Is PLEC p.Ala428= (c.1284A>G) pathogenic?

PLEC p.Ala428= (c.1284A>G) is classified Benign/Likely benign in PLEC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-15). Rare (popmax 0.811%, eas); Associated with epidermolysis bullosa simplex with nail dystrophy.

What condition is associated with PLEC p.Ala428= (c.1284A>G)?

PLEC p.Ala428= (c.1284A>G) is associated with epidermolysis bullosa simplex with nail dystrophy, epidermolysis bullosa simplex 5A, Ogna type, epidermolysis bullosa simplex 5B, with muscular dystrophy (ClinVar).

How common is PLEC p.Ala428= (c.1284A>G) in the general population?

PLEC p.Ala428= (c.1284A>G) is rare (popmax 0.811%, eas) (gnomAD).

PLEC p.Ala428=

c.1284A>G · rs189174850 · VCV705048

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.811%, eas)

Conditions

epidermolysis bullosa simplex with nail dystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.35	acceptor loss, 2 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -5.5
Overall
CADD	0.716	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.811% East Asian · 364/44,884 alleles

Filtering AF 0.742% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.715%

Overall 0.0235% 379/1,612,164 alleles · rare exomes 343/1,459,888 · genomes 36/152,276 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.811%	123
Remaining individualsnot grpmax-eligible	0.008%	12,497
European (non-Finnish)	0.000848%	117,993

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.Ala428=
Coding: c.1284A>G
MANE Select: NM_201384
dbSNP: rs189174850
Type: single nucleotide variant
Location: chr8:143933331 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI <0.01 (gnomAD)
Residue 428: 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 with nail dystrophy — 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 epidermolysis bullosa simplex 5C, with pyloric atresia autosomal recessive limb-girdle muscular dystrophy type 2Q

Similar variants

PLEC p.Ala428Val Conflicting classifications of pathogenicity ★ ⚠ 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-ala428 (accessed [today's date]).

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