# NM_001792.5(CDH2):c.177_178dup (p.Phe60fs)

https://sugi.bio/variant/cdh2-p-phe60fs

## Summary

**CDH2 p.Phe60fs (c.177_178dup)** is classified **Uncertain significance** in CDH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-09). No gnomAD frequency available for this variant.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2510819090 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CDH2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CDH2](https://sugi.bio/atlas/gene/CDH2/) |
| Protein change (HGVS p.) | p.Phe60fs |
| Coding change (HGVS c.) | c.177_178dup |
| MANE Select transcript | [NM_001792](https://www.ncbi.nlm.nih.gov/nuccore/NM_001792) |
| dbSNP | [rs2510819090](https://www.ncbi.nlm.nih.gov/snp/rs2510819090/) |
| Variant type | Duplication |
| Location | chr18:28013903-28013904 (GRCh38) |
| ClinVar | [VCV2751344](https://www.ncbi.nlm.nih.gov/clinvar/variation/2751344/) |

**All HGVS expressions:** `NC_000018.10:g.28013904_28013905dup`, `NC_000018.9:g.25593868_25593869dup`, `NG_011959.1:g.168577_168578dup`, `NG_011959.2:g.168225_168226dup`, `NM_001308176.2:c.84_85dup`, `NM_001792.5:c.177_178dup`

## 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 11.251, GERP 1.61, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.336, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 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 duplication 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}

**CDH2** population constraint: LOEUF 0.336, pLI 1, missense-Z 2.8683. *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):

- **agenesis of corpus callosum, cardiac, ocular, and genital syndrome** — Definitive (AD)
- **dilated cardiomyopathy** — Limited (AD)
- **arrhythmogenic right ventricular cardiomyopathy** — Limited (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 79.68, 51% of residues very-high.

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

*Describes the biological roles of CDH2 (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:** CDH2's established molecular role includes beta-catenin binding.


### Pathways affected {#pathways}

CDH2 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Adherens junctions interactions](https://reactome.org/content/detail/R-HSA-418990) | curated |
| [Post-translational protein phosphorylation](https://reactome.org/content/detail/R-HSA-8957275) | curated |
| [Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)](https://reactome.org/content/detail/R-HSA-381426) | 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 |
| [Myogenesis](https://reactome.org/content/detail/R-HSA-525793) | electronic |

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

**Molecular function:** beta-catenin binding, alpha-catenin binding, gamma-catenin binding.

**Biological process:** cell-cell adhesion.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-08-09.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-08-09 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related CDH2 variant pages (same residue, condition, or type): [CDH2 p.Phe60Cys](/variant/cdh2-p-phe60cys), [CDH2 p.Ser788delinsThrTer](/variant/cdh2-p-ser788delinsthrter), [CDH2 c.702+2dup](/variant/cdh2-c-702-plus-2dup), [CDH2 p.Leu856fs](/variant/cdh2-p-leu856fs), [CDH2 p.Thr404Ter](/variant/cdh2-p-thr404ter), [CDH2 p.Asp859delinsValTer](/variant/cdh2-p-asp859delinsvalter), [CDH2 p.Asp906fs](/variant/cdh2-p-asp906fs), [CDH2 p.Glu390Ter](/variant/cdh2-p-glu390ter).

### 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 2751344). 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.*