# NM_004415.4(DSP):c.3904C>T (p.Arg1302Cys)

https://sugi.bio/variant/dsp-p-arg1302cys

## Summary

**DSP p.Arg1302Cys (c.3904C>T)** is classified **Conflicting classifications of pathogenicity** in DSP (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-12-10). AlphaMissense: likely benign (0.1327); Ultra-rare (popmax 0.0107%, afr); Associated with arrhythmogenic right ventricular dysplasia 8.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs775594375 · 7 submitters · 7 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.0107%, afr)

## 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 7 submitters, and is linked to arrhythmogenic right ventricular dysplasia 8.

*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 |
| Age of onset (of this condition) | No data available |
| Diagnostic panels | DSP is a diagnostic-grade gene on 14 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024825/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.Arg1302Cys |
| Coding change (HGVS c.) | c.3904C>T |
| MANE Select transcript | [NM_004415](https://www.ncbi.nlm.nih.gov/nuccore/NM_004415) |
| dbSNP | [rs775594375](https://www.ncbi.nlm.nih.gov/snp/rs775594375/) |
| Variant type | single nucleotide variant |
| Location | chr6:7580094-7580094 (GRCh38) |
| ClinVar | [VCV691716](https://www.ncbi.nlm.nih.gov/clinvar/variation/691716/) |

**All HGVS expressions:** `LRG_423:g.43458C>T`, `LRG_423t1:c.3904C>T`, `NC_000006.11:g.7580327C>T`, `NC_000006.12:g.7580094C>T`, `NG_008803.1:g.43458C>T`, `NM_001008844.3:c.3582+322C>T`, `NM_001319034.2:c.3904C>T`, `NM_004415.4:c.3904C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.1327)
- REVEL 0.621 (indeterminate)
- Conservation: phyloP 7.666, GERP 1.62, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 29.1**. 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.*
- 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** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0107%** (afr) · FAF95 0.00528% · FAF99 0.00381% · 8/74,870 in the highest group · 23/1,613,920 alleles overall — ultra-rare (popmax 0.0107%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0203% | 4,934 |
| African / African-American (grpmax) | 0.0107% | 9,359 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,828 |
| South Asian | 0.00439% | 22,770 |
| European (non-Finnish) | 0.000169% | 589,995 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **1302** 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.Arg1302Cys 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-12-10.

**Submitter consensus:** conflicting (7 Uncertain significance, 1 Uncertain Significance, 1 Likely benign).

**Submission history:** 9 submissions (2017–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-04-17 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-04-27 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-10-13 |
| All of Us Research Program, National Institutes of Health | Uncertain Significance | criteria provided, single submitter | clinical testing | 2024-08-13 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-12-24 |
| Color Diagnostics, LLC DBA Color Health | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-12-10 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-09-08 |

## Associated conditions {#conditions}

[arrhythmogenic right ventricular dysplasia 8](https://sugi.bio/atlas/disease/arrhythmogenic-right-ventricular-dysplasia-8/), [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/), [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):** Arrhythmogenic right ventricular dysplasia 8, Cardiomyopathy, Lethal acantholytic epidermolysis bullosa, Woolly hair-skin fragility syndrome, Arrhythmogenic cardiomyopathy with wooly hair and keratoderma, Cardiovascular phenotype, Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis, Keratosis palmoplantaris striata 2, Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy 8, ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 8.

## Similar variants {#similar}

Related DSP variant pages (same residue, condition, or type): [DSP p.Arg1302His](/variant/dsp-p-arg1302his), [DSP p.Arg1302Leu](/variant/dsp-p-arg1302leu), [DSP c.1141-2A>T](/variant/dsp-c-1141-minus-2a-t), [DSP c.1266+2T>C](/variant/dsp-c-1266-plus-2t-c), [DSP c.1574+1G>A](/variant/dsp-c-1574-plus-1g-a), [DSP c.2130+1G>A](/variant/dsp-c-2130-plus-1g-a), [DSP c.2297+1G>A](/variant/dsp-c-2297-plus-1g-a), [DSP c.2298-1G>C](/variant/dsp-c-2298-minus-1g-c).

### 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 691716). 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.*