Is PLEC p.Arg4223= (c.12669C>T) pathogenic?

PLEC p.Arg4223= (c.12669C>T) is classified Conflicting classifications of pathogenicity in PLEC (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-08). Rare (popmax 0.432%, eas); Associated with epidermolysis bullosa simplex 5B, with muscular dystrophy.

What condition is associated with PLEC p.Arg4223= (c.12669C>T)?

PLEC p.Arg4223= (c.12669C>T) 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.Arg4223= (c.12669C>T) in the general population?

PLEC p.Arg4223= (c.12669C>T) is rare (popmax 0.432%, eas) (gnomAD).

PLEC p.Arg4223=

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.12669C>T · rs571894941 · VCV595339

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.432%, eas)

Conditions

epidermolysis bullosa simplex 5B, with muscular dystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -10	GERP -3.7
Overall
CADD	0.174	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.432% East Asian · 193/44,668 alleles

Filtering AF 0.382% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.363%

Overall 0.0184% 296/1,607,610 alleles · rare exomes 278/1,455,298 · genomes 18/152,312 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.432%	231
Remaining individualsnot grpmax-eligible	0.0177%	5,652
African / African-American	0.00801%	12,489
European (non-Finnish)	0.00706%	14,159
Admixed American	0.00167%	59,922
Finnishnot grpmax-eligible	0.00158%	63,174
South Asian	0.0011%	91,026

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.Arg4223=
Coding: c.12669C>T
MANE Select: NM_201384
dbSNP: rs571894941
Type: single nucleotide variant
Location: chr8:143917152 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI <0.01 (gnomAD)
Residue 4223: the 'required for interaction with intermediate filament proteins' region; the 'required for interaction with type2 keratins, des and vim' region; the 'globular 2' region

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.Arg4223His 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
PLEC p.Arg559Ter 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-arg4223 (accessed [today's date]).

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