Is PLEC p.Arg3482His (c.10445G>A) pathogenic?

PLEC p.Arg3482His (c.10445G>A) is classified Uncertain significance in PLEC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-13). AlphaMissense: likely benign (0.2282); Ultra-rare (popmax 0.0496%, mid); Associated with epidermolysis bullosa simplex with nail dystrophy.

What condition is associated with PLEC p.Arg3482His (c.10445G>A)?

PLEC p.Arg3482His (c.10445G>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.Arg3482His (c.10445G>A) in the general population?

PLEC p.Arg3482His (c.10445G>A) is ultra-rare (popmax 0.0496%, mid) (gnomAD).

What do computational predictors say about PLEC p.Arg3482His (c.10445G>A)?

AlphaMissense predicts likely benign (score 0.2282) — an in-silico prediction, not a clinical call.

PLEC p.Arg3482His

c.10445G>A · rs548876454 · VCV478526

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2282 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0496%, mid)

Conditions

epidermolysis bullosa simplex with nail dystrophy

Computational evidence

Protein change
AlphaMissense	0.2282	likely benign
REVEL	0.638	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 18 kb · p 4.9e-10 · regional, not allelic
Overall
CADD	25.4	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 R3619H vs ClinVar R3482H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0496% Middle Eastern · 3/6,054 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00719%

Overall 0.0062% 100/1,613,730 alleles · ultra-rare exomes 94/1,461,378 · genomes 6/152,352 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0496%	2,018
East Asian	0.0156%	6,410
Admixed American	0.01%	10,005
South Asian	0.00769%	13,012
European (non-Finnish)	0.00636%	15,733
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,590
Remaining individualsnot grpmax-eligible	0.0016%	62,500

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.Arg3482His
Coding: c.10445G>A
MANE Select: NM_201384
dbSNP: rs548876454
Type: single nucleotide variant
Location: chr8:143919376 (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

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.Arg3482Cys Uncertain significance ★★ same residue
PLEC p.Arg3482= Likely benign ★★ same residue
PLEC p.Arg3482Gly 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

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-arg3482his (accessed [today's date]).

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