# NM_004415.4(DSP):c.597G>A (p.Arg199=)

https://sugi.bio/variant/dsp-p-arg199

## Summary

**DSP p.Arg199= (c.597G>A)** is classified **Uncertain significance** in DSP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-29). Very rare (popmax 6.2e-05%); Associated with cardiomyopathy.

**At a glance:** Uncertain significance · review: Multiple submitters · 2 submitters · 1 linked condition · very rare (popmax 6.2e-05%)

## 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 2 submitters, and is linked to cardiomyopathy.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 333 registered for this condition — see ClinicalTrials.gov |

**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.Arg199= |
| Coding change (HGVS c.) | c.597G>A |
| MANE Select transcript | [NM_004415](https://www.ncbi.nlm.nih.gov/nuccore/NM_004415) |
| Variant type | single nucleotide variant |
| Location | chr6:7559400-7559400 (GRCh38) |
| ClinVar | [VCV3893848](https://www.ncbi.nlm.nih.gov/clinvar/variation/3893848/) |

**All HGVS expressions:** `LRG_423:g.22764G>A`, `LRG_423t1:c.597G>A`, `NC_000006.11:g.7559633G>A`, `NC_000006.12:g.7559400G>A`, `NG_008803.1:g.22764G>A`, `NM_001008844.3:c.597G>A`, `NM_001319034.2:c.597G>A`, `NM_001406591.1:c.597G>A`, `NM_004415.4:c.597G>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.66) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.629, GERP 2.17, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 21.6**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.66**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.66**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.45** (loss), gain 0.01 / loss 0.45. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): global (via dbSNP) **6.2e-05%** · 1/1,612,266 alleles overall — very rare (popmax 6.2e-05%).

*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 **199** lies in an α-helix; the 'globular 1' region; the 'interaction with mapre1' region; the 'interaction with jup and pkp2' region; the 'interaction with pkp1' region; a UniProt-annotated variant site (in arvd8; uncertain significance); a UniProt-annotated variant site (in dcwhkta; uncertain significance).

**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.Arg199= 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 2025-09-29.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Color Diagnostics, LLC DBA Color Health | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-11-17 |
| Dasa | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-09-29 |

## Associated conditions {#conditions}

[cardiomyopathy](https://sugi.bio/atlas/disease/cardiomyopathy/).

**Reported phenotype names (ClinVar):** Cardiomyopathy, not provided, Cardiomyopathies, none provided.

## Similar variants {#similar}

Related DSP variant pages (same residue, condition, or type): [DSP p.Arg199Lys](/variant/dsp-p-arg199lys), [DSP p.Arg199Met](/variant/dsp-p-arg199met), [DSP c.2130+1G>A](/variant/dsp-c-2130-plus-1g-a), [DSP c.2437-1G>C](/variant/dsp-c-2437-minus-1g-c), [DSP c.273+1G>A](/variant/dsp-c-273-plus-1g-a), [DSP c.939+1G>A](/variant/dsp-c-939-plus-1g-a), [DSP p.Arg1113Ter](/variant/dsp-p-arg1113ter), [DSP p.Arg1267Ter](/variant/dsp-p-arg1267ter).

### 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 3893848). 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.*