Is PLEC p.Arg90Gln (c.269G>A) pathogenic?

PLEC p.Arg90Gln (c.269G>A) is classified Uncertain significance in PLEC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-06). AlphaMissense: likely pathogenic (0.9192); Very rare (popmax 0.00891%, eas); Associated with epidermolysis bullosa simplex 5B, with muscular dystrophy.

What condition is associated with PLEC p.Arg90Gln (c.269G>A)?

PLEC p.Arg90Gln (c.269G>A) is associated with epidermolysis bullosa simplex 5B, with muscular dystrophy, epidermolysis bullosa simplex 5A, Ogna type, epidermolysis bullosa simplex 5C, with pyloric atresia (ClinVar).

How common is PLEC p.Arg90Gln (c.269G>A) in the general population?

PLEC p.Arg90Gln (c.269G>A) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about PLEC p.Arg90Gln (c.269G>A)?

AlphaMissense predicts likely pathogenic (score 0.9192) — an in-silico prediction, not a clinical call.

PLEC p.Arg90Gln

Q: How is Epidermolysis bullosa simplex with muscular dystrophy inherited?

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

c.269G>A · rs782376931 · VCV2051754

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9192 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

epidermolysis bullosa simplex 5B, with muscular dystrophy

Computational evidence

Protein change
AlphaMissense	0.9192	likely pathogenic · top 10% in PLEC
REVEL	0.881	moderately pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 2,464 bp · p 0.43 · regional, not allelic
Overall
CADD	32.0	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 R227Q vs ClinVar R90Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00891% East Asian · 4/44,880 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.00205% 33/1,612,046 alleles · very rare exomes 30/1,459,898 · genomes 3/152,148 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,220
European (non-Finnish)	0.00237%	42,120
Remaining individualsnot grpmax-eligible	0.0016%	62,424

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.Arg90Gln
Coding: c.269G>A
MANE Select: NM_201384
dbSNP: rs782376931
Type: single nucleotide variant
Location: chr8:143937238 (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 5B, with muscular dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: epidermolysis bullosa simplex 5A, Ogna type epidermolysis bullosa simplex 5C, with pyloric atresia autosomal recessive limb-girdle muscular dystrophy type 2Q epidermolysis bullosa simplex with nail dystrophy

For Epidermolysis bullosa simplex with muscular dystrophy (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

PLEC p.Arg90Trp Uncertain significance ★★ ⚠ same residue
PLEC p.Arg90Gly 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-arg90gln (accessed [today's date]).

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