Is PLEC p.Asp4187= (c.12561C>T) pathogenic?

PLEC p.Asp4187= (c.12561C>T) is classified Benign in PLEC (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-03). Common (popmax 27.9%, afr) — too common for a highly-penetrant pathogenic allele; Associated with epidermolysis bullosa simplex 5A, Ogna type.

What condition is associated with PLEC p.Asp4187= (c.12561C>T)?

PLEC p.Asp4187= (c.12561C>T) is associated with epidermolysis bullosa simplex 5A, Ogna type, epidermolysis bullosa simplex 5B, with muscular dystrophy, epidermolysis bullosa simplex 5C, with pyloric atresia (ClinVar).

PLEC p.Asp4187=

Q: How common is PLEC p.Asp4187= (c.12561C>T) in the general population?

PLEC p.Asp4187= (c.12561C>T) is common (popmax 27.9%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is PLEC-related intermediate epidermolysis bullosa simplex without extracutaneous involvement inherited?

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

c.12561C>T · rs11998271 · VCV93028

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Common

common (popmax 27.9%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

epidermolysis bullosa simplex 5A, Ogna type

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 -5.1	GERP -3.7
Overall
CADD	0.553	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 27.9% African / African-American · 20,907/74,996 alleles

Filtering AF 27.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 27.4%

Overall 1.5% 24,184/1,611,204 alleles · common exomes 12,157/1,458,946 · genomes 12,027/152,258 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	27.9%	4
Remaining individualsnot grpmax-eligible	1.87%	54
Admixed American	1.83%	55
Middle Eastern	1.12%	89
South Asian	0.412%	243
East Asian	0.0804%	1,244
European (non-Finnish)	0.0455%	2,200

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.Asp4187=
Coding: c.12561C>T
MANE Select: NM_201384
dbSNP: rs11998271
Type: single nucleotide variant
Location: chr8:143917260 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI <0.01 (gnomAD)
Residue 4187: 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 5A, Ogna type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: 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

For PLEC-related intermediate epidermolysis bullosa simplex without extracutaneous involvement (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal

Similar variants

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
PLEC p.Gln1591Ter Pathogenic/Likely 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-asp4187 (accessed [today's date]).

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