# NM_001943.5(DSG2):c.1496T>C (p.Leu499Pro)

https://sugi.bio/variant/dsg2-p-leu499pro

## Summary

**DSG2 p.Leu499Pro (c.1496T>C)** is classified **Uncertain significance** in DSG2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-13). AlphaMissense: likely pathogenic (0.7821); Absent from gnomAD v4.1; Associated with arrhythmogenic right ventricular cardiomyopathy.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs2510917845 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · 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.Leu499Pro |
| Coding change (HGVS c.) | c.1496T>C |
| MANE Select transcript | [NM_001943](https://www.ncbi.nlm.nih.gov/nuccore/NM_001943) |
| dbSNP | [rs2510917845](https://www.ncbi.nlm.nih.gov/snp/rs2510917845/) |
| Variant type | single nucleotide variant |
| Location | chr18:31536274-31536274 (GRCh38) |
| ClinVar | [VCV2300621](https://www.ncbi.nlm.nih.gov/clinvar/variation/2300621/) |

**All HGVS expressions:** `LRG_397:g.43033T>C`, `LRG_397t1:c.1496T>C`, `NC_000018.10:g.31536274T>C`, `NC_000018.9:g.29116237T>C`, `NG_007072.3:g.43033T>C`, `NM_001943.5:c.1496T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.7821)
- REVEL 0.607 (indeterminate)
- SaProt LLR -15.057 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP 7.785, GERP 1.76, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 23.6**. 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: **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: **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 **499** lies in a β-strand; 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.Leu499Pro 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 2023-12-13.

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

**Submission history:** 2 submissions (2022–2023); 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 | 2023-12-13 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-07-12 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Arrhythmogenic right ventricular cardiomyopathy, Cardiovascular phenotype, Arrhythmogenic right ventricular dysplasia, Cardiomyopathy, ARVC, Arrhythmogenic cardiomyopathy, Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC).

## Similar variants {#similar}

Related DSG2 variant pages (same residue, condition, or type): [DSG2 p.Arg46Gln](/variant/dsg2-p-arg46gln), [DSG2 p.Arg46Trp](/variant/dsg2-p-arg46trp), [DSG2 p.Arg49His](/variant/dsg2-p-arg49his), [DSG2 p.Ser314Ter](/variant/dsg2-p-ser314ter), [DSG2 p.Tyr130Ter](/variant/dsg2-p-tyr130ter), [DSG2 p.Tyr783Ter](/variant/dsg2-p-tyr783ter), [DSG2 c.216+2T>C](/variant/dsg2-c-216-plus-2t-c), [DSG2 c.216+3A>C](/variant/dsg2-c-216-plus-3a-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 2300621). 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.*