Is PLEC p.Arg2004Trp (c.6010C>T) pathogenic?

PLEC p.Arg2004Trp (c.6010C>T) is classified Uncertain significance in PLEC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-08). AlphaMissense: likely benign (0.2314); Ultra-rare (popmax 0.0204%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PLEC p.Arg2004Trp (c.6010C>T)?

PLEC p.Arg2004Trp (c.6010C>T) is associated with Inborn genetic diseases, epidermolysis bullosa simplex 5A, Ogna type, epidermolysis bullosa simplex 5B, with muscular dystrophy (ClinVar).

How common is PLEC p.Arg2004Trp (c.6010C>T) in the general population?

PLEC p.Arg2004Trp (c.6010C>T) is ultra-rare (popmax 0.0204%, nfe) (gnomAD).

What do computational predictors say about PLEC p.Arg2004Trp (c.6010C>T)?

AlphaMissense predicts likely benign (score 0.2314) — an in-silico prediction, not a clinical call.

PLEC p.Arg2004Trp

c.6010C>T · rs369813798 · VCV538962

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2314 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0204%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2314	likely benign
REVEL	0.214	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 18 kb · p 4.9e-10 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 R2141W vs ClinVar R2004W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0204% European (non-Finnish) · 240/1,178,152 alleles

Filtering AF 0.0182% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0174%

Overall 0.0167% 267/1,594,826 alleles · ultra-rare exomes 256/1,442,828 · genomes 11/151,998 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0204%	4,909
South Asian	0.0154%	6,482
Remaining individualsnot grpmax-eligible	0.0113%	8,868
East Asian	0.00671%	14,903
African / African-American	0.00268%	37,367
Finnishnot grpmax-eligible	0.00206%	48,432

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.Arg2004Trp
Coding: c.6010C>T
MANE Select: NM_201384
dbSNP: rs369813798
Type: single nucleotide variant
Location: chr8:143923919 (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

Inborn genetic diseases — 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 epidermolysis bullosa simplex with nail dystrophy

Similar variants

PLEC p.Arg2004= Conflicting classifications of pathogenicity ★ same residue
PLEC p.Arg2004Gln 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-arg2004trp (accessed [today's date]).

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