Is PLEC p.Ser421= (c.1263G>A) pathogenic?

PLEC p.Ser421= (c.1263G>A) is classified Pathogenic in PLEC (ClinVar, No assertion criteria, 1 submitter; last evaluated 2005-02-01). No allele count reported in gnomAD v4.1 (AN 1,609,052); Associated with epidermolysis bullosa simplex 5C, with pyloric atresia.

What condition is associated with PLEC p.Ser421= (c.1263G>A)?

PLEC p.Ser421= (c.1263G>A) is associated with epidermolysis bullosa simplex 5C, with pyloric atresia (ClinVar).

How common is PLEC p.Ser421= (c.1263G>A) in the general population?

PLEC p.Ser421= (c.1263G>A) is no allele count reported in gnomAD v4.1 (AN 1,609,052) (gnomAD).

PLEC p.Ser421=

Q: How is Epidermolysis bullosa simplex with pyloric atresia inherited?

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

c.1263G>A · rs864309672 · VCV8265

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,609,052)

Conditions

epidermolysis bullosa simplex 5C, with pyloric atresia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.76	donor gain · deltas
Pangolin	Δ0.78	loss · gain 0.73 · SpliceAI calls gain · independent
Constraint at this position
Conservation	phyloP 3.8	phastCons 1
Overall
CADD	27.3	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,609,052). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: PLEC
Protein: p.Ser421=
Coding: c.1263G>A
MANE Select: NM_201384
dbSNP: rs864309672
Type: single nucleotide variant
Location: chr8:143933998 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI <0.01 (gnomAD)
Residue 421: an α-helix; the 'globular 1' region

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

Disease context

epidermolysis bullosa simplex 5C, with pyloric atresia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Epidermolysis bullosa simplex with pyloric atresia (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

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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
PLEC p.Gln1591Ter Pathogenic/Likely 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-ser421 (accessed [today's date]).

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