# NM_004415.4(DSP):c.47G>C (p.Arg16Pro)

https://sugi.bio/variant/dsp-p-arg16pro

## Summary

**DSP p.Arg16Pro (c.47G>C)** is classified **Conflicting classifications of pathogenicity** in DSP (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-12-14). AlphaMissense: likely pathogenic (0.5769); Very rare (popmax 0.00505%, amr); Associated with arrhythmogenic cardiomyopathy with wooly hair and keratoderma.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs752387234 · 6 submitters · 7 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.00505%, amr)

## 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 6 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.Arg16Pro |
| Coding change (HGVS c.) | c.47G>C |
| dbSNP | [rs752387234](https://www.ncbi.nlm.nih.gov/snp/rs752387234/) |
| Variant type | single nucleotide variant |
| Location | chr6:7541962-7541962 (GRCh38) |
| ClinVar | [VCV199913](https://www.ncbi.nlm.nih.gov/clinvar/variation/199913/) |

**All HGVS expressions:** `LRG_423:g.5326G>C`, `LRG_423t1:c.47G>C`, `NC_000006.11:g.7542195G>C`, `NC_000006.12:g.7541962G>C`, `NG_008803.1:g.5326G>C`, `NM_001008844.3:c.47G>C`, `NM_001319034.2:c.47G>C`, `NM_004415.4:c.47G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.5769)
- REVEL 0.46 (indeterminate)
- Conservation: phyloP 8.979, GERP 2.06, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 24.7**. 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 0.94** 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 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 **0.00505%** (amr) · FAF95 0.00134% · FAF99 0.000719% · 3/59,456 in the highest group · 21/1,607,158 alleles overall — very rare (popmax 0.00505%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00505% | 19,819 |
| Remaining individuals (not grpmax-eligible) | 0.00161% | 62,132 |
| European (non-Finnish) | 0.00144% | 69,286 |

*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 2025-12-14.

**Submitter consensus:** conflicting (4 Uncertain significance, 1 Uncertain Significance, 1 Likely benign).

**Submission history:** 6 submissions (2021–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-02-22 |
| All of Us Research Program, National Institutes of Health | Uncertain Significance | criteria provided, single submitter | clinical testing | 2024-09-11 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-14 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-07-27 |
| Color Diagnostics, LLC DBA Color Health | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-07-31 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-03-29 |

## Associated conditions {#conditions}

[arrhythmogenic cardiomyopathy with wooly hair and keratoderma](https://sugi.bio/atlas/disease/arrhythmogenic-cardiomyopathy-with-wooly-hair-and-keratoderma/), [cardiomyopathy](https://sugi.bio/atlas/disease/cardiomyopathy/), [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):** Arrhythmogenic cardiomyopathy with wooly hair and keratoderma, not provided, Arrhythmogenic right ventricular dysplasia 8, Cardiomyopathy, Cardiovascular phenotype, Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis, Keratosis palmoplantaris striata 2, Lethal acantholytic epidermolysis bullosa, Woolly hair-skin fragility syndrome, Carvajal syndrome.

### 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 199913). 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.*