Is PLEC p.Ser4237= (c.12711G>A) pathogenic?

PLEC p.Ser4237= (c.12711G>A) is classified Conflicting classifications of pathogenicity in PLEC (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-20). Ultra-rare (popmax 0.0473%, sas); Associated with epidermolysis bullosa simplex 5B, with muscular dystrophy.

What condition is associated with PLEC p.Ser4237= (c.12711G>A)?

PLEC p.Ser4237= (c.12711G>A) is associated with epidermolysis bullosa simplex 5B, with muscular dystrophy, epidermolysis bullosa simplex 5A, Ogna type, epidermolysis bullosa simplex 5C, with pyloric atresia (ClinVar).

How common is PLEC p.Ser4237= (c.12711G>A) in the general population?

PLEC p.Ser4237= (c.12711G>A) is ultra-rare (popmax 0.0473%, sas) (gnomAD).

PLEC p.Ser4237=

Q: How is Epidermolysis bullosa simplex with muscular dystrophy inherited?

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

c.12711G>A · rs548342396 · VCV592807

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0473%, sas)

Conditions

epidermolysis bullosa simplex 5B, with muscular 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	GERP -3.7
Overall
CADD	0.141	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0473% South Asian · 43/90,968 alleles

Filtering AF 0.036% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0321%

Overall 0.00636% 102/1,604,606 alleles · ultra-rare exomes 90/1,452,294 · genomes 12/152,312 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0473%	2,116
Admixed American	0.0167%	5,989
Middle Eastern	0.0165%	6,048
Remaining individualsnot grpmax-eligible	0.00968%	10,335
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,508
European (non-Finnish)	0.00333%	30,071
Finnishnot grpmax-eligible	0.00159%	63,034
African / African-American	0.00134%	74,888

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.Ser4237=
Coding: c.12711G>A
MANE Select: NM_201384
dbSNP: rs548342396
Type: single nucleotide variant
Location: chr8:143917110 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI <0.01 (gnomAD)
Residue 4237: the 'required for interaction with intermediate filament proteins' region; the 'required for interaction with type2 keratins, des and vim' region; the 'globular 2' region

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

Disease context

epidermolysis bullosa simplex 5B, with muscular dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: epidermolysis bullosa simplex 5A, Ogna type epidermolysis bullosa simplex 5C, with pyloric atresia autosomal recessive limb-girdle muscular dystrophy type 2Q epidermolysis bullosa simplex with nail dystrophy

For Epidermolysis bullosa simplex with muscular dystrophy (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

PLEC p.Ser4237Leu 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-ser4237 (accessed [today's date]).

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