# NM_001943.5(DSG2):c.3333C>G (p.Ser1111Arg)

https://sugi.bio/variant/dsg2-p-ser1111arg

## Summary

**DSG2 p.Ser1111Arg (c.3333C>G)** is classified **Uncertain significance** in DSG2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-03-11). AlphaMissense: likely pathogenic (0.5664); Very rare (popmax 0.00178%, nfe); Associated with Cardiovascular phenotype.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs143867223 · 3 submitters · 3 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.00178%, nfe)

## 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 3 submitters, and is linked to Cardiovascular phenotype.

*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 | [DSG2](https://sugi.bio/atlas/gene/DSG2/) |
| Protein change (HGVS p.) | p.Ser1111Arg |
| Coding change (HGVS c.) | c.3333C>G |
| MANE Select transcript | [NM_001943](https://www.ncbi.nlm.nih.gov/nuccore/NM_001943) |
| dbSNP | [rs143867223](https://www.ncbi.nlm.nih.gov/snp/rs143867223/) |
| Variant type | single nucleotide variant |
| Location | chr18:31546719-31546719 (GRCh38) |
| ClinVar | [VCV1171476](https://www.ncbi.nlm.nih.gov/clinvar/variation/1171476/) |

**All HGVS expressions:** `LRG_397:g.53478C>G`, `NC_000018.10:g.31546719C>G`, `NC_000018.9:g.29126682C>G`, `NG_007072.3:g.53478C>G`, `NM_001943.3:c.3333C>G`, `NM_001943.5:c.3333C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.5664)
- REVEL 0.407 (indeterminate)
- SaProt LLR -6.811 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL makes no call
- Conservation: phyloP 0.442, GERP -1.33, phastCons 0.486 — weakly conserved position
- CADD: **PHRED 19.01**. 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 (gnomAD v4.1): grpmax **0.00178%** (nfe) · FAF95 0.00114% · FAF99 0.000971% · 21/1,180,016 in the highest group · 21/1,461,842 alleles overall — very rare (popmax 0.00178%, nfe).

*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 **1111** lies in the 'disordered' region; a UniProt-annotated variant site (in arvd10; uncertain significance; evidence of residual myocardium, fibrous tissue, fatty tissue, dysmetric and dysmorphic nuclei and prominent cytoplasmic vacuolization; decreases the number of desmosomes at intercalated disks also increases desmosome gap; smaller intercellular gaps, with repeating couplings, abnormally located desmosomes and pale internal plaques); a UniProt-annotated variant site (in arvd10; uncertain significance).

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.Ser1111Arg falls in the disordered region.


### 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 2026-03-11.

**Submitter consensus:** conflicting (2 Uncertain significance, 1 Uncertain Significance).

**Submission history:** 3 submissions (2023–2026); 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 | 2023-11-02 |
| Color Diagnostics, LLC DBA Color Health | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-03-06 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-03-11 |

## Associated conditions {#conditions}

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

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

## 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.Asn266Ser](/variant/dsg2-p-asn266ser), [DSG2 p.Gln873Ter](/variant/dsg2-p-gln873ter), [DSG2 p.Ser314Ter](/variant/dsg2-p-ser314ter), [DSG2 p.Ser404Ter](/variant/dsg2-p-ser404ter), [DSG2 p.Tyr130Ter](/variant/dsg2-p-tyr130ter).

### 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 1171476). 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.*