Is PLEC p.Ser4271= (c.12813A>G) pathogenic?

PLEC p.Ser4271= (c.12813A>G) is classified Benign in PLEC (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-04). Common (popmax 84.8%, afr) — too common for a highly-penetrant pathogenic allele; Associated with autosomal recessive limb-girdle muscular dystrophy type 2Q.

What condition is associated with PLEC p.Ser4271= (c.12813A>G)?

PLEC p.Ser4271= (c.12813A>G) 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).

PLEC p.Ser4271=

Q: How common is PLEC p.Ser4271= (c.12813A>G) in the general population?

PLEC p.Ser4271= (c.12813A>G) is common (popmax 84.8%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.12813A>G · rs6558405 · VCV93030

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Common

common (popmax 84.8%, afr) — too common for a highly-penetrant pathogenic allele

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 -11	GERP -3.7
Overall
CADD	0.013	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 84.8% African / African-American · 63,617/74,976 alleles

Filtering AF 84.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 84.1%

Overall 43.8% 706,849/1,612,292 alleles · common exomes 626,781/1,460,216 · genomes 80,068/152,076 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	84.8%	1
Ashkenazi Jewishnot grpmax-eligible	46.7%	2
Remaining individualsnot grpmax-eligible	44.7%	2
Middle Eastern	44.6%	2
Amishnot grpmax-eligible	43.4%	2
European (non-Finnish)	43.4%	2
Finnishnot grpmax-eligible	40.6%	2
South Asian	36.5%	3
Admixed American	33%	3
East Asian	17.3%	6

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.Ser4271=
Coding: c.12813A>G
MANE Select: NM_201384
dbSNP: rs6558405
Type: single nucleotide variant
Location: chr8:143917008 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI <0.01 (gnomAD)
Residue 4271: the 'required for interaction with intermediate filament proteins' region; the 'required for interaction with type2 keratins, des and vim' region; the 'globular 2' region; the 'binding to intermediate filaments' 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.Ser4271Leu 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-ser4271 (accessed [today's date]).

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