# NM_001943.5(DSG2):c.1373G>T (p.Arg458Ile)

https://sugi.bio/variant/dsg2-p-arg458ile

## Summary

**DSG2 p.Arg458Ile (c.1373G>T)** is classified **Uncertain significance** in DSG2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-23). AlphaMissense: likely benign (0.141); Absent from gnomAD v4.1; Associated with arrhythmogenic right ventricular cardiomyopathy.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs2144339865 · 2 submitters · 2 linked conditions · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the DSG2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to arrhythmogenic right ventricular cardiomyopathy.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 37 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005847/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.Arg458Ile |
| Coding change (HGVS c.) | c.1373G>T |
| MANE Select transcript | [NM_001943](https://www.ncbi.nlm.nih.gov/nuccore/NM_001943) |
| dbSNP | [rs2144339865](https://www.ncbi.nlm.nih.gov/snp/rs2144339865/) |
| Variant type | single nucleotide variant |
| Location | chr18:31535362-31535362 (GRCh38) |
| ClinVar | [VCV1512439](https://www.ncbi.nlm.nih.gov/clinvar/variation/1512439/) |

**All HGVS expressions:** `LRG_397:g.42121G>T`, `NC_000018.10:g.31535362G>T`, `NC_000018.9:g.29115325G>T`, `NG_007072.3:g.42121G>T`, `NM_001943.5:c.1373G>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.141)
- REVEL 0.109 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -9.202 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor loss** (Δ 0.42) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 1.774, GERP -0.056, phastCons 1 — weakly conserved position
- CADD: **PHRED 18.05**. 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 0.93** across the covering region of the MANE Select transcript (31,498,252–31,546,740), spanning 48,488 bp. Chi-square p 0.014. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.42**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.42**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **458** lies in the cadherin 4 domain.

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.Arg458Ile falls in the cadherin 4 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-09-23.

**Submitter consensus:** conflicting (1 Uncertain Significance, 1 Uncertain significance).

**Submission history:** 2 submissions (2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| All of Us Research Program, National Institutes of Health | Uncertain Significance | criteria provided, single submitter | clinical testing | 2024-09-23 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-02-19 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related DSG2 variant pages (same residue, condition, or type): [DSG2 p.Arg458=](/variant/dsg2-p-arg458), [DSG2 p.Arg458_Gly463delinsSer](/variant/dsg2-p-arg458-gly463delinsser), [DSG2 c.1423+1G>T](/variant/dsg2-c-1423-plus-1g-t), [DSG2 c.1424-1G>A](/variant/dsg2-c-1424-minus-1g-a), [DSG2 c.523+1G>T](/variant/dsg2-c-523-plus-1g-t), [DSG2 c.690+1G>A](/variant/dsg2-c-690-plus-1g-a), [DSG2 c.81+1G>T](/variant/dsg2-c-81-plus-1g-t), [DSG2 c.829-2A>T](/variant/dsg2-c-829-minus-2a-t).

### 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 1512439). 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.*