# NM_024422.6(DSC2):c.1521G>A (p.Arg507=)

https://sugi.bio/variant/dsc2-p-arg507

## Summary

**DSC2 p.Arg507= (c.1521G>A)** is classified **Conflicting classifications of pathogenicity** in DSC2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-10-12). Ultra-rare (popmax 0.03%, amr); Associated with Cardiovascular phenotype.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs1444350890 · 4 submitters · 3 linked conditions · ultra-rare (popmax 0.03%, amr)

## For patients & families {#patients}

This is a change in the DSC2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 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 | [DSC2](https://sugi.bio/atlas/gene/DSC2/) |
| Protein change (HGVS p.) | p.Arg507= |
| Coding change (HGVS c.) | c.1521G>A |
| MANE Select transcript | [NM_024422](https://www.ncbi.nlm.nih.gov/nuccore/NM_024422) |
| dbSNP | [rs1444350890](https://www.ncbi.nlm.nih.gov/snp/rs1444350890/) |
| Variant type | single nucleotide variant |
| Location | chr18:31079989-31079989 (GRCh38) |
| ClinVar | [VCV1723419](https://www.ncbi.nlm.nih.gov/clinvar/variation/1723419/) |

**All HGVS expressions:** `LRG_400:g.27437G>A`, `LRG_400t1:c.1521G>A`, `LRG_400t2:c.1521G>A`, `NC_000018.10:g.31079989C>T`, `NC_000018.9:g.28659955C>T`, `NG_008208.2:g.27437G>A`, `NM_001406506.1:c.1092G>A`, `NM_001406507.1:c.1092G>A`, `NM_004949.5:c.1521G>A`, `NM_024422.3:c.1521G>A`, `NM_024422.6:c.1521G>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 (below), not from a missing predictor score.
- Conservation: phyloP -2.729, GERP -4.01 — fast-evolving / accelerated position
- CADD: **PHRED 12.18**. 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 (C>A, Δ0.40 acceptor 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 (gnomAD v4.1): grpmax **0.03%** (amr) · FAF95 0.0194% · FAF99 0.016% · 18/59,966 in the highest group · 23/1,613,176 alleles overall — ultra-rare (popmax 0.03%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.03% | 3,331 |
| European (non-Finnish) | 0.000424% | 235,929 |

*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 1/3, triplosensitivity 0/3. *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 **507** lies in the cadherin 4 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-10-12.

**Submitter consensus:** conflicting (2 Uncertain significance, 2 Likely benign).

**Submission history:** 4 submissions (2022–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-10-28 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2025-08-03 |
| Color Diagnostics, LLC DBA Color Health | Likely benign | criteria provided, single submitter | clinical testing | 2025-03-28 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-10-12 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/), [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):** Cardiovascular phenotype, not specified, Arrhythmogenic right ventricular dysplasia 11, Cardiomyopathy, Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy11, ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 11, 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.Arg507Lys](/variant/dsc2-p-arg507lys), [DSC2 p.Arg507Thr](/variant/dsc2-p-arg507thr), [DSC2 c.1521-1G>A](/variant/dsc2-c-1521-minus-1g-a), [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 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 1723419). 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.*