# NM_004415.4(DSP):c.9C>T (p.Cys3=)

https://sugi.bio/variant/dsp-p-cys3

## Summary

**DSP p.Cys3= (c.9C>T)** is classified **Conflicting classifications of pathogenicity** in DSP (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-06-02). Very rare (popmax 0.000509%, nfe); Associated with arrhythmogenic cardiomyopathy with wooly hair and keratoderma.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs769032973 · 4 submitters · 4 linked conditions · very rare (popmax 0.000509%, nfe)

> **Built without this gene's context.** ClinVar files this variant under an overlapping gene, so its own gene's record set does not contain it and this page is assembled from the variant alone. Gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up — absent from this page, not from the data.

## 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 4 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 |

**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.Cys3= |
| Coding change (HGVS c.) | c.9C>T |
| MANE Select transcript | [NM_004415](https://www.ncbi.nlm.nih.gov/nuccore/NM_004415) |
| dbSNP | [rs769032973](https://www.ncbi.nlm.nih.gov/snp/rs769032973/) |
| Variant type | single nucleotide variant |
| Location | chr6:7541924-7541924 (GRCh38) |
| ClinVar | [VCV357935](https://www.ncbi.nlm.nih.gov/clinvar/variation/357935/) |

**All HGVS expressions:** `LRG_423:g.5288C>T`, `LRG_423t1:c.9C>T`, `NC_000006.11:g.7542157C>T`, `NC_000006.12:g.7541924C>T`, `NG_008803.1:g.5288C>T`, `NM_001008844.3:c.9C>T`, `NM_001319034.2:c.9C>T`, `NM_004415.4:c.9C>T`

## 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 3.521, GERP 1.15, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 15.4**. 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.*
- SpliceAI: **not looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency (gnomAD v4.1): grpmax **0.000509%** (nfe) · FAF95 0.000183% · FAF99 0.00012% · 6/1,178,600 in the highest group · 8/1,608,726 alleles overall — very rare (popmax 0.000509%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00339% | 29,512 |
| Remaining individuals (not grpmax-eligible) | 0.00161% | 62,272 |
| European (non-Finnish) (grpmax) | 0.000509% | 196,433 |

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.*

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-06-02.

**Submitter consensus:** conflicting (3 Uncertain significance, 2 Likely benign, 1 Likely Benign).

**Submission history:** 6 submissions (2016–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2016-06-08 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-06-02 |
| All of Us Research Program, National Institutes of Health | Likely Benign | criteria provided, single submitter | clinical testing | 2023-07-22 |

## 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/), [lethal acantholytic epidermolysis bullosa](https://sugi.bio/atlas/disease/lethal-acantholytic-epidermolysis-bullosa/), [woolly hair-skin fragility syndrome](https://sugi.bio/atlas/disease/woolly-hair-skin-fragility-syndrome/).

**Reported phenotype names (ClinVar):** Arrhythmogenic cardiomyopathy with wooly hair and keratoderma, Woolly hair-skin fragility syndrome, Lethal acantholytic epidermolysis bullosa, Arrhythmogenic right ventricular dysplasia 8, Cardiovascular phenotype, 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, FAMILIAL, 8.

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 357935). 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.*