Is PLEC p.Arg4490Ser (c.13468C>A) pathogenic?

PLEC p.Arg4490Ser (c.13468C>A) is classified Uncertain significance in PLEC (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-24). AlphaMissense: ambiguous (0.4891); Ultra-rare (popmax 0.0124%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PLEC p.Arg4490Ser (c.13468C>A)?

PLEC p.Arg4490Ser (c.13468C>A) is associated with Inborn genetic diseases, epidermolysis bullosa simplex 5A, Ogna type, epidermolysis bullosa simplex 5B, with muscular dystrophy (ClinVar).

How common is PLEC p.Arg4490Ser (c.13468C>A) in the general population?

PLEC p.Arg4490Ser (c.13468C>A) is ultra-rare (popmax 0.0124%, nfe) (gnomAD).

What do computational predictors say about PLEC p.Arg4490Ser (c.13468C>A)?

AlphaMissense predicts ambiguous (score 0.4891) — an in-silico prediction, not a clinical call.

PLEC p.Arg4490Ser

c.13468C>A · rs782717056 · VCV283285

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.4891 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0124%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4891	ambiguous
REVEL	0.453	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 397 bp · p 0.6 · regional, not allelic
Overall
CADD	21.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R4627S vs ClinVar R4490S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0124% European (non-Finnish) · 146/1,176,648 alleles

Filtering AF 0.0107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0101%

Overall 0.00996% 160/1,605,860 alleles · ultra-rare exomes 150/1,453,746 · genomes 10/152,114 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0124%	8,059
Admixed American	0.0101%	9,923
Remaining individualsnot grpmax-eligible	0.00966%	10,350
African / African-American	0.00268%	37,331

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.Arg4490Ser
Coding: c.13468C>A
MANE Select: NM_201384
dbSNP: rs782717056
Type: single nucleotide variant
Location: chr8:143916353 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI <0.01 (gnomAD)

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

Disease context

Inborn genetic diseases — 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 epidermolysis bullosa simplex with nail dystrophy

Similar variants

PLEC p.Arg4490Cys Uncertain significance ★★ same residue
PLEC p.Arg4490His Uncertain significance ★★ same residue
PLEC p.Arg4490= 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

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-arg4490ser (accessed [today's date]).

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