Is PLEC p.Asp4448= (c.13344C>T) pathogenic?

PLEC p.Asp4448= (c.13344C>T) is classified Benign/Likely benign in PLEC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-02). Rare (popmax 0.532%, eas); Associated with epidermolysis bullosa simplex 5C, with pyloric atresia.

What condition is associated with PLEC p.Asp4448= (c.13344C>T)?

PLEC p.Asp4448= (c.13344C>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.Asp4448= (c.13344C>T) in the general population?

PLEC p.Asp4448= (c.13344C>T) is rare (popmax 0.532%, eas) (gnomAD).

PLEC p.Asp4448=

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.13344C>T · rs192224737 · VCV478535

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.532%, eas)

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 -0.89	GERP -3.7
Overall
CADD	7.266	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.532% East Asian · 238/44,738 alleles

Filtering AF 0.477% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.455%

Overall 0.0241% 389/1,611,494 alleles · rare exomes 327/1,459,664 · genomes 62/151,830 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.532%	188
African / African-American	0.0681%	1,469
Remaining individualsnot grpmax-eligible	0.0176%	5,676
European (non-Finnish)	0.00695%	14,382
Admixed American	0.005%	19,989
South Asian	0.00329%	30,353
Finnishnot grpmax-eligible	0.0016%	62,532

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.Asp4448=
Coding: c.13344C>T
MANE Select: NM_201384
dbSNP: rs192224737
Type: single nucleotide variant
Location: chr8:143916477 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI <0.01 (gnomAD)
Residue 4448: an α-helix; the 'required for interaction with intermediate filament proteins' region; the 'globular 2' 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

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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-asp4448 (accessed [today's date]).

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