Is PLEC p.Val3322= (c.9966C>T) pathogenic?

PLEC p.Val3322= (c.9966C>T) is classified Benign in PLEC (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-03). Low-frequency (popmax 2.26%, afr); Associated with epidermolysis bullosa simplex 5C, with pyloric atresia.

What condition is associated with PLEC p.Val3322= (c.9966C>T)?

PLEC p.Val3322= (c.9966C>T) is associated with epidermolysis bullosa simplex 5C, with pyloric atresia, epidermolysis bullosa simplex 5A, Ogna type, epidermolysis bullosa simplex 5B, with muscular dystrophy (ClinVar).

How common is PLEC p.Val3322= (c.9966C>T) in the general population?

PLEC p.Val3322= (c.9966C>T) is low-frequency (popmax 2.26%, afr) (gnomAD).

PLEC p.Val3322=

Q: How is Epidermolysis bullosa simplex with pyloric atresia inherited?

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

c.9966C>T · rs35613096 · VCV129919

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.26%, afr)

Conditions

epidermolysis bullosa simplex 5C, with pyloric atresia

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 2.5	phastCons 1
Overall
CADD	1.808	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.26% African / African-American · 1,694/75,066 alleles

Filtering AF 2.17% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.13%

Overall 0.126% 2,028/1,613,136 alleles · low-frequency exomes 1,106/1,460,780 · genomes 922/152,356 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.26%	44
Middle Eastern	0.231%	433
Remaining individualsnot grpmax-eligible	0.222%	450
Admixed American	0.108%	924
European (non-Finnish)	0.00924%	10,826
South Asian	0.00659%	15,179
East Asian	0.00223%	44,888

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.Val3322=
Coding: c.9966C>T
MANE Select: NM_201384
dbSNP: rs35613096
Type: single nucleotide variant
Location: chr8:143919855 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI <0.01 (gnomAD)
Residue 3322: the 'required for interaction with intermediate filament proteins' region; the 'globular 2' region; the 'disordered' region

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

Disease context

epidermolysis bullosa simplex 5C, with pyloric atresia — 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 autosomal recessive limb-girdle muscular dystrophy type 2Q epidermolysis bullosa simplex with nail dystrophy

For Epidermolysis bullosa simplex with pyloric atresia (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

PLEC p.Val3322Ala Uncertain significance ★ same residue
PLEC p.Val3322Phe Uncertain significance ★ ⚠ same residue
PLEC p.Val3322fs Likely pathogenic ★ 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

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-val3322 (accessed [today's date]).

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