PLEC p.Arg596Gln
c.1787G>A · rs1346840219 · VCV478792
Computational evidence
| Protein change | ||
| AlphaMissense | 0.0861 | likely benign |
|---|---|---|
| REVEL | 0.15 | moderately benign-leaning |
| SaProt | — | not scored · why |
| ⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 5.6 | phastCons 1 |
| Regional constraint | o/e 1.08 | unconstrained · MANE · 18 kb · p 4.9e-10 · regional, not allelic |
| Overall | ||
| CADD | 25.3 | PHRED · no single calibrated threshold — expert panels disagree |
ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification
AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.
⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R733Q vs ClinVar R596Q) — verify the residue.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Remaining individualsnot grpmax-eligible | 0.00642% | 15,585 |
| Admixed Americangrpmax | 0.00334% | 29,911 |
| South Asian | 0.0022% | 45,453 |
| African / African-American | 0.00134% | 74,860 |
| European (non-Finnish) | 0.000678% | 147,407 |
Remaining individuals shows a higher raw frequency than the grpmax group above it. 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.
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
- PLEC
- Protein
- p.Arg596Gln
- Coding
- c.1787G>A
- MANE Select
- NM_201384
- dbSNP
- rs1346840219
- Type
- single nucleotide variant
- Location
- chr8:143932663 (GRCh38)
- Gene constraint
- LOEUF 0.726 · pLI <0.01 (gnomAD)
Disease context
epidermolysis bullosa simplex with nail dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: epidermolysis bullosa simplex 5A, Ogna typeepidermolysis bullosa simplex 5B, with muscular dystrophyepidermolysis bullosa simplex 5C, with pyloric atresiaautosomal recessive limb-girdle muscular dystrophy type 2Q
Similar variants
- PLEC p.Arg596Gly Uncertain significance ★★ same residue
- PLEC p.Arg596Trp Uncertain significance ★ same residue
- PLEC p.Arg596= Likely benign ★ same residue
- PLEC p.Arg1490Ter Pathogenic/Likely pathogenic ★★ same condition
- PLEC p.Arg1973Trp Pathogenic ★★ ⚠ same condition
- PLEC p.Arg2027Ter Pathogenic ★★ same condition
- PLEC p.Arg2292Ter Pathogenic ★★ same condition
- PLEC p.Arg2324Ter 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/plec-p-arg596gln (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown