Is PLEC p.Arg4414= (c.13242C>T) pathogenic?

PLEC p.Arg4414= (c.13242C>T) is classified Conflicting classifications of pathogenicity in PLEC (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-11-12). Ultra-rare (popmax 0.02%, amr); Associated with Inborn genetic diseases.

What condition is associated with PLEC p.Arg4414= (c.13242C>T)?

PLEC p.Arg4414= (c.13242C>T) 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.Arg4414= (c.13242C>T) in the general population?

PLEC p.Arg4414= (c.13242C>T) is ultra-rare (popmax 0.02%, amr) (gnomAD).

PLEC p.Arg4414=

c.13242C>T · rs200589588 · VCV282509

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, amr)

Conditions

Inborn genetic diseases

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 -8.8	GERP -3.7
Overall
CADD	0.07	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.02% Admixed American · 12/59,964 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.00614% 99/1,611,302 alleles · ultra-rare exomes 80/1,459,104 · genomes 19/152,198 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.02%	4,997
Remaining individualsnot grpmax-eligible	0.0128%	7,803
African / African-American	0.012%	8,322
South Asian	0.00659%	15,177
European (non-Finnish)	0.00526%	19,025
East Asian	0.00446%	22,429

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.Arg4414=
Coding: c.13242C>T
MANE Select: NM_201384
dbSNP: rs200589588
Type: single nucleotide variant
Location: chr8:143916579 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI <0.01 (gnomAD)
Residue 4414: the 'required for interaction with intermediate filament proteins' region; the 'globular 2' region

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.Arg4414Cys Conflicting classifications of pathogenicity ★ same residue
PLEC p.Arg4414His 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-arg4414 (accessed [today's date]).

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