Is PLEC p.Ala1669= (c.5007G>A) pathogenic?

PLEC p.Ala1669= (c.5007G>A) is classified Likely benign in PLEC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-22). Very rare (popmax 0.00909%, eas); Associated with epidermolysis bullosa simplex 5C, with pyloric atresia.

What condition is associated with PLEC p.Ala1669= (c.5007G>A)?

PLEC p.Ala1669= (c.5007G>A) 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.Ala1669= (c.5007G>A) in the general population?

PLEC p.Ala1669= (c.5007G>A) is very rare (popmax 0.00909%, eas) (gnomAD).

PLEC p.Ala1669=

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.5007G>A · rs781796614 · VCV779803

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00909%, 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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -20
Overall
CADD	1.209	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00909% East Asian · 4/44,000 alleles

Filtering AF 0.00367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.00353% 56/1,584,664 alleles · very rare exomes 52/1,432,452 · genomes 4/152,212 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00909%	11,000
Remaining individualsnot grpmax-eligible	0.00811%	12,332
African / African-American	0.00806%	12,410
South Asian	0.00788%	12,691
European (non-Finnish)	0.0029%	34,513

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.Ala1669=
Coding: c.5007G>A
MANE Select: NM_201384
dbSNP: rs781796614
Type: single nucleotide variant
Location: chr8:143924922 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI <0.01 (gnomAD)
Residue 1669: the 'required for interaction with intermediate filament proteins' region; the 'central fibrous rod domain' 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.Ala1669Val 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
PLEC p.Arg559Ter 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-ala1669 (accessed [today's date]).

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