# NM_004360.5(CDH1):c.1315_1316delinsCAA (p.Ala439fs)

https://sugi.bio/variant/cdh1-p-ala439fs

## Summary

**CDH1 p.Ala439fs (c.1315_1316delinsCAA)** is classified **Pathogenic** in CDH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-13). No gnomAD frequency available for this variant; Associated with hereditary diffuse gastric adenocarcinoma.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2543927284 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CDH1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to hereditary diffuse gastric adenocarcinoma.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Adult |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 5 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CDH1 is a diagnostic-grade gene on 8 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010900/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.Ala439fs |
| Coding change (HGVS c.) | c.1315_1316delinsCAA |
| MANE Select transcript | [NM_004360](https://www.ncbi.nlm.nih.gov/nuccore/NM_004360) |
| dbSNP | [rs2543927284](https://www.ncbi.nlm.nih.gov/snp/rs2543927284/) |
| Variant type | Indel |
| Location | chr16:68813490-68813491 (GRCh38) |
| ClinVar | [VCV2583762](https://www.ncbi.nlm.nih.gov/clinvar/variation/2583762/) |

**All HGVS expressions:** `LRG_301:g.81199_81200delinsCAA`, `LRG_301t1:c.1315_1316delGCinsCAA`, `NC_000016.10:g.68813490_68813491delinsCAA`, `NC_000016.9:g.68847393_68847394delinsCAA`, `NG_008021.1:g.81199_81200delinsCAA`, `NM_001317184.2:c.1137+1227_1137+1228delinsCAA`, `NM_001317185.2:c.-301_-300delinsCAA`, `NM_001317186.2:c.-505_-504delinsCAA`, `NM_004360.5:c.1315_1316delinsCAA`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 1.055, GERP -0.187, phastCons 0.012 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 9 of 16**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no indel variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

Residue **439** lies in the cadherin 3 domain; a β-strand.

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. p.Ala439fs falls in the cadherin 3 domain. 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}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-06-13.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Myriad Genetics, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2023-06-13 |

## Associated conditions {#conditions}

[hereditary diffuse gastric adenocarcinoma](https://sugi.bio/atlas/disease/hereditary-diffuse-gastric-adenocarcinoma/).

**Reported phenotype names (ClinVar):** Hereditary diffuse gastric adenocarcinoma, DIFFUSE GASTRIC AND LOBULAR BREAST CANCER SYNDROME.

## Similar variants {#similar}

Related CDH1 variant pages (same residue, condition, or type): [CDH1 p.Ala439Glu](/variant/cdh1-p-ala439glu), [CDH1 p.Ala439=](/variant/cdh1-p-ala439), [CDH1 p.Ala439Thr](/variant/cdh1-p-ala439thr), [CDH1 p.Pro42fs](/variant/cdh1-p-pro42fs), [CDH1 p.Asp514_Thr522delinsValTer](/variant/cdh1-p-asp514-thr522delinsvalter), [CDH1 p.Ala137Arg](/variant/cdh1-p-ala137arg), [CDH1 p.Asp805Ser](/variant/cdh1-p-asp805ser), [CDH1 p.His121_His122delinsGlnAsp](/variant/cdh1-p-his121-his122delinsglnasp).

### 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 2583762). 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.*