Is PLEC p.Ala1648= (c.4944G>A) pathogenic?

PLEC p.Ala1648= (c.4944G>A) is classified Likely benign in PLEC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-15). Very rare (popmax 0.00459%, eas); Associated with epidermolysis bullosa simplex with nail dystrophy.

What condition is associated with PLEC p.Ala1648= (c.4944G>A)?

PLEC p.Ala1648= (c.4944G>A) 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.Ala1648= (c.4944G>A) in the general population?

PLEC p.Ala1648= (c.4944G>A) is very rare (popmax 0.00459%, eas) (gnomAD).

PLEC p.Ala1648=

c.4944G>A · rs782665485 · VCV805214

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00459%, eas)

Conditions

epidermolysis bullosa simplex with nail dystrophy

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 -16
Overall
CADD	0.54	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00459% East Asian · 2/43,526 alleles

Filtering AF 0.000762% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000543%

Overall 0.00133% 21/1,577,460 alleles · very rare exomes 18/1,425,262 · genomes 3/152,198 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00459%	21,763
African / African-American	0.00269%	37,173
South Asian	0.00227%	44,143
Admixed American	0.00173%	57,684
European (non-Finnish)	0.0012%	83,578

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.Ala1648=
Coding: c.4944G>A
MANE Select: NM_201384
dbSNP: rs782665485
Type: single nucleotide variant
Location: chr8:143924985 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI <0.01 (gnomAD)
Residue 1648: the 'required for interaction with intermediate filament proteins' region; the 'central fibrous rod domain' region; the 'disordered' 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.Ala1648Val 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-ala1648 (accessed [today's date]).

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