Is PLEC p.Arg2139His (c.6416G>A) pathogenic?

PLEC p.Arg2139His (c.6416G>A) is classified Conflicting classifications of pathogenicity in PLEC (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-11-24). AlphaMissense: likely benign (0.2204); Ultra-rare (popmax 0.025%, nfe); Associated with epidermolysis bullosa simplex 5C, with pyloric atresia.

What condition is associated with PLEC p.Arg2139His (c.6416G>A)?

PLEC p.Arg2139His (c.6416G>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.Arg2139His (c.6416G>A) in the general population?

PLEC p.Arg2139His (c.6416G>A) is ultra-rare (popmax 0.025%, nfe) (gnomAD).

What do computational predictors say about PLEC p.Arg2139His (c.6416G>A)?

AlphaMissense predicts likely benign (score 0.2204) — an in-silico prediction, not a clinical call.

PLEC p.Arg2139His

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.6416G>A · rs372652727 · VCV471631

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.2204 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.025%, nfe)

Conditions

epidermolysis bullosa simplex 5C, with pyloric atresia

Computational evidence

Protein change
AlphaMissense	0.2204	likely benign
REVEL	0.383	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 18 kb · p 4.9e-10 · regional, not allelic
Overall
CADD	24.7	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 R2276H vs ClinVar R2139H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.025% European (non-Finnish) · 294/1,174,718 alleles

Filtering AF 0.0227% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0218%

Overall 0.0199% 318/1,596,442 alleles · ultra-rare exomes 291/1,444,742 · genomes 27/151,700 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.025%	3,996
Ashkenazi Jewishnot grpmax-eligible	0.017%	5,878
Middle Eastern	0.0166%	6,010
Remaining individualsnot grpmax-eligible	0.0129%	7,756
East Asian	0.0112%	8,947
Admixed American	0.0067%	14,928
African / African-American	0.00134%	74,688

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.Arg2139His
Coding: c.6416G>A
MANE Select: NM_201384
dbSNP: rs372652727
Type: single nucleotide variant
Location: chr8:143923513 (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.Arg2139Cys Uncertain significance ★★ same residue
PLEC p.Arg2139= Likely benign ★★ 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-arg2139his (accessed [today's date]).

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