# NM_024422.6(DSC2):c.408A>G (p.Arg136=)

https://sugi.bio/variant/dsc2-p-arg136

## Summary

**DSC2 p.Arg136= (c.408A>G)** is classified **Conflicting classifications of pathogenicity** in DSC2 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-01-19). Ultra-rare (popmax 0.0334%, eas); Associated with Cardiovascular phenotype.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs561653481 · 9 submitters · 4 linked conditions · ultra-rare (popmax 0.0334%, eas)

## 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 9 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.Arg136= |
| Coding change (HGVS c.) | c.408A>G |
| MANE Select transcript | [NM_024422](https://www.ncbi.nlm.nih.gov/nuccore/NM_024422) |
| dbSNP | [rs561653481](https://www.ncbi.nlm.nih.gov/snp/rs561653481/) |
| Variant type | single nucleotide variant |
| Location | chr18:31091094-31091094 (GRCh38) |
| ClinVar | [VCV234987](https://www.ncbi.nlm.nih.gov/clinvar/variation/234987/) |

**All HGVS expressions:** `LRG_400:g.16332A>G`, `NC_000018.10:g.31091094T>C`, `NC_000018.9:g.28671057T>C`, `NG_008208.2:g.16332A>G`, `NM_004949.5:c.408A>G`, `NM_024422.6:c.408A>G`

## 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 **acceptor loss** (Δ 0.24) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 3.429, GERP 2.01, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 14.0**. 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 **0.24**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.06**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.24**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.06**.
- Population frequency (gnomAD v4.1): grpmax **0.0334%** (eas) · FAF95 0.0206% · FAF99 0.0166% · 15/44,866 in the highest group · 53/1,614,066 alleles overall — ultra-rare (popmax 0.0334%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0334% | 2,991 |
| South Asian | 0.0143% | 7,007 |
| Remaining individuals (not grpmax-eligible) | 0.0128% | 7,813 |
| European (non-Finnish) | 0.00144% | 69,409 |

*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 **136** lies in the cadherin 1 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 2026-01-19.

**Submitter consensus:** conflicting (4 Uncertain significance, 2 Likely benign, 1 Benign, 1 Likely Benign).

**Submission history:** 10 submissions (2014–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-09-09 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-04-20 |
| Ambry Genetics | Benign | criteria provided, single submitter | clinical testing | 2021-08-04 |
| Color Diagnostics, LLC DBA Color Health | Likely benign | criteria provided, single submitter | clinical testing | 2023-12-05 |
| Stanford Center for Inherited Cardiovascular Disease, Stanford University | Uncertain significance | criteria provided, single submitter | provider interpretation | 2014-05-16 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-01-23 |
| All of Us Research Program, National Institutes of Health | Likely Benign | criteria provided, single submitter | clinical testing | 2024-01-11 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-19 |

## 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/), [familial isolated arrhythmogenic right ventricular dysplasia](https://sugi.bio/atlas/disease/familial-isolated-arrhythmogenic-right-ventricular-dysplasia/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, not specified, Arrhythmogenic right ventricular dysplasia 11, Cardiomyopathy, Familial isolated arrhythmogenic right ventricular dysplasia, not provided, Gastric cancer, Malignant tumor of esophagus, AllHighlyPenetrant, none provided.

## Same-residue context {#hotspot}

Residue **136** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [DSC2 p.Arg136fs](/variant/dsc2-p-arg136fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related DSC2 variant pages (same residue, condition, or type): [DSC2 p.Arg136Ser](/variant/dsc2-p-arg136ser), [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), [DSC2 p.Glu127Ter](/variant/dsc2-p-glu127ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 234987). 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.*