Is PLEC p.Ser520Phe (c.1559C>T) pathogenic?

PLEC p.Ser520Phe (c.1559C>T) is classified Uncertain significance in PLEC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-17). AlphaMissense: likely benign (0.2327); Ultra-rare (popmax 0.0334%, amr); Associated with epidermolysis bullosa simplex with nail dystrophy.

What condition is associated with PLEC p.Ser520Phe (c.1559C>T)?

PLEC p.Ser520Phe (c.1559C>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.Ser520Phe (c.1559C>T) in the general population?

PLEC p.Ser520Phe (c.1559C>T) is ultra-rare (popmax 0.0334%, amr) (gnomAD).

What do computational predictors say about PLEC p.Ser520Phe (c.1559C>T)?

AlphaMissense predicts likely benign (score 0.2327) — an in-silico prediction, not a clinical call.

PLEC p.Ser520Phe

c.1559C>T · rs201605325 · VCV283675

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2327 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0334%, amr)

Conditions

epidermolysis bullosa simplex with nail dystrophy

Computational evidence

Protein change
AlphaMissense	0.2327	likely benign
REVEL	0.366	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 18 kb · p 4.9e-10 · regional, not allelic
Overall
CADD	24.4	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 S657F vs ClinVar S520F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0334% Admixed American · 20/59,968 alleles

Filtering AF 0.0221% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0184%

Overall 0.00515% 83/1,612,166 alleles · ultra-rare exomes 71/1,459,854 · genomes 12/152,312 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0334%	2,998
European (non-Finnish)	0.005%	19,996
Remaining individualsnot grpmax-eligible	0.0032%	31,210
African / African-American	0.00267%	37,521

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.Ser520Phe
Coding: c.1559C>T
MANE Select: NM_201384
dbSNP: rs201605325
Type: single nucleotide variant
Location: chr8:143932971 (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.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
PLEC p.Arg559Ter Pathogenic ★★ same condition
PLEC p.Gln1591Ter Pathogenic/Likely 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-ser520phe (accessed [today's date]).

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