# NM_004360.5(CDH1):c.88C>A (p.Pro30Thr)

https://sugi.bio/variant/cdh1-p-pro30thr

## Summary

**CDH1 p.Pro30Thr (c.88C>A)** is classified **Benign** in CDH1 (ClinVar, Expert panel, 28 submitters; last evaluated 2023-08-17). AlphaMissense: likely benign (0.147); Rare (popmax 0.257%, nfe); Associated with CDH1-related diffuse gastric and lobular breast cancer syndrome.

**At a glance:** Benign · review: Expert panel · rsID rs139866691 · 28 submitters · 9 linked conditions · AlphaMissense likely benign · rare (popmax 0.257%, nfe)

## For patients & families {#patients}

This is a change in the CDH1 gene that is classified as benign — not considered disease-causing, submitted by 28 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.Pro30Thr |
| Coding change (HGVS c.) | c.88C>A |
| MANE Select transcript | [NM_004360](https://www.ncbi.nlm.nih.gov/nuccore/NM_004360) |
| dbSNP | [rs139866691](https://www.ncbi.nlm.nih.gov/snp/rs139866691/) |
| Variant type | single nucleotide variant |
| Location | chr16:68738336-68738336 (GRCh38) |
| ClinVar | [VCV127933](https://www.ncbi.nlm.nih.gov/clinvar/variation/127933/) |

**All HGVS expressions:** `LRG_301:g.6045C>A`, `LRG_301t1:c.88C>A`, `NC_000016.10:g.68738336C>A`, `NC_000016.9:g.68772239C>A`, `NG_008021.1:g.6045C>A`, `NM_001317184.2:c.88C>A`, `NM_001317185.2:c.-1528C>A`, `NM_001317186.2:c.-1732C>A`, `NM_004360.5:c.88C>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.147)
- REVEL 0.586 (indeterminate)
- SaProt LLR -11.231 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL makes no call
- Conservation: phyloP 1.377, GERP -0.039, phastCons 0.626 — weakly conserved position
- CADD: **PHRED 20.5**. 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 **0.257%** (nfe) · FAF95 0.249% · FAF99 0.246% · 2,927/1,137,734 in the highest group · 3,158/1,531,846 alleles overall — rare (popmax 0.257%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.257% | 389 |
| Remaining individuals (not grpmax-eligible) | 0.163% | 613 |
| Admixed American | 0.106% | 943 |
| South Asian | 0.0486% | 2,059 |
| Finnish (not grpmax-eligible) | 0.0389% | 2,569 |
| African / African-American | 0.026% | 3,847 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00354% | 28,278 |

*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}

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

**Submitter consensus:** conflicting (14 Likely benign, 11 Benign, 2 Uncertain significance, 1 not provided).

**Submission history:** 28 submissions (2013–2026); classifications have differed over time.

**ClinGen expert panel:** 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`, `BA1`.
*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`, `PM4`.
Inheritance: Autosomal dominant inheritance.

> **Curation rationale (ClinGen, verbatim):** The c.88C>A (p.Pro30Thr) variant has an allele frequency of 0.00249 (0.25%, 178/71372 alleles) in the European (non-Finnish) subpopulation of the gnomAD cohort (BA1). In addition to meeting stand along criteria for a benign classification, this variant has also been seen in >900 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors).  In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, 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/d1e6757d-87b2-428c-a699-e2ac2893485c).*
*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 |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Likely benign | criteria provided, single submitter | clinical testing | 2016-10-05 |
| Mendelics | Likely benign | criteria provided, single submitter | clinical testing | 2019-05-28 |
| Sema4, Sema4 | Benign | criteria provided, single submitter | curation | 2020-10-22 |
| Clingen Gastric Cancer Variant Curation Expert Panel | Benign | reviewed by expert panel | curation | 2023-08-17 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | Benign | criteria provided, single submitter | clinical testing | 2022-11-15 |
| ITMI | not provided | no classification provided | reference population | 2013-09-19 |
| CSER _CC_NCGL, University of Washington | Likely benign | no assertion criteria provided | research | 2014-06-01 |
| Knight Diagnostic Laboratories, Oregon Health and Sciences University | Uncertain significance | no assertion criteria provided | clinical testing | 2016-01-27 |
| Color Diagnostics, LLC DBA Color Health | Likely benign | criteria provided, single submitter | clinical testing | 2015-10-27 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Likely benign | criteria provided, single submitter | clinical testing | 2016-03-29 |
| True Health Diagnostics | Likely benign | no assertion criteria provided | clinical testing | 2017-07-17 |
| PreventionGenetics, part of Exact Sciences | Likely benign | criteria provided, single submitter | clinical testing | 2017-03-31 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2020-01-23 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Likely benign | no assertion criteria provided | clinical testing |  |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-04-19 |
| European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto | Benign | criteria provided, single submitter | clinical testing | 2022-08-01 |
| CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Likely benign | criteria provided, single submitter | clinical testing | 2023-01-18 |
| Ambry Genetics | Benign | criteria provided, single submitter | clinical testing | 2014-08-07 |
| Counsyl | Likely benign | no assertion criteria provided | clinical testing | 2016-05-27 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Benign | criteria provided, single submitter | clinical testing | 2025-01-17 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| CeGaT Center for Human Genetics Tuebingen | Benign | criteria provided, single submitter | clinical testing | 2026-04-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-26 |
| Mayo Clinic Laboratories, Mayo Clinic | Uncertain significance | no assertion criteria provided | clinical testing |  |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2017-04-27 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2020-07-28 |
| Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Benign | criteria provided, single submitter | clinical testing | 2025-03-04 |
| Myriad Genetics, Inc. | Benign | criteria provided, single submitter | clinical testing | 2025-01-16 |

## 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/), [orofacial cleft](https://sugi.bio/atlas/disease/orofacial-cleft/), [endometrial carcinoma](https://sugi.bio/atlas/disease/endometrial-carcinoma/), [hereditary diffuse gastric adenocarcinoma](https://sugi.bio/atlas/disease/hereditary-diffuse-gastric-adenocarcinoma/), [prostate cancer](https://sugi.bio/atlas/disease/prostate-cancer/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [hereditary breast carcinoma](https://sugi.bio/atlas/disease/hereditary-breast-carcinoma/), [ovarian neoplasm](https://sugi.bio/atlas/disease/ovarian-neoplasm/), [blepharocheilodontic syndrome 1](https://sugi.bio/atlas/disease/blepharocheilodontic-syndrome-1/).

**Reported phenotype names (ClinVar):** CDH1-related diffuse gastric and lobular breast cancer syndrome, Hereditary cancer-predisposing syndrome, not specified, Hereditary diffuse gastric adenocarcinoma, Orofacial cleft, not provided, Breast and/or ovarian cancer, Blepharocheilodontic syndrome 1, Endometrial carcinoma, Familial cancer of breast.

## Same-residue context {#hotspot}

Residue **30** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CDH1 p.Pro30fs](/variant/cdh1-p-pro30fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CDH1 variant pages (same residue, condition, or type): [CDH1 p.Pro30Arg](/variant/cdh1-p-pro30arg), [CDH1 p.Pro30Ser](/variant/cdh1-p-pro30ser), [CDH1 p.Pro30=](/variant/cdh1-p-pro30), [CDH1 p.Pro30fs](/variant/cdh1-p-pro30fs), [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), [CDH1 c.1320+1G>C](/variant/cdh1-c-1320-plus-1g-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 127933). 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.*