Is PLEC p.Arg1096= (c.3288C>T) pathogenic?

PLEC p.Arg1096= (c.3288C>T) is classified Likely benign in PLEC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-24). Very rare (popmax 0.00937%, afr); Associated with epidermolysis bullosa simplex 5C, with pyloric atresia.

What condition is associated with PLEC p.Arg1096= (c.3288C>T)?

PLEC p.Arg1096= (c.3288C>T) is associated with epidermolysis bullosa simplex 5C, with pyloric atresia, epidermolysis bullosa simplex 5A, Ogna type, epidermolysis bullosa simplex 5B, with muscular dystrophy (ClinVar).

How common is PLEC p.Arg1096= (c.3288C>T) in the general population?

PLEC p.Arg1096= (c.3288C>T) is very rare (popmax 0.00937%, afr) (gnomAD).

PLEC p.Arg1096=

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.3288C>T · rs370987177 · VCV1110819

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00937%, afr)

Conditions

epidermolysis bullosa simplex 5C, with pyloric atresia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.24	phastCons 0.001
Overall
CADD	7.1	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00937% African / African-American · 7/74,688 alleles

Filtering AF 0.00439% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0031%

Overall 0.00381% 61/1,601,502 alleles · very rare exomes 50/1,449,242 · genomes 11/152,260 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00937%	10,670
Admixed American	0.00839%	11,912
East Asian	0.0045%	22,241
European (non-Finnish)	0.00358%	27,899
Ashkenazi Jewishnot grpmax-eligible	0.00341%	29,350
Remaining individualsnot grpmax-eligible	0.00324%	30,900
South Asian	0.00221%	45,304

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.Arg1096=
Coding: c.3288C>T
MANE Select: NM_201384
dbSNP: rs370987177
Type: single nucleotide variant
Location: chr8:143927965 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI <0.01 (gnomAD)
Residue 1096: an α-helix; the 'required for interaction with intermediate filament proteins' region; 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

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

For Epidermolysis bullosa simplex with pyloric atresia (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

PLEC p.Arg1096Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
PLEC p.Arg1096His 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-arg1096 (accessed [today's date]).

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