Is PLEC p.Arg2139= (c.6417C>T) pathogenic?

PLEC p.Arg2139= (c.6417C>T) is classified Likely benign in PLEC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-18). Ultra-rare (popmax 0.0167%, mid); Associated with epidermolysis bullosa simplex 5A, Ogna type.

What condition is associated with PLEC p.Arg2139= (c.6417C>T)?

PLEC p.Arg2139= (c.6417C>T) 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.Arg2139= (c.6417C>T) in the general population?

PLEC p.Arg2139= (c.6417C>T) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

PLEC p.Arg2139=

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.6417C>T · rs781983706 · VCV642949

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Conditions

epidermolysis bullosa simplex 5A, Ogna type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.42	phastCons 0.98
Overall
CADD	2.648	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0167% Middle Eastern · 1/5,998 alleles

Filtering AF 0.00178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00106%

Overall 0.00201% 32/1,593,250 alleles · ultra-rare exomes 31/1,444,966 · genomes 1/148,284 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	5,998
Remaining individualsnot grpmax-eligible	0.0113%	8,857
African / African-American	0.00547%	18,286
European (non-Finnish)	0.0017%	58,693

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.Arg2139=
Coding: c.6417C>T
MANE Select: NM_201384
dbSNP: rs781983706
Type: single nucleotide variant
Location: chr8:143923512 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI <0.01 (gnomAD)
Residue 2139: the 'required for interaction with intermediate filament proteins' region; the 'central fibrous rod domain' region; the 'disordered' region

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.Arg2139Cys Uncertain significance ★★ same residue
PLEC p.Arg2139His Conflicting classifications of pathogenicity ★ same residue
PLEC p.Arg2139Leu 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

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-arg2139 (accessed [today's date]).

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