# NM_001943.5(DSG2):c.630del (p.Phe211fs)

https://sugi.bio/variant/dsg2-p-phe211fs

## Summary

**DSG2 p.Phe211fs (c.630del)** is classified **Pathogenic** in DSG2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-08-30). No gnomAD frequency available for this variant; Associated with arrhythmogenic right ventricular dysplasia 10.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs2510911656 · 2 submitters · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the DSG2 gene that is considered disease-causing, submitted by 2 submitters, and is linked to arrhythmogenic right ventricular dysplasia 10.

*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) | No data available |
| Diagnostic panels | DSG2 is a diagnostic-grade gene on 5 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024865/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DSG2](https://sugi.bio/atlas/gene/DSG2/) |
| Protein change (HGVS p.) | p.Phe211fs |
| Coding change (HGVS c.) | c.630del |
| MANE Select transcript | [NM_001943](https://www.ncbi.nlm.nih.gov/nuccore/NM_001943) |
| dbSNP | [rs2510911656](https://www.ncbi.nlm.nih.gov/snp/rs2510911656/) |
| Variant type | Deletion |
| Location | chr18:31522189-31522189 (GRCh38) |
| ClinVar | [VCV1752786](https://www.ncbi.nlm.nih.gov/clinvar/variation/1752786/) |

**All HGVS expressions:** `LRG_397:g.28948del`, `LRG_397t1:c.630del`, `NC_000018.10:g.31522189del`, `NC_000018.9:g.29102152del`, `NG_007072.3:g.28948del`, `NM_001943.5:c.630del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 3.996, GERP -1.07, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.764, pLI 1.4607e-07. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 6 of 15**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion 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}

**DSG2** population constraint: LOEUF 0.764, pLI 1.4607e-07, missense-Z 1.3758; ClinGen dosage — haploinsufficiency 2, 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):

- **dilated cardiomyopathy 1BB** — Limited (AD)
- **arrhythmogenic right ventricular cardiomyopathy** — Definitive (AD)

## Protein context {#protein}

Residue **211** lies in the cadherin 2 domain; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 65.27, 43% of residues very-high.

**12 experimental structure(s)** (PDB): [2YQG](https://www.rcsb.org/structure/2YQG), [5ERD](https://www.rcsb.org/structure/5ERD), [5J5J](https://www.rcsb.org/structure/5J5J), [6QNT](https://www.rcsb.org/structure/6QNT), [6QNU](https://www.rcsb.org/structure/6QNU), [6SIT](https://www.rcsb.org/structure/6SIT).

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

*Describes the biological roles of DSG2 (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:** DSG2's established molecular role includes cell adhesion molecule binding. p.Phe211fs falls in the cadherin 2 domain.


### Pathways affected {#pathways}

DSG2 participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Apoptotic cleavage of cell adhesion  proteins](https://reactome.org/content/detail/R-HSA-351906) | curated |
| [Formation of the cornified envelope](https://reactome.org/content/detail/R-HSA-6809371) | curated |
| [Keratinization](https://reactome.org/content/detail/R-HSA-6805567) | curated |
| [RAC2 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013404) | curated |
| [RAC3 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013423) | curated |
| [RHOG GTPase cycle](https://reactome.org/content/detail/R-HSA-9013408) | curated |

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

**Molecular function:** cell adhesion molecule binding.

**Biological process:** desmosome organization, Purkinje myocyte development, cell adhesion, homophilic cell-cell adhesion, negative regulation of epithelial to mesenchymal transition, negative regulation of apoptotic process.

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2022-08-30.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2019–2022); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2019-01-17 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-08-30 |

## Associated conditions {#conditions}

[arrhythmogenic right ventricular dysplasia 10](https://sugi.bio/atlas/disease/arrhythmogenic-right-ventricular-dysplasia-10/).

**Reported phenotype names (ClinVar):** Arrhythmogenic right ventricular dysplasia 10, Cardiovascular phenotype, Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy10, ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 10, Arrhythmogenic right ventricular dysplasia/cardiomyopathy, type 10.

## Similar variants {#similar}

Related DSG2 variant pages (same residue, condition, or type): [DSG2 p.Phe211=](/variant/dsg2-p-phe211), [DSG2 c.2001_2001+5del](/variant/dsg2-c-2001-2001-plus-5del), [DSG2 c.523+1_523+2del](/variant/dsg2-c-523-plus-1-523-plus-2del), [DSG2 p.Asn462fs](/variant/dsg2-p-asn462fs), [DSG2 p.Leu171fs](/variant/dsg2-p-leu171fs), [DSG2 p.Thr31fs](/variant/dsg2-p-thr31fs), [DSG2 p.Val103fs](/variant/dsg2-p-val103fs), [DSG2 c.1423+5del](/variant/dsg2-c-1423-plus-5del).

### 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 1752786). 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.*