Is PLEC p.Val3417= (c.10251G>A) pathogenic?

PLEC p.Val3417= (c.10251G>A) is classified Likely benign in PLEC (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-18). Very rare (popmax 0.00661%, sas); Associated with epidermolysis bullosa simplex with nail dystrophy.

What condition is associated with PLEC p.Val3417= (c.10251G>A)?

PLEC p.Val3417= (c.10251G>A) 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.Val3417= (c.10251G>A) in the general population?

PLEC p.Val3417= (c.10251G>A) is very rare (popmax 0.00661%, sas) (gnomAD).

PLEC p.Val3417=

c.10251G>A · rs782333871 · VCV2936829

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00661%, sas)

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 -15
Overall
CADD	0.006	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00661% South Asian · 6/90,738 alleles

Filtering AF 0.00287% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00196%

Overall 0.000623% 10/1,605,008 alleles · very rare exomes 10/1,452,654 · genomes 0/152,354 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00661%	15,123
European (non-Finnish)	0.00034%	294,291

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.Val3417=
Coding: c.10251G>A
MANE Select: NM_201384
dbSNP: rs782333871
Type: single nucleotide variant
Location: chr8:143919570 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI <0.01 (gnomAD)
Residue 3417: the 'required for interaction with intermediate filament proteins' region; the 'globular 2' 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.Val3417Met 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-val3417 (accessed [today's date]).

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