# NM_004415.4(DSP):c.8442dup (p.Ser2815fs)

https://sugi.bio/variant/dsp-p-ser2815fs

## Summary

**DSP p.Ser2815fs (c.8442dup)** is classified **Conflicting classifications of pathogenicity** in DSP (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2021-08-24). Very rare (popmax 0.000169%, nfe); Associated with arrhythmogenic cardiomyopathy with wooly hair and keratoderma.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs1554109247 · 2 submitters · 2 linked conditions · very rare (popmax 0.000169%, nfe)

## For patients & families {#patients}

This is a change in the DSP gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to arrhythmogenic cardiomyopathy with wooly hair and keratoderma.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive |
| Age of onset (of this condition) | Childhood, Infancy, Neonatal |
| Diagnostic panels | DSP is a diagnostic-grade gene on 14 Genomics England panels |

**Commonly reported features of Carvajal syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Dilated cardiomyopathy — Very frequent (99-80%)
- Woolly hair — Very frequent (99-80%)
- Patchy palmoplantar keratoderma — Very frequent (99-80%)
- Congestive heart failure — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005595/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DSP](https://sugi.bio/atlas/gene/DSP/) |
| Protein change (HGVS p.) | p.Ser2815fs |
| Coding change (HGVS c.) | c.8442dup |
| MANE Select transcript | [NM_004415](https://www.ncbi.nlm.nih.gov/nuccore/NM_004415) |
| dbSNP | [rs1554109247](https://www.ncbi.nlm.nih.gov/snp/rs1554109247/) |
| Variant type | Duplication |
| Location | chr6:7585701-7585702 (GRCh38) |
| ClinVar | [VCV421616](https://www.ncbi.nlm.nih.gov/clinvar/variation/421616/) |

**All HGVS expressions:** `LRG_423:g.49068dup`, `LRG_423t1:c.8442dup`, `NC_000006.11:g.7585937dup`, `NC_000006.12:g.7585704dup`, `NG_008803.1:g.49068dup`, `NM_001008844.3:c.6645dup`, `NM_001319034.2:c.7113dup`, `NM_004415.4:c.8442dup`

## 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 1.623, GERP -3.81, phastCons 1 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.443, pLI 0.99991), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (24 of 24)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000169%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,179,996 in the highest group · 2/1,461,740 alleles overall — very rare (popmax 0.000169%, nfe).

*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}

**DSP** population constraint: LOEUF 0.443, pLI 0.99991, missense-Z 2.6512; ClinGen dosage — haploinsufficiency 3, 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):

- **hypertrophic cardiomyopathy** — Disputed (AD)
- **arrhythmogenic cardiomyopathy with wooly hair and keratoderma** — Definitive (AD)

## Protein context {#protein}

Residue **2815** lies in a UniProt-annotated variant site (in arvd8; uncertain significance); a UniProt-annotated variant site (in dcwhkta; uncertain significance); a UniProt-annotated variant site (in dcwhk; uncertain significance; abolishes expression in the myocardium); a UniProt-annotated variant site (in ebla; uncertain significance); a UniProt-annotated variant site (in dcwhk; uncertain significance); the 'binds to telomeres' region; the 'globular 2' region; the '4.5 x 38 aa tandem repeats (domain c)' region; the 'disordered' region; a modified residue (phosphoserine); a UniProt-annotated variant site (in arvd8; likely pathogenic; results in an unstable protein that forms perinuclear aggregates); a UniProt-annotated variant site (in arvd8 and dcwhkta; uncertain significance); a UniProt-annotated variant site (in arvd8).

**4 experimental structure(s)** (PDB): [1LM5](https://www.rcsb.org/structure/1LM5), [1LM7](https://www.rcsb.org/structure/1LM7), [3R6N](https://www.rcsb.org/structure/3R6N), [5DZZ](https://www.rcsb.org/structure/5DZZ).

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

*Describes the biological roles of DSP (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:** DSP's established molecular role includes RNA binding. p.Ser2815fs falls in the binds to telomeres region.


### Pathways affected {#pathways}

DSP 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 |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [RND1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9696273) | curated |
| [RND3 GTPase cycle](https://reactome.org/content/detail/R-HSA-9696264) | curated |

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

**Molecular function:** RNA binding, protein kinase C binding, scaffold protein binding.

**Biological process:** peptide cross-linking, keratinocyte differentiation, bundle of His cell-Purkinje myocyte adhesion involved in cell communication, regulation of heart rate by cardiac conduction, epithelial cell-cell adhesion, regulation of ventricular cardiac muscle cell action potential.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2021-08-24.

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

**Submission history:** 2 submissions (2016–2021); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2016-07-11 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-08-24 |

## Associated conditions {#conditions}

[arrhythmogenic cardiomyopathy with wooly hair and keratoderma](https://sugi.bio/atlas/disease/arrhythmogenic-cardiomyopathy-with-wooly-hair-and-keratoderma/), [arrhythmogenic right ventricular dysplasia 8](https://sugi.bio/atlas/disease/arrhythmogenic-right-ventricular-dysplasia-8/).

**Reported phenotype names (ClinVar):** Arrhythmogenic cardiomyopathy with wooly hair and keratoderma, not provided, Arrhythmogenic right ventricular dysplasia 8, Carvajal syndrome, Dilated cardiomyopathy with woolly hair and keratoderma, Arrhythmogenic cardiomyopathy with woolly hair and keratoderma, PALMOPLANTAR KERATODERMA WITH LEFT VENTRICULAR CARDIOMYOPATHY AND WOOLLY HAIR, ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 8, ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY 8, Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy 8.

## Similar variants {#similar}

Related DSP variant pages (same residue, condition, or type): [DSP p.Ser2815=](/variant/dsp-p-ser2815), [DSP p.Arg2151fs](/variant/dsp-p-arg2151fs), [DSP p.Arg2156fs](/variant/dsp-p-arg2156fs), [DSP p.Asn1865fs](/variant/dsp-p-asn1865fs), [DSP p.Asn274fs](/variant/dsp-p-asn274fs), [DSP p.Asp1248fs](/variant/dsp-p-asp1248fs), [DSP p.Gln216fs](/variant/dsp-p-gln216fs), [DSP p.Gln2672fs](/variant/dsp-p-gln2672fs).

### 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 421616). 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.*