# NM_001943.5(DSG2):c.447T>C (p.Val149=)

https://sugi.bio/variant/dsg2-p-val149

## Summary

**DSG2 p.Val149= (c.447T>C)** is classified **Conflicting classifications of pathogenicity** in DSG2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2024-03-05). Ultra-rare (popmax 0.0401%, eas); Associated with Cardiovascular phenotype.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs1389484271 · 5 submitters · 4 linked conditions · ultra-rare (popmax 0.0401%, eas)

## For patients & families {#patients}

This is a change in the DSG2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 5 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 | [DSG2](https://sugi.bio/atlas/gene/DSG2/) |
| Protein change (HGVS p.) | p.Val149= |
| Coding change (HGVS c.) | c.447T>C |
| MANE Select transcript | [NM_001943](https://www.ncbi.nlm.nih.gov/nuccore/NM_001943) |
| dbSNP | [rs1389484271](https://www.ncbi.nlm.nih.gov/snp/rs1389484271/) |
| Variant type | single nucleotide variant |
| Location | chr18:31521167-31521167 (GRCh38) |
| ClinVar | [VCV889472](https://www.ncbi.nlm.nih.gov/clinvar/variation/889472/) |

**All HGVS expressions:** `LRG_397:g.27926T>C`, `LRG_397t1:c.447T>C`, `NC_000018.10:g.31521167T>C`, `NC_000018.9:g.29101130T>C`, `NG_007072.3:g.27926T>C`, `NM_001943.5:c.447T>C`

## 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 0.308, phastCons 0.997 — weakly conserved position
- CADD: **PHRED 3.708**. 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 (T>A, Δ0.41 donor 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 **0.0401%** (eas) · FAF95 0.0259% · FAF99 0.0214% · 18/44,850 in the highest group · 18/1,461,776 alleles overall — ultra-rare (popmax 0.0401%, eas).

*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}

**DSG2** population constraint: LOEUF 0.764, pLI 1.4607e-07, missense-Z 1.3758; ClinGen dosage — haploinsufficiency 2, 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):

- **dilated cardiomyopathy 1BB** — Limited (AD)
- **arrhythmogenic right ventricular cardiomyopathy** — Definitive (AD)

## Protein context {#protein}

Residue **149** lies in the cadherin 1 domain; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 65.27, 43% of residues very-high.

**12 experimental structure(s)** (PDB): [2YQG](https://www.rcsb.org/structure/2YQG), [5ERD](https://www.rcsb.org/structure/5ERD), [5J5J](https://www.rcsb.org/structure/5J5J), [6QNT](https://www.rcsb.org/structure/6QNT), [6QNU](https://www.rcsb.org/structure/6QNU), [6SIT](https://www.rcsb.org/structure/6SIT).

## What this gene does {#gene-function}

*Describes the biological roles of DSG2 (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.*

**How this variant is thought to act:** DSG2's established molecular role includes cell adhesion molecule binding. p.Val149= falls in the cadherin 1 domain.


### Pathways affected {#pathways}

DSG2 participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Apoptotic cleavage of cell adhesion  proteins](https://reactome.org/content/detail/R-HSA-351906) | curated |
| [Formation of the cornified envelope](https://reactome.org/content/detail/R-HSA-6809371) | curated |
| [Keratinization](https://reactome.org/content/detail/R-HSA-6805567) | curated |
| [RAC2 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013404) | curated |
| [RAC3 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013423) | curated |
| [RHOG GTPase cycle](https://reactome.org/content/detail/R-HSA-9013408) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** cell adhesion molecule binding.

**Biological process:** desmosome organization, Purkinje myocyte development, cell adhesion, homophilic cell-cell adhesion, negative regulation of epithelial to mesenchymal transition, negative regulation of apoptotic process.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-03-05.

**Submitter consensus:** conflicting (3 Likely benign, 1 Uncertain significance, 1 Likely Benign).

**Submission history:** 5 submissions (2018–2024); 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 | 2018-01-15 |
| Color Diagnostics, LLC DBA Color Health | Likely benign | criteria provided, single submitter | clinical testing | 2018-12-03 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-06-26 |
| All of Us Research Program, National Institutes of Health | Likely Benign | criteria provided, single submitter | clinical testing | 2024-03-05 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2022-09-23 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/), [cardiomyopathy](https://sugi.bio/atlas/disease/cardiomyopathy/), [arrhythmogenic right ventricular dysplasia 10](https://sugi.bio/atlas/disease/arrhythmogenic-right-ventricular-dysplasia-10/), [arrhythmogenic right ventricular cardiomyopathy](https://sugi.bio/atlas/disease/arrhythmogenic-right-ventricular-cardiomyopathy/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, Arrhythmogenic right ventricular dysplasia 10, Cardiomyopathy, Arrhythmogenic right ventricular cardiomyopathy, Arrhythmogenic cardiomyopathy, Cardiomyopathy, ARVC, Arrhythmogenic right ventricular dysplasia, Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), Cardiomyopathies, Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy10.

## Similar variants {#similar}

Related DSG2 variant pages (same residue, condition, or type): [DSG2 p.Val149Ile](/variant/dsg2-p-val149ile), [DSG2 p.Val149Phe](/variant/dsg2-p-val149phe), [DSG2 c.1423+1G>T](/variant/dsg2-c-1423-plus-1g-t), [DSG2 c.1424-1G>A](/variant/dsg2-c-1424-minus-1g-a), [DSG2 c.523+1G>T](/variant/dsg2-c-523-plus-1g-t), [DSG2 c.690+1G>A](/variant/dsg2-c-690-plus-1g-a), [DSG2 c.81+1G>T](/variant/dsg2-c-81-plus-1g-t), [DSG2 c.829-2A>T](/variant/dsg2-c-829-minus-2a-t).

### 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 889472). 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.*