Is PLEC p.Val1305= (c.3915C>T) pathogenic?

PLEC p.Val1305= (c.3915C>T) is classified Likely benign in PLEC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-11). Ultra-rare (popmax 0.0133%, nfe); Associated with epidermolysis bullosa simplex 5A, Ogna type.

What condition is associated with PLEC p.Val1305= (c.3915C>T)?

PLEC p.Val1305= (c.3915C>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).

How common is PLEC p.Val1305= (c.3915C>T) in the general population?

PLEC p.Val1305= (c.3915C>T) is ultra-rare (popmax 0.0133%, nfe) (gnomAD).

PLEC p.Val1305=

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.3915C>T · rs377758049 · VCV436326

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, nfe)

Conditions

epidermolysis bullosa simplex 5A, Ogna type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.294	indeterminate
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.87 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.5	phastCons 1
Overall
CADD	11.3	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% European (non-Finnish) · 157/1,179,980 alleles

Filtering AF 0.0116% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0109%

Overall 0.0102% 164/1,613,006 alleles · ultra-rare exomes 155/1,460,750 · genomes 9/152,256 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0133%	7,516
Remaining individualsnot grpmax-eligible	0.008%	12,494
Finnishnot grpmax-eligible	0.00317%	31,500

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.Val1305=
Coding: c.3915C>T
MANE Select: NM_201384
dbSNP: rs377758049
Type: single nucleotide variant
Location: chr8:143927007 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI <0.01 (gnomAD)
Residue 1305: 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 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-val1305 (accessed [today's date]).

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