Is PLEC p.Pro465= (c.1395G>C) pathogenic?

PLEC p.Pro465= (c.1395G>C) is classified Benign in PLEC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-30). Rare (popmax 0.394%, eas); Associated with epidermolysis bullosa simplex with nail dystrophy.

What condition is associated with PLEC p.Pro465= (c.1395G>C)?

PLEC p.Pro465= (c.1395G>C) 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.Pro465= (c.1395G>C) in the general population?

PLEC p.Pro465= (c.1395G>C) is rare (popmax 0.394%, eas) (gnomAD).

PLEC p.Pro465=

c.1395G>C · rs199865222 · VCV539015

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.394%, eas)

Conditions

epidermolysis bullosa simplex with nail dystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20
Overall
CADD	0.154	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.394% East Asian · 177/44,878 alleles

Filtering AF 0.347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.329%

Overall 0.0141% 227/1,612,824 alleles · rare exomes 207/1,460,506 · genomes 20/152,318 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.394%	254
Remaining individualsnot grpmax-eligible	0.0336%	2,975
South Asian	0.0231%	4,337
Admixed American	0.00167%	60,004
African / African-American	0.00133%	75,048
European (non-Finnish)	0.000509%	196,655

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.Pro465=
Coding: c.1395G>C
MANE Select: NM_201384
dbSNP: rs199865222
Type: single nucleotide variant
Location: chr8:143933220 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI <0.01 (gnomAD)
Residue 465: an α-helix; the 'globular 1' region

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.Pro465Leu 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
PLEC p.Arg2394Ter Pathogenic ★★ same condition
PLEC p.Arg559Ter 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-pro465 (accessed [today's date]).

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