Is PLEC p.Arg280His (c.839G>A) pathogenic?

PLEC p.Arg280His (c.839G>A) is classified Uncertain significance in PLEC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-08-09). AlphaMissense: likely benign (0.1295); Very rare (popmax 0.00667%, amr); Associated with epidermolysis bullosa simplex 5C, with pyloric atresia.

What condition is associated with PLEC p.Arg280His (c.839G>A)?

PLEC p.Arg280His (c.839G>A) is associated with epidermolysis bullosa simplex 5C, with pyloric atresia, epidermolysis bullosa simplex 5A, Ogna type, epidermolysis bullosa simplex 5B, with muscular dystrophy (ClinVar).

How common is PLEC p.Arg280His (c.839G>A) in the general population?

PLEC p.Arg280His (c.839G>A) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about PLEC p.Arg280His (c.839G>A)?

AlphaMissense predicts likely benign (score 0.1295) — an in-silico prediction, not a clinical call.

PLEC p.Arg280His

Q: How is Epidermolysis bullosa simplex with pyloric atresia inherited?

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

c.839G>A · rs782124459 · VCV493487

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1295 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Conditions

epidermolysis bullosa simplex 5C, with pyloric atresia

Computational evidence

Protein change
AlphaMissense	0.1295	likely benign
REVEL	0.301	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 18 kb · p 4.9e-10 · regional, not allelic
Overall
CADD	27.0	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 R417H vs ClinVar R280H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/59,984 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00137% 22/1,611,114 alleles · very rare exomes 15/1,458,902 · genomes 7/152,212 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,996
African / African-American	0.00534%	18,732
South Asian	0.0022%	45,535
Finnishnot grpmax-eligible	0.00162%	61,542
Remaining individualsnot grpmax-eligible	0.0016%	62,404
European (non-Finnish)	0.000848%	117,974

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.Arg280His
Coding: c.839G>A
MANE Select: NM_201384
dbSNP: rs782124459
Type: single nucleotide variant
Location: chr8:143934916 (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 5C, with pyloric atresia — 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 autosomal recessive limb-girdle muscular dystrophy type 2Q epidermolysis bullosa simplex with nail dystrophy

For Epidermolysis bullosa simplex with pyloric atresia (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

PLEC p.Arg280Cys 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-arg280his (accessed [today's date]).

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