Is PLEC p.Arg1249= (c.3745C>A) pathogenic?

PLEC p.Arg1249= (c.3745C>A) is classified Benign/Likely benign in PLEC (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-27). Rare (popmax 0.798%, afr); Associated with epidermolysis bullosa simplex with nail dystrophy.

What condition is associated with PLEC p.Arg1249= (c.3745C>A)?

PLEC p.Arg1249= (c.3745C>A) is associated with epidermolysis bullosa simplex with nail dystrophy, epidermolysis bullosa simplex 5A, Ogna type, epidermolysis bullosa simplex 5B, with muscular dystrophy (ClinVar).

How common is PLEC p.Arg1249= (c.3745C>A) in the general population?

PLEC p.Arg1249= (c.3745C>A) is rare (popmax 0.798%, afr) (gnomAD).

PLEC p.Arg1249=

c.3745C>A · rs201552166 · VCV196104

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.798%, afr)

Conditions

epidermolysis bullosa simplex with nail dystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.4	phastCons 1
Overall
CADD	12.35	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.798% African / African-American · 598/74,956 alleles

Filtering AF 0.745% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.724%

Overall 0.0426% 682/1,602,368 alleles · rare exomes 337/1,450,140 · genomes 345/152,228 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.798%	125
Remaining individualsnot grpmax-eligible	0.0867%	1,154
Admixed American	0.0317%	3,154
South Asian	0.0077%	12,994
European (non-Finnish)	0.000339%	294,719

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.Arg1249=
Coding: c.3745C>A
MANE Select: NM_201384
dbSNP: rs201552166
Type: single nucleotide variant
Location: chr8:143927421 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI <0.01 (gnomAD)
Residue 1249: an α-helix; the 'required for interaction with intermediate filament proteins' region; the 'globular 1' region

Full PLEC gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

epidermolysis bullosa simplex with nail dystrophy — 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

Similar variants

PLEC p.Arg1249Trp 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-arg1249 (accessed [today's date]).

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