# NM_024422.6(DSC2):c.1788G>A (p.Ala596=)

https://sugi.bio/variant/dsc2-p-ala596

## Summary

**DSC2 p.Ala596= (c.1788G>A)** is classified **Conflicting classifications of pathogenicity** in DSC2 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-01-28). Ultra-rare (popmax 0.0158%, nfe); Associated with cardiomyopathy.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs146161960 · 10 submitters · 3 linked conditions · ultra-rare (popmax 0.0158%, nfe)

## 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 10 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.Ala596= |
| Coding change (HGVS c.) | c.1788G>A |
| MANE Select transcript | [NM_024422](https://www.ncbi.nlm.nih.gov/nuccore/NM_024422) |
| dbSNP | [rs146161960](https://www.ncbi.nlm.nih.gov/snp/rs146161960/) |
| Variant type | single nucleotide variant |
| Location | chr18:31074783-31074783 (GRCh38) |
| ClinVar | [VCV326397](https://www.ncbi.nlm.nih.gov/clinvar/variation/326397/) |

**All HGVS expressions:** `LRG_400:g.32643G>A`, `NC_000018.10:g.31074783C>T`, `NC_000018.9:g.28654749C>T`, `NG_008208.2:g.32643G>A`, `NM_004949.5:c.1788G>A`, `NM_024422.6:c.1788G>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 -2.312, GERP -4.01 — fast-evolving / accelerated position
- CADD: **PHRED 0.746**. 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 assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0158%** (nfe) · FAF95 0.0139% · FAF99 0.0133% · 187/1,179,972 in the highest group · 225/1,613,970 alleles overall — ultra-rare (popmax 0.0158%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0192% | 5,208 |
| European (non-Finnish) (grpmax) | 0.0158% | 6,310 |
| South Asian | 0.0154% | 6,505 |
| African / African-American | 0.00933% | 10,715 |
| Finnish (not grpmax-eligible) | 0.00469% | 21,336 |
| East Asian | 0.00446% | 22,422 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **596** lies in the cadherin 5 domain; a UniProt-annotated variant site (in arvd11; likely pathogenic; mislocalization of dsc2 to the cytoplasm within intercalated disks of the heart); a UniProt-annotated variant site (in).

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 2026-01-28.

**Submitter consensus:** conflicting (6 Likely benign, 2 Benign, 1 Uncertain significance, 1 Likely Benign).

**Submission history:** 10 submissions (2012–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Benign | criteria provided, single submitter | clinical testing | 2017-12-01 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Likely benign | criteria provided, single submitter | clinical testing | 2012-03-19 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2020-12-06 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-02-07 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2019-01-28 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2020-06-21 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-28 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Color Diagnostics, LLC DBA Color Health | Likely benign | criteria provided, single submitter | clinical testing | 2018-12-13 |
| All of Us Research Program, National Institutes of Health | Likely Benign | criteria provided, single submitter | clinical testing | 2023-12-13 |

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

**Reported phenotype names (ClinVar):** Cardiomyopathy, not specified, Arrhythmogenic right ventricular dysplasia 11, not provided, Cardiovascular phenotype, Familial isolated arrhythmogenic right ventricular dysplasia, Cardiomyopathies, Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy11, ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 11, Arrhythmogenic right ventricular dysplasia 11 with mild palmoplantar keratoderma and woolly hair.

## Similar variants {#similar}

Related DSC2 variant pages (same residue, condition, or type): [DSC2 p.Ala596Thr](/variant/dsc2-p-ala596thr), [DSC2 p.Ala596Pro](/variant/dsc2-p-ala596pro), [DSC2 p.Ala596Val](/variant/dsc2-p-ala596val), [DSC2 p.Ala596Gly](/variant/dsc2-p-ala596gly), [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).

### 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 326397). 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.*