Is PLEC p.Arg951Trp (c.2851C>T) pathogenic?

PLEC p.Arg951Trp (c.2851C>T) is classified Uncertain significance in PLEC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-19). AlphaMissense: likely benign (0.2957); Very rare (popmax 0.00669%, amr); Associated with epidermolysis bullosa simplex 5C, with pyloric atresia.

What condition is associated with PLEC p.Arg951Trp (c.2851C>T)?

PLEC p.Arg951Trp (c.2851C>T) 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.Arg951Trp (c.2851C>T) in the general population?

PLEC p.Arg951Trp (c.2851C>T) is very rare (popmax 0.00669%, amr) (gnomAD).

What do computational predictors say about PLEC p.Arg951Trp (c.2851C>T)?

AlphaMissense predicts likely benign (score 0.2957) — an in-silico prediction, not a clinical call.

PLEC p.Arg951Trp

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.2851C>T · rs781867218 · VCV3214695

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2957 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, amr)

Conditions

epidermolysis bullosa simplex 5C, with pyloric atresia

Computational evidence

Protein change
AlphaMissense	0.2957	likely benign
REVEL	0.516	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.8	phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 18 kb · p 4.9e-10 · regional, not allelic
Overall
CADD	23.7	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 R1088W vs ClinVar R951W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00669% Admixed American · 4/59,772 alleles

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

Overall 0.00131% 21/1,599,446 alleles · very rare exomes 15/1,447,216 · genomes 6/152,230 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00669%	14,943
Remaining individualsnot grpmax-eligible	0.00482%	20,746
African / African-American	0.00401%	24,964
South Asian	0.0011%	90,852
European (non-Finnish)	0.000848%	117,915

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.Arg951Trp
Coding: c.2851C>T
MANE Select: NM_201384
dbSNP: rs781867218
Type: single nucleotide variant
Location: chr8:143929718 (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.Arg951Gln Uncertain significance ★★ same residue
PLEC p.Arg951Pro 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

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-arg951trp (accessed [today's date]).

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