Is PLEC p.Arg2139Cys (c.6415C>T) pathogenic?

PLEC p.Arg2139Cys (c.6415C>T) is classified Uncertain significance in PLEC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-04-12). AlphaMissense: ambiguous (0.3478); Ultra-rare (popmax 0.0166%, mid); Associated with autosomal recessive limb-girdle muscular dystrophy type 2Q.

What condition is associated with PLEC p.Arg2139Cys (c.6415C>T)?

PLEC p.Arg2139Cys (c.6415C>T) is associated with autosomal recessive limb-girdle muscular dystrophy type 2Q, epidermolysis bullosa simplex 5A, Ogna type, epidermolysis bullosa simplex 5B, with muscular dystrophy (ClinVar).

How common is PLEC p.Arg2139Cys (c.6415C>T) in the general population?

PLEC p.Arg2139Cys (c.6415C>T) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about PLEC p.Arg2139Cys (c.6415C>T)?

AlphaMissense predicts ambiguous (score 0.3478) — an in-silico prediction, not a clinical call.

PLEC p.Arg2139Cys

Q: How is Plectin-related limb-girdle muscular dystrophy R17 inherited?

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

c.6415C>T · rs782717631 · VCV586338

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.3478 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Conditions

autosomal recessive limb-girdle muscular dystrophy type 2Q

Computational evidence

Protein change
AlphaMissense	0.3478	ambiguous
REVEL	0.438	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 18 kb · p 4.9e-10 · regional, not allelic
Overall
CADD	26.0	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 R2276C vs ClinVar R2139C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0166% Middle Eastern · 1/6,008 alleles

Filtering AF 0.000248% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000626% 10/1,596,598 alleles · ultra-rare exomes 8/1,444,686 · genomes 2/151,912 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,008
African / African-American	0.00134%	74,720
South Asian	0.00111%	90,492
European (non-Finnish)	0.000596%	167,826

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.Arg2139Cys
Coding: c.6415C>T
MANE Select: NM_201384
dbSNP: rs782717631
Type: single nucleotide variant
Location: chr8:143923514 (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

autosomal recessive limb-girdle muscular dystrophy type 2Q — 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 epidermolysis bullosa simplex with nail dystrophy

For Plectin-related limb-girdle muscular dystrophy R17 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

PLEC p.Arg2139= Likely benign ★★ 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-arg2139cys (accessed [today's date]).

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