# NM_004415.4(DSP):c.3919_3920delinsTT (p.Ala1307Phe)

https://sugi.bio/variant/dsp-p-ala1307phe

## Summary

**DSP p.Ala1307Phe (c.3919_3920delinsTT)** is classified **Uncertain significance** in DSP (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-04). No gnomAD frequency available for this variant; Associated with arrhythmogenic cardiomyopathy with wooly hair and keratoderma.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2533926619 · 1 submitter · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the DSP gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, 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.Ala1307Phe |
| Coding change (HGVS c.) | c.3919_3920delinsTT |
| MANE Select transcript | [NM_004415](https://www.ncbi.nlm.nih.gov/nuccore/NM_004415) |
| dbSNP | [rs2533926619](https://www.ncbi.nlm.nih.gov/snp/rs2533926619/) |
| Variant type | Indel |
| Location | chr6:7580109-7580110 (GRCh38) |
| ClinVar | [VCV2950835](https://www.ncbi.nlm.nih.gov/clinvar/variation/2950835/) |

**All HGVS expressions:** `LRG_423:g.43473_43474delinsTT`, `LRG_423t1:c.3919_3920delGCinsTT`, `NC_000006.11:g.7580342_7580343delinsTT`, `NC_000006.12:g.7580109_7580110delinsTT`, `NG_008803.1:g.43473_43474delinsTT`, `NM_001008844.3:c.3582+337_3582+338delinsTT`, `NM_001319034.2:c.3919_3920delinsTT`, `NM_004415.4:c.3919_3920delinsTT`

## 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 3.43, GERP -1.51, phastCons 1 — highly conserved position (PP3-type support)
- Regional missense constraint: **o/e 0.93** across the covering region of the MANE Select transcript (7,571,856–7,583,869), spanning 12,013 bp. Chi-square p 0.0024. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no indel variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — 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}

**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 **1307** lies in a UniProt-annotated variant site (in arvd8; uncertain significance); a UniProt-annotated variant site (in dcwhkta; uncertain significance); 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.Ala1307Phe 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-12-04.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-12-04 |

## 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, Arrhythmogenic right ventricular dysplasia 8, PALMOPLANTAR KERATODERMA WITH LEFT VENTRICULAR CARDIOMYOPATHY AND WOOLLY HAIR, Carvajal syndrome, Dilated cardiomyopathy with woolly hair and keratoderma, Arrhythmogenic cardiomyopathy with woolly hair and keratoderma, Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy 8, ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 8, ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY 8.

## Similar variants {#similar}

Related DSP variant pages (same residue, condition, or type): [DSP p.Ala1307Ser](/variant/dsp-p-ala1307ser), [DSP p.Ala1307Thr](/variant/dsp-p-ala1307thr), [DSP c.2793+1_2793+5delinsAACAAAAAG](/variant/dsp-c-2793-plus-1-2793-plus-5delinsaacaaaaag), [DSP c.5671_*835+957del4738insAGAACAGTCTT](/variant/dsp-c-5671-star-835-plus-957del4738insagaacagtctt), [DSP p.Tyr1139fs](/variant/dsp-p-tyr1139fs), [DSP c.274-8_274-7delinsAT](/variant/dsp-c-274-minus-8-274-minus-7delinsat), [DSP p.Glu1369_Ile1370delinsAspVal](/variant/dsp-p-glu1369-ile1370delinsaspval), [DSP p.Gly171Glu](/variant/dsp-p-gly171glu).

### 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 2950835). 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.*