Is PLEC p.Arg71Cys (c.211C>T) pathogenic?

PLEC p.Arg71Cys (c.211C>T) is classified Uncertain significance in PLEC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-08-13). AlphaMissense: likely pathogenic (0.978); Very rare (popmax 0.000339%, nfe); Associated with epidermolysis bullosa simplex with nail dystrophy.

What condition is associated with PLEC p.Arg71Cys (c.211C>T)?

PLEC p.Arg71Cys (c.211C>T) is associated with epidermolysis bullosa simplex with nail dystrophy, epidermolysis bullosa simplex 5A, Ogna type, epidermolysis bullosa simplex 5B, with muscular dystrophy (ClinVar).

How common is PLEC p.Arg71Cys (c.211C>T) in the general population?

PLEC p.Arg71Cys (c.211C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about PLEC p.Arg71Cys (c.211C>T)?

AlphaMissense predicts likely pathogenic (score 0.978) — an in-silico prediction, not a clinical call.

PLEC p.Arg71Cys

c.211C>T · rs781901742 · VCV432735

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.978 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

epidermolysis bullosa simplex with nail dystrophy

Computational evidence

Protein change
AlphaMissense	0.978	likely pathogenic · top 5% in PLEC
REVEL	0.751	pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.8	phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 2,464 bp · p 0.43 · regional, not allelic
Overall
CADD	28.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R208C vs ClinVar R71C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,178,616 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000249% 4/1,608,074 alleles · very rare exomes 4/1,456,000 · genomes 0/152,074 · joint denominator

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.Arg71Cys
Coding: c.211C>T
MANE Select: NM_201384
dbSNP: rs781901742
Type: single nucleotide variant
Location: chr8:143938204 (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 with nail dystrophy — 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 epidermolysis bullosa simplex 5C, with pyloric atresia autosomal recessive limb-girdle muscular dystrophy type 2Q

Similar variants

PLEC p.Arg71His Uncertain significance ★★ ⚠ same residue
PLEC p.Arg71= Likely benign ★ 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-arg71cys (accessed [today's date]).

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