Is PLEC p.Ala2984= (c.8952C>T) pathogenic?

PLEC p.Ala2984= (c.8952C>T) is classified Conflicting classifications of pathogenicity in PLEC (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-12-19). Ultra-rare (popmax 0.0535%, eas); Associated with epidermolysis bullosa simplex 5A, Ogna type.

What condition is associated with PLEC p.Ala2984= (c.8952C>T)?

PLEC p.Ala2984= (c.8952C>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.Ala2984= (c.8952C>T) in the general population?

PLEC p.Ala2984= (c.8952C>T) is ultra-rare (popmax 0.0535%, eas) (gnomAD).

PLEC p.Ala2984=

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.8952C>T · rs371672166 · VCV290450

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0535%, eas)

Conditions

epidermolysis bullosa simplex 5A, Ogna type

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 -12
Overall
CADD	0.07	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0535% East Asian · 24/44,854 alleles

Filtering AF 0.0368% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0313%

Overall 0.00813% 131/1,610,410 alleles · ultra-rare exomes 121/1,458,114 · genomes 10/152,296 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0535%	1,869
Remaining individualsnot grpmax-eligible	0.0304%	3,287
African / African-American	0.0173%	5,771
Middle Eastern	0.0165%	6,060
European (non-Finnish)	0.00619%	16,163
Admixed American	0.00167%	59,982

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.Ala2984=
Coding: c.8952C>T
MANE Select: NM_201384
dbSNP: rs371672166
Type: single nucleotide variant
Location: chr8:143920869 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI <0.01 (gnomAD)
Residue 2984: 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 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

Similar variants

PLEC p.Ala2984Thr Uncertain significance ★ ⚠ same residue
PLEC p.Ala2984Val 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

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-ala2984 (accessed [today's date]).

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