Is PLEC p.Arg1908Gln (c.5723G>A) pathogenic?

PLEC p.Arg1908Gln (c.5723G>A) is classified Uncertain significance in PLEC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-13). AlphaMissense: likely benign (0.1627); Ultra-rare (popmax 0.0384%, amr); Associated with PLEC-related disorder.

What condition is associated with PLEC p.Arg1908Gln (c.5723G>A)?

PLEC p.Arg1908Gln (c.5723G>A) is associated with PLEC-related disorder, epidermolysis bullosa simplex 5A, Ogna type, epidermolysis bullosa simplex 5B, with muscular dystrophy (ClinVar).

How common is PLEC p.Arg1908Gln (c.5723G>A) in the general population?

PLEC p.Arg1908Gln (c.5723G>A) is ultra-rare (popmax 0.0384%, amr) (gnomAD).

What do computational predictors say about PLEC p.Arg1908Gln (c.5723G>A)?

AlphaMissense predicts likely benign (score 0.1627) — an in-silico prediction, not a clinical call.

PLEC p.Arg1908Gln

c.5723G>A · rs369142466 · VCV571120

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1627 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0384%, amr)

Conditions

PLEC-related disorder

Computational evidence

Protein change
AlphaMissense	0.1627	likely benign
REVEL	0.434	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	28.8	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 R2045Q vs ClinVar R1908Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0384% Admixed American · 23/59,960 alleles

Filtering AF 0.0261% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0222%

Overall 0.00457% 73/1,598,830 alleles · ultra-rare exomes 50/1,446,692 · genomes 23/152,138 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0384%	2,607
East Asian	0.0178%	5,605
Remaining individualsnot grpmax-eligible	0.00481%	20,782
African / African-American	0.00401%	24,961
South Asian	0.00329%	30,357
European (non-Finnish)	0.0028%	35,744

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.Arg1908Gln
Coding: c.5723G>A
MANE Select: NM_201384
dbSNP: rs369142466
Type: single nucleotide variant
Location: chr8:143924206 (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

PLEC-related disorder

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.Arg1908Trp Uncertain significance ★★ same residue
PLEC p.Arg1908Leu Uncertain significance ★ same residue
PLEC p.Arg1908Pro Uncertain significance ★ same residue
PLEC p.Arg1908= 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

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-arg1908gln (accessed [today's date]).

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