# NM_024422.6(DSC2):c.993G>C (p.Gln331His)

https://sugi.bio/variant/dsc2-p-gln331his

## Summary

**DSC2 p.Gln331His (c.993G>C)** is classified **Uncertain significance** in DSC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-25). AlphaMissense: likely pathogenic (0.7529); No allele count reported in gnomAD v4.1 (AN 1,613,378); Associated with cardiomyopathy.

**At a glance:** Uncertain significance · review: Multiple submitters · 2 submitters · 2 linked conditions · AlphaMissense likely pathogenic · no allele count reported in gnomAD v4.1 (AN 1,613,378)

## 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 2 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.Gln331His |
| Coding change (HGVS c.) | c.993G>C |
| MANE Select transcript | [NM_024422](https://www.ncbi.nlm.nih.gov/nuccore/NM_024422) |
| Variant type | single nucleotide variant |
| Location | chr18:31083010-31083010 (GRCh38) |
| ClinVar | [VCV3386539](https://www.ncbi.nlm.nih.gov/clinvar/variation/3386539/) |

**All HGVS expressions:** `LRG_400:g.24416G>C`, `LRG_400t1:c.993G>C`, `LRG_400t2:c.993G>C`, `NC_000018.10:g.31083010C>G`, `NC_000018.9:g.28662976C>G`, `NG_008208.2:g.24416G>C`, `NM_001406506.1:c.564G>C`, `NM_001406507.1:c.564G>C`, `NM_004949.5:c.993G>C`, `NM_024422.6:c.993G>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.7529)
- REVEL 0.279 (benign-leaning) — differs from AlphaMissense
- SaProt LLR -7.96 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; REVEL and SaProt do not
- SpliceAI predicts **donor loss** (Δ 0.24) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP -5.446, GERP -3.68 — fast-evolving / accelerated position
- CADD: **PHRED 10.23**. 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.*
- Regional missense constraint: **o/e 0.98** across the covering region of the MANE Select transcript (31,068,018–31,101,971), spanning 33,953 bp. Chi-square p 0.48. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.24**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.24**, acceptor gain **0.00**, donor gain **0.00**.
- Population frequency: **no allele count reported in gnomAD v4.1 (AN 1,613,378)** — 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 **331** 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-04-25.

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

**Submission history:** 2 submissions (2024); 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 | 2024-04-25 |
| Color Diagnostics, LLC DBA Color Health | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-02-14 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Cardiomyopathy, Familial isolated arrhythmogenic right ventricular dysplasia, Cardiomyopathies.

## Same-residue context {#hotspot}

Residue **331** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [DSC2 p.Gln331Ter](/variant/dsc2-p-gln331ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related DSC2 variant pages (same residue, condition, or type): [DSC2 p.Gln331Ter](/variant/dsc2-p-gln331ter), [DSC2 c.1077+2T>G](/variant/dsc2-c-1077-plus-2t-g), [DSC2 c.1520+4C>T](/variant/dsc2-c-1520-plus-4c-t), [DSC2 c.1520+6T>C](/variant/dsc2-c-1520-plus-6t-c), [DSC2 c.942+3A>G](/variant/dsc2-c-942-plus-3a-g), [DSC2 c.942+6A>G](/variant/dsc2-c-942-plus-6a-g), [DSC2 p.Ala138Ser](/variant/dsc2-p-ala138ser), [DSC2 p.Ala13Val](/variant/dsc2-p-ala13val).

### 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 3386539). 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.*