Is PLEC p.Arg4530Cys (c.13588C>T) pathogenic?

PLEC p.Arg4530Cys (c.13588C>T) is classified Uncertain significance in PLEC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-09). AlphaMissense: ambiguous (0.5577); Very rare (popmax 0.00196%, amr); Associated with epidermolysis bullosa simplex with nail dystrophy.

What condition is associated with PLEC p.Arg4530Cys (c.13588C>T)?

PLEC p.Arg4530Cys (c.13588C>T) is associated with epidermolysis bullosa simplex with nail dystrophy, epidermolysis bullosa simplex 5A, Ogna type, epidermolysis bullosa simplex 5B, with muscular dystrophy (ClinVar).

How common is PLEC p.Arg4530Cys (c.13588C>T) in the general population?

PLEC p.Arg4530Cys (c.13588C>T) is very rare (popmax 0.00196%, amr) (gnomAD).

What do computational predictors say about PLEC p.Arg4530Cys (c.13588C>T)?

AlphaMissense predicts ambiguous (score 0.5577) — an in-silico prediction, not a clinical call.

PLEC p.Arg4530Cys

c.13588C>T · rs781867655 · VCV2926168

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5577 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00196%, amr)

Conditions

epidermolysis bullosa simplex with nail dystrophy

Computational evidence

Protein change
AlphaMissense	0.5577	ambiguous
REVEL	0.594	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 397 bp · p 0.6 · regional, not allelic
Overall
CADD	28.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R4667C vs ClinVar R4530C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00196% Admixed American · 1/50,934 alleles

Filtering AF 0.000254% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000163%

Overall 0.000905% 14/1,546,470 alleles · very rare exomes 12/1,394,348 · genomes 2/152,122 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0175%	5,714
Admixed Americangrpmax	0.00196%	50,934
African / African-American	0.00137%	72,850
European (non-Finnish)	0.000611%	163,667

Ashkenazi Jewish 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.Arg4530Cys
Coding: c.13588C>T
MANE Select: NM_201384
dbSNP: rs781867655
Type: single nucleotide variant
Location: chr8:143916233 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI <0.01 (gnomAD)

Full PLEC gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

epidermolysis bullosa simplex with nail dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: epidermolysis bullosa simplex 5A, Ogna type epidermolysis bullosa simplex 5B, with muscular dystrophy epidermolysis bullosa simplex 5C, with pyloric atresia autosomal recessive limb-girdle muscular dystrophy type 2Q

Similar variants

PLEC p.Arg4530His Uncertain significance ★★ 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
PLEC p.Arg2394Ter Pathogenic ★★ same condition
PLEC p.Arg559Ter 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-arg4530cys (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown