DSP p.Leu749Pro
c.2246T>C · rs935504136 · VCV910737
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9862 | likely pathogenic · top 5% in DSP |
|---|---|---|
| REVEL | 0.733 | pathogenic-leaning |
| SaProt | LLR -15.90 | damaging |
| ⇒ AlphaMissense, REVEL and SaProt all call this damaging. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
| Constraint at this position | ||
| Conservation | phyloP 7.8 | GERP 1.9, phastCons 1 |
| Regional constraint | o/e 0.93 | unconstrained · MANE · 12 kb · p 0.0024 · regional, not allelic |
| Overall | ||
| CADD | 27.5 | PHRED · no single calibrated threshold — expert panels disagree |
ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 0.00167% | 60,010 |
| European (non-Finnish) | 0.00127% | 78,665 |
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- DSP
- Protein
- p.Leu749Pro
- Coding
- c.2246T>C
- MANE Select
- NM_004415
- dbSNP
- rs935504136
- Type
- single nucleotide variant
- Location
- chr6:7574201 (GRCh38)
- Gene constraint
- LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Residue 749
- a UniProt-annotated variant site (in arvd8; uncertain significance); the 'globular 1' region; the 'interaction with mapre1' region; 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)
Disease context
Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: arrhythmogenic cardiomyopathy with wooly hair and keratodermaarrhythmogenic right ventricular dysplasia 8lethal acantholytic epidermolysis bullosawoolly hair-skin fragility syndrome
Similar variants
- DSP p.Leu749= Likely benign ★★ same residue
- DSP c.1141-2A>T Likely pathogenic ★★ same condition
- DSP c.1266+2T>C Likely pathogenic ★★ same condition
- DSP c.1574+1G>A Likely pathogenic ★★ same condition
- DSP c.2130+1G>A Pathogenic/Likely pathogenic ★★ same condition
- DSP c.2297+1G>A Likely pathogenic ★★ same condition
- DSP c.2298-1G>C Likely pathogenic ★★ same condition
- DSP c.2298-2A>C Pathogenic/Likely pathogenic ★★ same condition
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/dsp-p-leu749pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown