Is PLEC p.Arg4530His (c.13589G>A) pathogenic?

PLEC p.Arg4530His (c.13589G>A) is classified Uncertain significance in PLEC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-12). AlphaMissense: likely benign (0.3326); Ultra-rare (popmax 0.0154%, sas); Associated with epidermolysis bullosa simplex 5A, Ogna type.

What condition is associated with PLEC p.Arg4530His (c.13589G>A)?

PLEC p.Arg4530His (c.13589G>A) is associated with epidermolysis bullosa simplex 5A, Ogna type, epidermolysis bullosa simplex 5B, with muscular dystrophy, epidermolysis bullosa simplex 5C, with pyloric atresia (ClinVar).

How common is PLEC p.Arg4530His (c.13589G>A) in the general population?

PLEC p.Arg4530His (c.13589G>A) is ultra-rare (popmax 0.0154%, sas) (gnomAD).

What do computational predictors say about PLEC p.Arg4530His (c.13589G>A)?

AlphaMissense predicts likely benign (score 0.3326) — an in-silico prediction, not a clinical call.

PLEC p.Arg4530His

Q: How is PLEC-related intermediate epidermolysis bullosa simplex without extracutaneous involvement inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.13589G>A · VCV3375429

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.3326 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0154%, sas)

Conditions

epidermolysis bullosa simplex 5A, Ogna type

Computational evidence

Protein change
AlphaMissense	0.3326	likely benign
REVEL	0.505	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.6, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 397 bp · p 0.6 · regional, not allelic
Overall
CADD	25.6	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 R4667H vs ClinVar R4530H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0154% South Asian · 13/84,318 alleles

Filtering AF 0.00908% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0072%

Overall 0.00181% 28/1,546,384 alleles · ultra-rare exomes 26/1,394,194 · genomes 2/152,190 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0154%	6,486
Remaining individualsnot grpmax-eligible	0.00501%	19,949
East Asian	0.00491%	20,377
African / African-American	0.00137%	72,936
European (non-Finnish)	0.000786%	127,290

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.Arg4530His
Coding: c.13589G>A
MANE Select: NM_201384
Type: single nucleotide variant
Location: chr8:143916232 (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 5A, Ogna type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

For PLEC-related intermediate epidermolysis bullosa simplex without extracutaneous involvement (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal

Similar variants

PLEC p.Arg4530Cys 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-arg4530his (accessed [today's date]).

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