Is PLEC p.Ala585Pro (c.1753G>C) pathogenic?

PLEC p.Ala585Pro (c.1753G>C) is classified Uncertain significance in PLEC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-11). AlphaMissense: likely benign (0.0971); Very rare (popmax 0.00169%, amr); Associated with Inborn genetic diseases.

What condition is associated with PLEC p.Ala585Pro (c.1753G>C)?

PLEC p.Ala585Pro (c.1753G>C) 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.Ala585Pro (c.1753G>C) in the general population?

PLEC p.Ala585Pro (c.1753G>C) is very rare (popmax 0.00169%, amr) (gnomAD).

What do computational predictors say about PLEC p.Ala585Pro (c.1753G>C)?

AlphaMissense predicts likely benign (score 0.0971) — an in-silico prediction, not a clinical call.

PLEC p.Ala585Pro

c.1753G>C · rs368520468 · VCV1412264

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0971 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00169%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0971	likely benign
REVEL	0.354	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	phastCons 0.87
Regional constraint	o/e 1.08	unconstrained · MANE · 18 kb · p 4.9e-10 · regional, not allelic
Overall
CADD	14.82	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 A722P vs ClinVar A585P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00169% Admixed American · 1/59,276 alleles

Overall 6.22e-05% 1/1,606,702 alleles · very rare exomes 0/1,454,540 · genomes 1/152,162 · joint denominator

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.Ala585Pro
Coding: c.1753G>C
MANE Select: NM_201384
dbSNP: rs368520468
Type: single nucleotide variant
Location: chr8:143932697 (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

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.Ala585Ser Uncertain significance ★★ ⚠ same residue
PLEC p.Ala585Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
PLEC p.Ala585Val 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-ala585pro (accessed [today's date]).

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