Is PLEC p.Arg2457Pro (c.7370G>C) pathogenic?

PLEC p.Arg2457Pro (c.7370G>C) is classified Conflicting classifications of pathogenicity in PLEC (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-01). AlphaMissense: likely pathogenic (0.7706); Ultra-rare (popmax 0.0558%, nfe); Associated with autosomal recessive limb-girdle muscular dystrophy.

How common is PLEC p.Arg2457Pro (c.7370G>C) in the general population?

PLEC p.Arg2457Pro (c.7370G>C) is ultra-rare (popmax 0.0558%, nfe) (gnomAD).

What do computational predictors say about PLEC p.Arg2457Pro (c.7370G>C)?

AlphaMissense predicts likely pathogenic (score 0.7706) — an in-silico prediction, not a clinical call.

PLEC p.Arg2457Pro

Q: What condition is associated with PLEC p.Arg2457Pro (c.7370G>C)?

PLEC p.Arg2457Pro (c.7370G>C) is associated with autosomal recessive limb-girdle muscular dystrophy, epidermolysis bullosa simplex 5A, Ogna type, epidermolysis bullosa simplex 5B, with muscular dystrophy (ClinVar).

c.7370G>C · rs199504105 · VCV471647

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.7706 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0558%, nfe)

Conditions

autosomal recessive limb-girdle muscular dystrophy

Computational evidence

Protein change
AlphaMissense	0.7706	likely pathogenic
REVEL	0.356	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.084	phastCons 0.002
Regional constraint	o/e 1.08	unconstrained · MANE · 18 kb · p 4.9e-10 · regional, not allelic
Overall
CADD	19.24	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R2594P vs ClinVar R2457P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0558% European (non-Finnish) · 658/1,179,988 alleles

Filtering AF 0.0522% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0508%

Overall 0.0417% 672/1,613,184 alleles · ultra-rare exomes 635/1,460,992 · genomes 37/152,192 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0558%	1,793
Remaining individualsnot grpmax-eligible	0.0144%	6,942
Admixed American	0.00333%	30,000
Finnishnot grpmax-eligible	0.00316%	31,619
African / African-American	0.00133%	74,930

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.Arg2457Pro
Coding: c.7370G>C
MANE Select: NM_201384
dbSNP: rs199504105
Type: single nucleotide variant
Location: chr8:143922559 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI <0.01 (gnomAD)

Full PLEC gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive limb-girdle muscular 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 epidermolysis bullosa simplex with nail dystrophy

Similar variants

PLEC p.Arg2457His Uncertain significance ★★ ⚠ same residue
PLEC p.Arg2457Cys 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-arg2457pro (accessed [today's date]).

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