# NM_004415.4(DSP):c.1483_1485delinsTTT (p.Val495Phe)

https://sugi.bio/variant/dsp-p-val495phe

## Summary

**DSP p.Val495Phe (c.1483_1485delinsTTT)** is classified **Uncertain significance** in DSP (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-06-02). No gnomAD frequency available for this variant; Associated with Cardiovascular phenotype.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1064795582 · 4 submitters · 7 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 4 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 | [DSP](https://sugi.bio/atlas/gene/DSP/) |
| Protein change (HGVS p.) | p.Val495Phe |
| Coding change (HGVS c.) | c.1483_1485delinsTTT |
| MANE Select transcript | [NM_004415](https://www.ncbi.nlm.nih.gov/nuccore/NM_004415) |
| dbSNP | [rs1064795582](https://www.ncbi.nlm.nih.gov/snp/rs1064795582/) |
| Variant type | Indel |
| Location | chr6:7569249-7569251 (GRCh38) |
| ClinVar | [VCV422139](https://www.ncbi.nlm.nih.gov/clinvar/variation/422139/) |

**All HGVS expressions:** `LRG_423:g.32613_32615delinsTTT`, `LRG_423t1:c.1483_1485delinsTTT`, `NC_000006.11:g.7569482_7569484delinsTTT`, `NC_000006.12:g.7569249_7569251delinsTTT`, `NG_008803.1:g.32613_32615delinsTTT`, `NM_001008844.3:c.1483_1485delinsTTT`, `NM_001319034.2:c.1483_1485delinsTTT`, `NM_004415.2:c.1483_1485delGTGinsTTT`, `NM_004415.4:c.1483_1485delinsTTT`

## 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 11.763, GERP 1.85, phastCons 1 — highly conserved position (PP3-type support)
- Regional missense constraint: **o/e 0.94** across the covering region of the MANE Select transcript (7,541,916–7,570,467), spanning 28,551 bp. Chi-square p 0.14. 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 3/3, triplosensitivity 0/3. *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 **495** lies in a β-strand; the 'globular 1' region; the 'interaction with mapre1' region; the 'interaction with jup and pkp2' region; the sh3 domain; a UniProt-annotated variant site (in arvd8; uncertain significance); a UniProt-annotated variant site (in dcwhkta; uncertain significance); 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.Val495Phe falls in the globular 1 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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-06-02.

**Submitter consensus:** unanimous (4/4 Uncertain significance).

**Submission history:** 4 submissions (2018–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-09-07 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-05-04 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-07-17 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-06-02 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/), [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/), [woolly hair-skin fragility syndrome](https://sugi.bio/atlas/disease/woolly-hair-skin-fragility-syndrome/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, not provided, Arrhythmogenic cardiomyopathy with wooly hair and keratoderma, Arrhythmogenic right ventricular dysplasia 8, Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis, Keratosis palmoplantaris striata 2, Lethal acantholytic epidermolysis bullosa, Woolly hair-skin fragility syndrome, not specified, Erythrokeratodermia-cardiomyopathy syndrome.

## Similar variants {#similar}

Related DSP variant pages (same residue, condition, or type): [DSP p.Val495Ala](/variant/dsp-p-val495ala), [DSP p.Val495Leu](/variant/dsp-p-val495leu), [DSP p.Val495=](/variant/dsp-p-val495), [DSP p.Val495Gly](/variant/dsp-p-val495gly), [DSP p.Val495Met](/variant/dsp-p-val495met), [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.Asp352fs](/variant/dsp-p-asp352fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 422139). 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.*