# NM_024422.6(DSC2):c.942G>A (p.Glu314=)

https://sugi.bio/variant/dsc2-p-glu314

## Summary

**DSC2 p.Glu314= (c.942G>A)** is classified **Uncertain significance** in DSC2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-06-20). Very rare (popmax 8.47e-05%, nfe); Associated with familial isolated arrhythmogenic right ventricular dysplasia.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs2510951090 · 4 submitters · 3 linked conditions · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the DSC2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 4 submitters, and is linked to familial isolated arrhythmogenic right ventricular dysplasia.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | No data available |
| Diagnostic panels | DSC2 is a diagnostic-grade gene on 8 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017129/index) · [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.Glu314= |
| Coding change (HGVS c.) | c.942G>A |
| MANE Select transcript | [NM_024422](https://www.ncbi.nlm.nih.gov/nuccore/NM_024422) |
| dbSNP | [rs2510951090](https://www.ncbi.nlm.nih.gov/snp/rs2510951090/) |
| Variant type | single nucleotide variant |
| Location | chr18:31086576-31086576 (GRCh38) |
| ClinVar | [VCV2775185](https://www.ncbi.nlm.nih.gov/clinvar/variation/2775185/) |

**All HGVS expressions:** `LRG_400:g.20850G>A`, `LRG_400t1:c.942G>A`, `LRG_400t2:c.942G>A`, `NC_000018.10:g.31086576C>T`, `NC_000018.9:g.28666539C>T`, `NG_008208.2:g.20850G>A`, `NM_001406506.1:c.513G>A`, `NM_001406507.1:c.513G>A`, `NM_004949.5:c.942G>A`, `NM_024422.6:c.942G>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.94) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 4.851, GERP 0.259, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 21.9**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.94**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.94**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.72** (loss), gain 0.01 / loss 0.72. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **8.47e-05%** (nfe) · 1/1,179,942 in the highest group · 1/1,461,794 alleles overall — very rare (popmax 8.47e-05%, 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}

**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 **314** lies in a turn; 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-06-20.

**Submitter consensus:** conflicting (3 Uncertain significance, 1 Uncertain Significance).

**Submission history:** 4 submissions (2021–2025); 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 | 2024-05-09 |
| Color Diagnostics, LLC DBA Color Health | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-08-30 |
| Laboratory of Genetics, Children's Clinical University Hospital Latvia | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-02-16 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-06-20 |

## Associated conditions {#conditions}

[familial isolated arrhythmogenic right ventricular dysplasia](https://sugi.bio/atlas/disease/familial-isolated-arrhythmogenic-right-ventricular-dysplasia/), [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):** Familial isolated arrhythmogenic right ventricular dysplasia, Cardiomyopathy, not specified, Arrhythmogenic right ventricular dysplasia 11, ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 11, Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy11, Arrhythmogenic right ventricular dysplasia 11 with mild palmoplantar keratoderma and woolly hair, AllHighlyPenetrant, Cardiomyopathies.

## Similar variants {#similar}

Related DSC2 variant pages (same residue, condition, or type): [DSC2 p.Glu314Lys](/variant/dsc2-p-glu314lys), [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), [DSC2 p.Glu127Ter](/variant/dsc2-p-glu127ter), [DSC2 p.Glu593Ter](/variant/dsc2-p-glu593ter).

### 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 2775185). 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.*