# NM_004415.4(DSP):c.5680_5683del (p.Ser1894fs)

https://sugi.bio/variant/dsp-p-ser1894fs

## Summary

**DSP p.Ser1894fs (c.5680_5683del)** is classified **Pathogenic/Likely pathogenic** in DSP (ClinVar, Multiple submitters, 11 submitters; last evaluated 2025-12-04). Very rare (popmax 0.005%, amr); Associated with DSP-related disorder.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs774763657 · 11 submitters · 8 linked conditions · very rare (popmax 0.005%, amr)

## For patients & families {#patients}

This is a change in the DSP gene that is considered likely disease-causing, submitted by 11 submitters, and is linked to DSP-related disorder.

*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 | [DSP](https://sugi.bio/atlas/gene/DSP/) |
| Protein change (HGVS p.) | p.Ser1894fs |
| Coding change (HGVS c.) | c.5680_5683del |
| MANE Select transcript | [NM_004415](https://www.ncbi.nlm.nih.gov/nuccore/NM_004415) |
| dbSNP | [rs774763657](https://www.ncbi.nlm.nih.gov/snp/rs774763657/) |
| Variant type | Deletion |
| Location | chr6:7582941-7582944 (GRCh38) |
| ClinVar | [VCV405232](https://www.ncbi.nlm.nih.gov/clinvar/variation/405232/) |

**All HGVS expressions:** `LRG_423:g.46306_46309del`, `LRG_423t1:c.5680_5683del`, `NC_000006.11:g.7583175_7583178del`, `NC_000006.12:g.7582942_7582945del`, `NG_008803.1:g.46306_46309del`, `NM_001008844.3:c.3883_3886del`, `NM_001319034.2:c.4351_4354del`, `NM_004415.2:c.5680_5683del`, `NM_004415.3:c.5680_5683delAGTC`, `NM_004415.4:c.5680_5683del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 4.089, GERP 1.44, phastCons 0.997 — highly conserved position (PP3-type support)
- 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 deletion 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 **0.005%** (amr) · FAF95 0.00133% · FAF99 0.000668% · 3/60,012 in the highest group · 3/1,461,870 alleles overall — very rare (popmax 0.005%, amr).

*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 **1894** 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); the 'central fibrous rod domain' region; the 'binds to telomeres' region; 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.Ser1894fs falls in the central fibrous rod domain 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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-04.

**Submitter consensus:** conflicting (7 Pathogenic, 3 Likely pathogenic, 1 Likely Pathogenic).

**Submission history:** 11 submissions (2022–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-05-16 |
| PreventionGenetics, part of Exact Sciences | Pathogenic | no assertion criteria provided | clinical testing | 2024-04-12 |
| CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-09-18 |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-05-29 |
| Color Diagnostics, LLC DBA Color Health | Pathogenic | criteria provided, single submitter | clinical testing | 2024-08-05 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-05-04 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-08-21 |
| All of Us Research Program, National Institutes of Health | Likely Pathogenic | criteria provided, single submitter | clinical testing | 2024-01-08 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-04 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-11-24 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-11-06 |

## Associated conditions {#conditions}

[DSP-related disorder](https://sugi.bio/atlas/disease/dsp-related-disorder/), [cardiomyopathy](https://sugi.bio/atlas/disease/cardiomyopathy/), [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/), [lethal acantholytic epidermolysis bullosa](https://sugi.bio/atlas/disease/lethal-acantholytic-epidermolysis-bullosa/), [keratosis palmoplantaris striata 2](https://sugi.bio/atlas/disease/keratosis-palmoplantaris-striata-2/), [cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis](https://sugi.bio/atlas/disease/cardiomyopathy-dilated-with-wooly-hair-keratoderma-and-tooth-agenesis/), [familial isolated arrhythmogenic right ventricular dysplasia](https://sugi.bio/atlas/disease/familial-isolated-arrhythmogenic-right-ventricular-dysplasia/).

**Reported phenotype names (ClinVar):** DSP-related disorder, Arrhythmogenic cardiomyopathy with wooly hair and keratoderma, Arrhythmogenic right ventricular dysplasia 8, not provided, Cardiomyopathy, Cardiovascular phenotype, Familial isolated arrhythmogenic right ventricular dysplasia, Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis, Keratosis palmoplantaris striata 2, Lethal acantholytic epidermolysis bullosa.

## Similar variants {#similar}

Related DSP variant pages (same residue, condition, or type): [DSP p.Ser1894Arg](/variant/dsp-p-ser1894arg), [DSP p.Ser1894Thr](/variant/dsp-p-ser1894thr), [DSP c.2131-3_2131del](/variant/dsp-c-2131-minus-3-2131del), [DSP p.Ala2092fs](/variant/dsp-p-ala2092fs), [DSP p.Arg1113fs](/variant/dsp-p-arg1113fs), [DSP p.Arg1173fs](/variant/dsp-p-arg1173fs), [DSP p.Arg1506fs](/variant/dsp-p-arg1506fs), [DSP p.Asn1346fs](/variant/dsp-p-asn1346fs).

### 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 405232). 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.*