Is PLEC p.Arg1908Leu (c.5723G>T) pathogenic?

PLEC p.Arg1908Leu (c.5723G>T) is classified Uncertain significance in PLEC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-28). AlphaMissense: likely benign (0.3226); Very rare (popmax 0.000593%, nfe).

How common is PLEC p.Arg1908Leu (c.5723G>T) in the general population?

PLEC p.Arg1908Leu (c.5723G>T) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about PLEC p.Arg1908Leu (c.5723G>T)?

AlphaMissense predicts likely benign (score 0.3226) — an in-silico prediction, not a clinical call.

PLEC p.Arg1908Leu

c.5723G>T · rs369142466 · VCV2683032

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3226 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3226	likely benign
REVEL	0.509	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
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	27.1	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 R2045L vs ClinVar R1908L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000593% European (non-Finnish) · 7/1,179,530 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000438% 7/1,598,948 alleles · very rare exomes 7/1,446,692 · genomes 0/152,256 · 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.Arg1908Leu
Coding: c.5723G>T
MANE Select: NM_201384
dbSNP: rs369142466
Type: single nucleotide variant
Location: chr8:143924206 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI <0.01 (gnomAD)

Full PLEC gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PLEC p.Arg1908Gln Uncertain significance ★★ same residue
PLEC p.Arg1908Trp Uncertain significance ★★ same residue
PLEC p.Arg1908Pro Uncertain significance ★ same residue
PLEC p.Arg1908= Likely benign ★ same residue
PLEC p.Arg1490Ter Pathogenic/Likely pathogenic ★★ same type
PLEC p.Arg1973Trp Pathogenic ★★ ⚠ same type
PLEC p.Arg2027Ter Pathogenic ★★ same type
PLEC p.Arg2292Ter Pathogenic ★★ same type

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-arg1908leu (accessed [today's date]).

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