Is PLEC p.Arg523Ser (c.1567C>A) pathogenic?

PLEC p.Arg523Ser (c.1567C>A) is classified Uncertain significance in PLEC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-25). AlphaMissense: likely benign (0.2926); Very rare (popmax 0.000339%, nfe).

How common is PLEC p.Arg523Ser (c.1567C>A) in the general population?

PLEC p.Arg523Ser (c.1567C>A) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about PLEC p.Arg523Ser (c.1567C>A)?

AlphaMissense predicts likely benign (score 0.2926) — an in-silico prediction, not a clinical call.

PLEC p.Arg523Ser

c.1567C>A · VCV4079743

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2926 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.2926	likely benign
REVEL	0.741	pathogenic-leaning
SaProt	—	not scored · why
⇒ REVEL calls this damaging; AlphaMissense does not; SaProt makes no call.
Splicing
SpliceAI	Δ0.32	acceptor loss, 12 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 11	phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 18 kb · p 4.9e-10 · regional, not allelic
Overall
CADD	24.8	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 R660S vs ClinVar R523S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,826 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,612,356 alleles · very rare exomes 4/1,460,002 · genomes 0/152,354 · 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.Arg523Ser
Coding: c.1567C>A
MANE Select: NM_201384
Type: single nucleotide variant
Location: chr8:143932963 (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.Arg523His Uncertain significance ★★ ⚠ 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
PLEC p.Arg2324Ter Pathogenic ★★ same type
PLEC p.Arg2394Ter Pathogenic ★★ same type
PLEC p.Arg559Ter 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-arg523ser (accessed [today's date]).

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