Is PLEC p.Asp416= (c.1248C>T) pathogenic?

PLEC p.Asp416= (c.1248C>T) is classified Conflicting classifications of pathogenicity in PLEC (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-08-18). Ultra-rare (popmax 0.0176%, sas); Associated with epidermolysis bullosa simplex 5A, Ogna type.

What condition is associated with PLEC p.Asp416= (c.1248C>T)?

PLEC p.Asp416= (c.1248C>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.Asp416= (c.1248C>T) in the general population?

PLEC p.Asp416= (c.1248C>T) is ultra-rare (popmax 0.0176%, sas) (gnomAD).

PLEC p.Asp416=

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.1248C>T · rs572481168 · VCV514094

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0176%, sas)

Conditions

epidermolysis bullosa simplex 5A, Ogna type

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 2.3	phastCons 1
Overall
CADD	14.1	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0176% South Asian · 16/90,754 alleles

Filtering AF 0.011% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00901%

Overall 0.00373% 60/1,607,894 alleles · ultra-rare exomes 58/1,457,342 · genomes 2/150,552 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0176%	5,672
Middle Eastern	0.0165%	6,056
Admixed American	0.00668%	14,960
East Asian	0.00448%	22,344
European (non-Finnish)	0.00297%	33,684
Remaining individualsnot grpmax-eligible	0.00161%	62,282
African / African-American	0.00138%	72,614

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.Asp416=
Coding: c.1248C>T
MANE Select: NM_201384
dbSNP: rs572481168
Type: single nucleotide variant
Location: chr8:143934013 (GRCh38)

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

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-asp416 (accessed [today's date]).

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