Is PLEC p.Arg1607Trp (c.4819C>T) pathogenic?

PLEC p.Arg1607Trp (c.4819C>T) is classified Uncertain significance in PLEC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-16). AlphaMissense: likely benign (0.196); Very rare (popmax 0.0093%, amr); Associated with epidermolysis bullosa simplex 5A, Ogna type.

What condition is associated with PLEC p.Arg1607Trp (c.4819C>T)?

PLEC p.Arg1607Trp (c.4819C>T) is associated with epidermolysis bullosa simplex 5A, Ogna type, epidermolysis bullosa simplex 5B, with muscular dystrophy, epidermolysis bullosa simplex 5C, with pyloric atresia (ClinVar).

How common is PLEC p.Arg1607Trp (c.4819C>T) in the general population?

PLEC p.Arg1607Trp (c.4819C>T) is very rare (popmax 0.0093%, amr) (gnomAD).

What do computational predictors say about PLEC p.Arg1607Trp (c.4819C>T)?

AlphaMissense predicts likely benign (score 0.196) — an in-silico prediction, not a clinical call.

PLEC p.Arg1607Trp

Q: How is PLEC-related intermediate epidermolysis bullosa simplex without extracutaneous involvement inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.4819C>T · rs781818101 · VCV566146

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.196 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0093%, amr)

Conditions

epidermolysis bullosa simplex 5A, Ogna type

Computational evidence

Protein change
AlphaMissense	0.196	likely benign
REVEL	0.364	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 18 kb · p 4.9e-10 · regional, not allelic
Overall
CADD	25.8	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 R1744W vs ClinVar R1607W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0093% Admixed American · 5/53,786 alleles

Filtering AF 0.00366% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00237%

Overall 0.00161% 25/1,554,256 alleles · very rare exomes 21/1,402,554 · genomes 4/151,702 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0093%	10,757
Finnishnot grpmax-eligible	0.00666%	15,006
Remaining individualsnot grpmax-eligible	0.00495%	20,201
East Asian	0.00238%	41,970
South Asian	0.00116%	85,838
European (non-Finnish)	0.00104%	96,499

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.Arg1607Trp
Coding: c.4819C>T
MANE Select: NM_201384
dbSNP: rs781818101
Type: single nucleotide variant
Location: chr8:143925110 (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 5A, Ogna type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: 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

For PLEC-related intermediate epidermolysis bullosa simplex without extracutaneous involvement (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal

Similar variants

PLEC p.Arg1607Gln Uncertain significance ★★ ⚠ same residue
PLEC p.Arg1607= 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
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-arg1607trp (accessed [today's date]).

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