Is PLEC p.Ser4084= (c.12252G>A) pathogenic?

PLEC p.Ser4084= (c.12252G>A) is classified Likely benign in PLEC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-29). Ultra-rare (popmax 0.0626%, sas); Associated with epidermolysis bullosa simplex with nail dystrophy.

What condition is associated with PLEC p.Ser4084= (c.12252G>A)?

PLEC p.Ser4084= (c.12252G>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.Ser4084= (c.12252G>A) in the general population?

PLEC p.Ser4084= (c.12252G>A) is ultra-rare (popmax 0.0626%, sas) (gnomAD).

PLEC p.Ser4084=

c.12252G>A · VCV3761781

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0626%, sas)

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 -20	GERP -3.7
Overall
CADD	0.054	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0626% South Asian · 57/91,082 alleles

Filtering AF 0.0496% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0449%

Overall 0.00514% 83/1,613,912 alleles · ultra-rare exomes 74/1,461,644 · genomes 9/152,268 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0626%	1,598
East Asian	0.00891%	11,218
Remaining individualsnot grpmax-eligible	0.0048%	20,835
African / African-American	0.004%	25,008
Finnishnot grpmax-eligible	0.00314%	31,894
European (non-Finnish)	0.00119%	84,288

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.Ser4084=
Coding: c.12252G>A
MANE Select: NM_201384
Type: single nucleotide variant
Location: chr8:143917569 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI <0.01 (gnomAD)
Residue 4084: 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 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.Ser4084Leu 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-ser4084 (accessed [today's date]).

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