# NM_001943.5(DSG2):c.2586T>C (p.Ser862=)

https://sugi.bio/variant/dsg2-p-ser862

## Summary

**DSG2 p.Ser862= (c.2586T>C)** is classified **Benign/Likely benign** in DSG2 (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-02-03). Rare (popmax 0.887%, afr); Associated with arrhythmogenic right ventricular cardiomyopathy.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs78310842 · 13 submitters · 3 linked conditions · rare (popmax 0.887%, afr)

## For patients & families {#patients}

This is a change in the DSG2 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 13 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.Ser862= |
| Coding change (HGVS c.) | c.2586T>C |
| dbSNP | [rs78310842](https://www.ncbi.nlm.nih.gov/snp/rs78310842/) |
| Variant type | single nucleotide variant |
| Location | chr18:31545972-31545972 (GRCh38) |
| ClinVar | [VCV44303](https://www.ncbi.nlm.nih.gov/clinvar/variation/44303/) |

**All HGVS expressions:** `LRG_397:g.52731T>C`, `LRG_397t1:c.2586T>C`, `NC_000018.10:g.31545972T>C`, `NC_000018.9:g.29125935T>C`, `NG_007072.3:g.52731T>C`, `NM_001943.5:c.2586T>C`

## 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 -6.864 — fast-evolving / accelerated position
- CADD: **PHRED 0.245**. 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.*
- SpliceAI: **not looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency (gnomAD v4.1): grpmax **0.887%** (afr) · FAF95 0.831% · FAF99 0.809% · 666/75,058 in the highest group · 770/1,614,180 alleles overall — rare (popmax 0.887%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.887% | 113 |
| Admixed American | 0.0966% | 1,035 |
| Middle Eastern | 0.066% | 1,516 |
| Remaining individuals (not grpmax-eligible) | 0.048% | 2,084 |
| East Asian | 0.00223% | 44,886 |
| South Asian | 0.0011% | 91,084 |
| European (non-Finnish) | 0.000847% | 118,002 |

*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.*

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-03.

**Submitter consensus:** conflicting (10 Benign, 3 Likely benign).

**Submission history:** 13 submissions (2012–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Benign | criteria provided, single submitter | clinical testing | 2012-02-09 |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Likely benign | no assertion criteria provided | clinical testing |  |
| Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Benign | criteria provided, single submitter | clinical testing | 2025-04-09 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-03 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2013-05-29 |
| Color Diagnostics, LLC DBA Color Health | Benign | criteria provided, single submitter | clinical testing | 2018-06-04 |
| Clinical Genetics, Academic Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Benign | criteria provided, single submitter | clinical testing | 2023-06-07 |
| All of Us Research Program, National Institutes of Health | Benign | criteria provided, single submitter | clinical testing | 2024-02-05 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2024-07-31 |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-09-04 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Arrhythmogenic right ventricular cardiomyopathy, not specified, Arrhythmogenic right ventricular dysplasia 10, Cardiomyopathy, not provided, AllHighlyPenetrant, none provided, Cardiomyopathy, ARVC, Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), Arrhythmogenic right ventricular dysplasia.

### 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 44303). 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.*