Is PLEC p.Pro4273Arg (c.12818C>G) pathogenic?

PLEC p.Pro4273Arg (c.12818C>G) is classified Uncertain significance in PLEC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-18). AlphaMissense: ambiguous (0.5351); Absent from gnomAD v4.1.

How common is PLEC p.Pro4273Arg (c.12818C>G) in the general population?

PLEC p.Pro4273Arg (c.12818C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PLEC p.Pro4273Arg (c.12818C>G)?

AlphaMissense predicts ambiguous (score 0.5351) — an in-silico prediction, not a clinical call.

PLEC p.Pro4273Arg

c.12818C>G · rs2130823282 · VCV2689772

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5351 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
AlphaMissense	0.5351	ambiguous
REVEL	0.393	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 1,466 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	22.3	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 P4410R vs ClinVar P4273R) — 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.Pro4273Arg
Coding: c.12818C>G
MANE Select: NM_201384
dbSNP: rs2130823282
Type: single nucleotide variant
Location: chr8:143917003 (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.Pro4273Ser Benign/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
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-pro4273arg (accessed [today's date]).

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