Is PLEC p.Arg1983Pro (c.5948G>C) pathogenic?

PLEC p.Arg1983Pro (c.5948G>C) is classified Uncertain significance in PLEC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-14). AlphaMissense: likely pathogenic (0.9454); Absent from gnomAD v4.1; Associated with epidermolysis bullosa simplex with nail dystrophy.

What condition is associated with PLEC p.Arg1983Pro (c.5948G>C)?

PLEC p.Arg1983Pro (c.5948G>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.Arg1983Pro (c.5948G>C) in the general population?

PLEC p.Arg1983Pro (c.5948G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PLEC p.Arg1983Pro (c.5948G>C)?

AlphaMissense predicts likely pathogenic (score 0.9454) — an in-silico prediction, not a clinical call.

PLEC p.Arg1983Pro

c.5948G>C · rs527947459 · VCV2932976

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9454 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

epidermolysis bullosa simplex with nail dystrophy

Computational evidence

Protein change
AlphaMissense	0.9454	likely pathogenic · top 8% in PLEC
REVEL	0.405	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 18 kb · p 4.9e-10 · regional, not allelic
Overall
CADD	27.2	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 R2120P vs ClinVar R1983P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PLEC
Protein: p.Arg1983Pro
Coding: c.5948G>C
MANE Select: NM_201384
dbSNP: rs527947459
Type: single nucleotide variant
Location: chr8:143923981 (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.Arg1983Cys Uncertain significance ★★ same residue
PLEC p.Arg1983His Conflicting classifications of pathogenicity ★ same residue
PLEC p.Arg1983Ser 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-arg1983pro (accessed [today's date]).

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