 by cadherin engagement](https://reactome.org/content/detail/R-HSA-9958825) | electronic |
| [Degradation of the extracellular matrix](https://reactome.org/content/detail/R-HSA-1474228) | electronic |
| [Formation of definitive endoderm](https://reactome.org/content/detail/R-HSA-9823730) | electronic |
| [Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell](https://reactome.org/content/detail/R-HSA-198933) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** beta-catenin binding, ankyrin binding, GTPase activating protein binding, identical protein binding, gamma-catenin binding, cadherin binding.

**Biological process:** desmosome assembly, regulation of gene expression, negative regulation of cell-cell adhesion, negative regulation of cell migration, adherens junction organization, positive regulation of protein import into nucleus.

## Clinical significance {#significance}

**Likely benign** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2023-08-17.

**Submitter consensus:** conflicting (16 Likely benign, 3 Uncertain significance, 1 Benign, 1 not provided).

**Submission history:** 21 submissions (2016–2026); classifications have differed over time.

**ClinGen expert panel:** Likely Benign — CDH1 VCEP (CDH1-related diffuse gastric and lobular breast cancer). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `BS2`.
*Considered but not met:* `PM6`, `PM2`, `PVS1`, `PS1`, `PS2`, `PS3`, `PS4`, `PM1`, `PP1`, `PP2`, `PP3`, `PP4`, `PM3`, `BS1`, `BS4`, `BS3`, `BP5`, `BP7`, `PM5`, `BP4`, `BP3`, `BP1`, `BP2`, `BA1`, `PM4`.
Inheritance: Autosomal dominant inheritance.

> **Curation rationale (ClinGen, verbatim):** The c.8C>G (p.Pro3Arg) variant has an allele frequency of 0.00025 (39/155276) in gnomAD and is observed in multiple subpopulations, with a maximum frequency of 0.00072 (7/9712) in the European (Finnish) subpopulation (http://gnomad.broadinstitute.org). This variant was observed more than 70 probands without a personal history of DGC, SRC tumours or LBC and whose families do not meet HDGC clinical criteria (BS2; SCV000210891.12, SCV000186617.6).  The variant has also been identified in at least 5 individuals with LBC but whose families do not meet HDGC clinical criteria (PMID: 20921021, SCV000210891.12). This variant is located in the signal peptide of the E-cadherin pre-protein and would be predicted to impact membrane localization. However, localization to the plasma membrane was not affected when the variant was expressed in cells lacking endogenous expression of E-cadherin (PMID: 20921021). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50014 · approved 2023-08-17 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/e8086e46-6b34-49be-97a3-19ddcfa1b1db).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Sema4, Sema4 | Likely benign | criteria provided, single submitter | curation | 2021-04-12 |
| European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto | Likely benign | criteria provided, single submitter | clinical testing | 2022-08-01 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-31 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-09-13 |
| Color Diagnostics, LLC DBA Color Health | Likely benign | criteria provided, single submitter | clinical testing | 2020-05-11 |
| Centre for Mendelian Genomics, University Medical Centre Ljubljana | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-11-17 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2019-12-01 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | Likely benign | criteria provided, single submitter | clinical testing | 2021-01-06 |
| Myriad Genetics, Inc. | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-03-06 |
| Clingen Gastric Cancer Variant Curation Expert Panel | Likely benign | reviewed by expert panel | curation | 2023-08-17 |
| CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Likely benign | criteria provided, single submitter | clinical testing | 2022-12-08 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2021-02-18 |
| Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Likely benign | criteria provided, single submitter | clinical testing | 2025-03-04 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Likely benign | criteria provided, single submitter | clinical testing | 2023-03-10 |
| Counsyl | Uncertain significance | no assertion criteria provided | clinical testing | 2016-03-10 |
| Laboratory of Genetics, Children's Clinical University Hospital Latvia | Benign | criteria provided, single submitter | clinical testing | 2025-02-16 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2022-05-31 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2019-11-27 |
| GenomeConnect - Invitae Patient Insights Network | not provided | no classification provided | phenotyping only |  |
| Molecular Pathology, Peter Maccallum Cancer Centre | Likely benign | criteria provided, single submitter | clinical testing | 2024-03-19 |

## Associated conditions {#conditions}

[CDH1-related diffuse gastric and lobular breast cancer syndrome](https://sugi.bio/atlas/disease/cdh1-related-diffuse-gastric-and-lobular-breast-cancer-syndrome/), [endometrial carcinoma](https://sugi.bio/atlas/disease/endometrial-carcinoma/), [breast cancer](https://sugi.bio/atlas/disease/breast-cancer/), [hereditary diffuse gastric adenocarcinoma](https://sugi.bio/atlas/disease/hereditary-diffuse-gastric-adenocarcinoma/), [ovarian cancer](https://sugi.bio/atlas/disease/ovarian-cancer/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [hereditary breast carcinoma](https://sugi.bio/atlas/disease/hereditary-breast-carcinoma/).

**Reported phenotype names (ClinVar):** CDH1-related diffuse gastric and lobular breast cancer syndrome, Hereditary cancer-predisposing syndrome, Hereditary diffuse gastric adenocarcinoma, not specified, not provided, Endometrial carcinoma, Breast and/or ovarian cancer, Malignant tumor of breast, CDH1-related disorder, Familial cancer of breast.

## Same-residue context {#hotspot}

Residue **3** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CDH1 p.Pro3fs](/variant/cdh1-p-pro3fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CDH1 variant pages (same residue, condition, or type): [CDH1 p.Pro3Ser](/variant/cdh1-p-pro3ser), [CDH1 p.Pro3Thr](/variant/cdh1-p-pro3thr), [CDH1 p.Pro3=](/variant/cdh1-p-pro3), [CDH1 p.Pro3fs](/variant/cdh1-p-pro3fs), [CDH1 p.Pro3Phe](/variant/cdh1-p-pro3phe), [CDH1 c.1008+2T>C](/variant/cdh1-c-1008-plus-2t-c), [CDH1 c.1137+1G>A](/variant/cdh1-c-1137-plus-1g-a), [CDH1 c.1137+2T>C](/variant/cdh1-c-1137-plus-2t-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 142469). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*