# NM_024422.6(DSC2):c.1041T>C (p.Asp347=)

https://sugi.bio/variant/dsc2-p-asp347

## Summary

**DSC2 p.Asp347= (c.1041T>C)** is classified **Likely benign** in DSC2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-07). No allele count reported in gnomAD v4.1 (AN 1,613,616); Associated with cardiomyopathy.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs758394251 · 3 submitters · 2 linked conditions · no allele count reported in gnomAD v4.1 (AN 1,613,616)

## For patients & families {#patients}

This is a change in the DSC2 gene that is classified as likely benign — not considered disease-causing, submitted by 3 submitters, and is linked to 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 | 333 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DSC2](https://sugi.bio/atlas/gene/DSC2/) |
| Protein change (HGVS p.) | p.Asp347= |
| Coding change (HGVS c.) | c.1041T>C |
| MANE Select transcript | [NM_024422](https://www.ncbi.nlm.nih.gov/nuccore/NM_024422) |
| dbSNP | [rs758394251](https://www.ncbi.nlm.nih.gov/snp/rs758394251/) |
| Variant type | single nucleotide variant |
| Location | chr18:31082962-31082962 (GRCh38) |
| ClinVar | [VCV798582](https://www.ncbi.nlm.nih.gov/clinvar/variation/798582/) |

**All HGVS expressions:** `LRG_400:g.24464T>C`, `NC_000018.10:g.31082962A>G`, `NC_000018.9:g.28662928A>G`, `NG_008208.2:g.24464T>C`, `NM_004949.5:c.1041T>C`, `NM_024422.6:c.1041T>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 0.496, GERP -3.68, phastCons 0.796 — weakly conserved position
- CADD: **PHRED 3.979**. 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: **below the reporting threshold**. This position is scored for a different substitution (A>C, Δ0.98 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency: **no allele count reported in gnomAD v4.1 (AN 1,613,616)** — 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}

**DSC2** population constraint: LOEUF 0.743, pLI 7.7585e-10, missense-Z 0.84916; ClinGen dosage — haploinsufficiency 1, 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):

- **familial isolated arrhythmogenic right ventricular dysplasia** — Definitive (AD)

## Protein context {#protein}

Residue **347** lies in the cadherin 2 domain.

AlphaFold model confidence (whole protein): pLDDT 77.26, 49% of residues very-high.

**3 experimental structure(s)** (PDB): [5ERP](https://www.rcsb.org/structure/5ERP), [5J5J](https://www.rcsb.org/structure/5J5J), [7A7D](https://www.rcsb.org/structure/7A7D).

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

*Describes the biological roles of DSC2 (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.*


### Pathways affected {#pathways}

DSC2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Formation of the cornified envelope](https://reactome.org/content/detail/R-HSA-6809371) | curated |
| [Keratinization](https://reactome.org/content/detail/R-HSA-6805567) | curated |

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

**Biological process:** cardiac muscle cell-cardiac muscle cell adhesion, bundle of His cell-Purkinje myocyte adhesion involved in cell communication, regulation of heart rate by cardiac conduction, regulation of ventricular cardiac muscle cell action potential, positive regulation of p38MAPK cascade.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-07.

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2020–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Color Diagnostics, LLC DBA Color Health | Likely benign | criteria provided, single submitter | clinical testing | 2020-11-17 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-05-14 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-07 |

## Associated conditions {#conditions}

[cardiomyopathy](https://sugi.bio/atlas/disease/cardiomyopathy/), [arrhythmogenic right ventricular dysplasia 11](https://sugi.bio/atlas/disease/arrhythmogenic-right-ventricular-dysplasia-11/).

**Reported phenotype names (ClinVar):** Cardiomyopathy, Arrhythmogenic right ventricular dysplasia 11, Cardiovascular phenotype, Cardiomyopathies, Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy11, ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 11, Arrhythmogenic right ventricular dysplasia 11 with mild palmoplantar keratoderma and woolly hair.

## Same-residue context {#hotspot}

Residue **347** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [DSC2 p.Asp347fs](/variant/dsc2-p-asp347fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related DSC2 variant pages (same residue, condition, or type): [DSC2 p.Asp347Tyr](/variant/dsc2-p-asp347tyr), [DSC2 p.Asp347Gly](/variant/dsc2-p-asp347gly), [DSC2 p.Asp347fs](/variant/dsc2-p-asp347fs), [DSC2 c.1664-1G>A](/variant/dsc2-c-1664-minus-1g-a), [DSC2 c.354+2T>A](/variant/dsc2-c-354-plus-2t-a), [DSC2 c.355-1G>A](/variant/dsc2-c-355-minus-1g-a), [DSC2 p.Gln554Ter](/variant/dsc2-p-gln554ter), [DSC2 p.Gln620Ter](/variant/dsc2-p-gln620ter).

### 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 798582). 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.*