Is PLEC p.Arg2139Leu (c.6416G>T) pathogenic?

PLEC p.Arg2139Leu (c.6416G>T) is classified Uncertain significance in PLEC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-16). AlphaMissense: likely benign (0.293); Very rare (popmax 8.51e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PLEC p.Arg2139Leu (c.6416G>T)?

PLEC p.Arg2139Leu (c.6416G>T) is associated with Inborn genetic diseases (ClinVar).

How common is PLEC p.Arg2139Leu (c.6416G>T) in the general population?

PLEC p.Arg2139Leu (c.6416G>T) is very rare (popmax 8.51e-05%, nfe) (gnomAD).

What do computational predictors say about PLEC p.Arg2139Leu (c.6416G>T)?

AlphaMissense predicts likely benign (score 0.293) — an in-silico prediction, not a clinical call.

PLEC p.Arg2139Leu

c.6416G>T · VCV3933944

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.293 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.51e-05%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.293	likely benign
REVEL	0.36	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 18 kb · p 4.9e-10 · regional, not allelic
Overall
CADD	23.6	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 R2276L vs ClinVar R2139L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.51e-05% European (non-Finnish) · 1/1,174,710 alleles

Overall 6.26e-05% 1/1,596,562 alleles · very rare exomes 1/1,444,742 · genomes 0/151,820 · 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.Arg2139Leu
Coding: c.6416G>T
MANE Select: NM_201384
Type: single nucleotide variant
Location: chr8:143923513 (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

Similar variants

PLEC p.Arg2139Cys Uncertain significance ★★ same residue
PLEC p.Arg2139= Likely benign ★★ same residue
PLEC p.Arg2139His Conflicting classifications of pathogenicity ★ same residue
PLEC p.Ala1041Thr Uncertain significance ★★ ⚠ same condition
PLEC p.Ala1221Ser Uncertain significance ★★ ⚠ same condition
PLEC p.Ala1368Val Uncertain significance ★★ ⚠ same condition
PLEC p.Ala1390Val Uncertain significance ★★ ⚠ same condition
PLEC p.Ala1411Thr Uncertain significance ★★ ⚠ 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-arg2139leu (accessed [today's date]).

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