Is PLEC p.Pro515= (c.1545C>T) pathogenic?

PLEC p.Pro515= (c.1545C>T) is classified Conflicting classifications of pathogenicity in PLEC (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-09-24). Rare (popmax 0.235%, mid); Associated with epidermolysis bullosa simplex with nail dystrophy.

What condition is associated with PLEC p.Pro515= (c.1545C>T)?

PLEC p.Pro515= (c.1545C>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.Pro515= (c.1545C>T) in the general population?

PLEC p.Pro515= (c.1545C>T) is rare (popmax 0.235%, mid) (gnomAD).

PLEC p.Pro515=

c.1545C>T · rs199968254 · VCV194475

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.235%, mid)

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	0.237	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.235% Middle Eastern · 14/5,966 alleles

Filtering AF 0.142% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.114%

Overall 0.0308% 496/1,611,092 alleles · rare exomes 427/1,458,792 · genomes 69/152,300 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.235%	426
African / African-American	0.109%	914
Ashkenazi Jewishnot grpmax-eligible	0.0948%	1,055
Remaining individualsnot grpmax-eligible	0.0834%	1,199
Admixed American	0.0468%	2,139
European (non-Finnish)	0.0243%	4,124
East Asian	0.00447%	22,373
South Asian	0.0033%	30,269
Finnishnot grpmax-eligible	0.0016%	62,514

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.Pro515=
Coding: c.1545C>T
MANE Select: NM_201384
dbSNP: rs199968254
Type: single nucleotide variant
Location: chr8:143932985 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI <0.01 (gnomAD)
Residue 515: 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.Pro515Leu 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-pro515 (accessed [today's date]).

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