Is PLEC p.Arg596Trp (c.1786C>T) pathogenic?

PLEC p.Arg596Trp (c.1786C>T) is classified Uncertain significance in PLEC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-12). AlphaMissense: likely benign (0.1808); Very rare (popmax 0.00893%, eas); Associated with epidermolysis bullosa simplex with nail dystrophy.

What condition is associated with PLEC p.Arg596Trp (c.1786C>T)?

PLEC p.Arg596Trp (c.1786C>T) 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.Arg596Trp (c.1786C>T) in the general population?

PLEC p.Arg596Trp (c.1786C>T) is very rare (popmax 0.00893%, eas) (gnomAD).

What do computational predictors say about PLEC p.Arg596Trp (c.1786C>T)?

AlphaMissense predicts likely benign (score 0.1808) — an in-silico prediction, not a clinical call.

PLEC p.Arg596Trp

c.1786C>T · rs556691235 · VCV478591

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1808 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00893%, eas)

Conditions

epidermolysis bullosa simplex with nail dystrophy

Computational evidence

Protein change
AlphaMissense	0.1808	likely benign
REVEL	0.511	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.7	phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 18 kb · p 4.9e-10 · regional, not allelic
Overall
CADD	25.6	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 R733W vs ClinVar R596W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00893% East Asian · 4/44,808 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000869% 14/1,610,562 alleles · very rare exomes 11/1,458,402 · genomes 3/152,160 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00893%	11,202
Admixed American	0.00669%	14,949
South Asian	0.0033%	30,285
African / African-American	0.00134%	74,856
European (non-Finnish)	0.00017%	589,570

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.Arg596Trp
Coding: c.1786C>T
MANE Select: NM_201384
dbSNP: rs556691235
Type: single nucleotide variant
Location: chr8:143932664 (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.Arg596Gly Uncertain significance ★★ same residue
PLEC p.Arg596Gln Uncertain significance ★ ⚠ same residue
PLEC p.Arg596= Likely benign ★ 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-arg596trp (accessed [today's date]).

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