Is PLEC p.Val693= (c.2079G>A) pathogenic?

PLEC p.Val693= (c.2079G>A) is classified Conflicting classifications of pathogenicity in PLEC (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-03-01). Very rare (popmax 0.00509%, nfe); Associated with epidermolysis bullosa simplex 5B, with muscular dystrophy.

What condition is associated with PLEC p.Val693= (c.2079G>A)?

PLEC p.Val693= (c.2079G>A) 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.Val693= (c.2079G>A) in the general population?

PLEC p.Val693= (c.2079G>A) is very rare (popmax 0.00509%, nfe) (gnomAD).

PLEC p.Val693=

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.2079G>A · rs371155701 · VCV855989

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00509%, nfe)

Conditions

epidermolysis bullosa simplex 5B, with muscular dystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.77	donor gain · deltas
Pangolin	Δ0.41	gain · loss 0.06 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -0.016	phastCons 0.74
Overall
CADD	19.73	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00509% European (non-Finnish) · 60/1,179,512 alleles

Filtering AF 0.00402% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00362%

Overall 0.00379% 61/1,610,590 alleles · very rare exomes 53/1,458,402 · genomes 8/152,188 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00509%	19,659
Remaining individualsnot grpmax-eligible	0.00161%	62,260

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.Val693=
Coding: c.2079G>A
MANE Select: NM_201384
dbSNP: rs371155701
Type: single nucleotide variant
Location: chr8:143932133 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI <0.01 (gnomAD)
Residue 693: an α-helix; the 'globular 1' 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.Val693Met Uncertain significance ★ ⚠ same residue
PLEC p.Val693Gly 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

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-val693 (accessed [today's date]).

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