Is PLEC p.Val1040= (c.3120C>T) pathogenic?

PLEC p.Val1040= (c.3120C>T) is classified Likely benign in PLEC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-10). Rare (popmax 0.132%, mid); Associated with epidermolysis bullosa simplex with nail dystrophy.

What condition is associated with PLEC p.Val1040= (c.3120C>T)?

PLEC p.Val1040= (c.3120C>T) 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.Val1040= (c.3120C>T) in the general population?

PLEC p.Val1040= (c.3120C>T) is rare (popmax 0.132%, mid) (gnomAD).

PLEC p.Val1040=

c.3120C>T · rs782246688 · VCV705077

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.132%, mid)

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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.6
Overall
CADD	0.249	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.132% Middle Eastern · 8/6,078 alleles

Filtering AF 0.0655% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0477%

Overall 0.00449% 72/1,601,798 alleles · rare exomes 47/1,449,628 · genomes 25/152,170 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.132%	760
African / African-American	0.0481%	2,080
Remaining individualsnot grpmax-eligible	0.00321%	31,131
South Asian	0.0022%	45,354
European (non-Finnish)	0.00195%	51,277
Finnishnot grpmax-eligible	0.00187%	53,488

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.Val1040=
Coding: c.3120C>T
MANE Select: NM_201384
dbSNP: rs782246688
Type: single nucleotide variant
Location: chr8:143929243 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI <0.01 (gnomAD)
Residue 1040: 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.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-val1040 (accessed [today's date]).

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