Is PLEC p.Ala2083= (c.6249G>A) pathogenic?

PLEC p.Ala2083= (c.6249G>A) is classified Conflicting classifications of pathogenicity in PLEC (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-20). Rare (popmax 0.28%, mid); Associated with autosomal recessive limb-girdle muscular dystrophy type 2Q.

What condition is associated with PLEC p.Ala2083= (c.6249G>A)?

PLEC p.Ala2083= (c.6249G>A) is associated with autosomal recessive limb-girdle muscular dystrophy type 2Q, epidermolysis bullosa simplex 5A, Ogna type, epidermolysis bullosa simplex 5B, with muscular dystrophy (ClinVar).

How common is PLEC p.Ala2083= (c.6249G>A) in the general population?

PLEC p.Ala2083= (c.6249G>A) is rare (popmax 0.28%, mid) (gnomAD).

PLEC p.Ala2083=

Q: How is Plectin-related limb-girdle muscular dystrophy R17 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.6249G>A · rs377026986 · VCV287903

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.28%, mid)

Conditions

autosomal recessive limb-girdle muscular dystrophy type 2Q

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	0.022	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.28% Middle Eastern · 16/5,722 alleles

Filtering AF 0.175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.143%

Overall 0.00775% 120/1,548,000 alleles · rare exomes 108/1,395,754 · genomes 12/152,246 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.28%	358
East Asian	0.029%	3,451
South Asian	0.0257%	3,898
African / African-American	0.0245%	4,083
Remaining individualsnot grpmax-eligible	0.0183%	5,479
Finnishnot grpmax-eligible	0.00881%	11,348
Admixed American	0.00375%	26,692
European (non-Finnish)	0.00304%	32,944

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.Ala2083=
Coding: c.6249G>A
MANE Select: NM_201384
dbSNP: rs377026986
Type: single nucleotide variant
Location: chr8:143923680 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI <0.01 (gnomAD)
Residue 2083: 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

autosomal recessive limb-girdle muscular dystrophy type 2Q — 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 epidermolysis bullosa simplex with nail dystrophy

For Plectin-related limb-girdle muscular dystrophy R17 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

PLEC p.Ala2083Thr Uncertain significance ★★ ⚠ same residue
PLEC p.Ala2083Val 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

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-ala2083 (accessed [today's date]).

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