Is GPC3 p.Pro363Arg (c.1088C>G) pathogenic?

GPC3 p.Pro363Arg (c.1088C>G) is classified Uncertain significance in GPC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-07). AlphaMissense: ambiguous (0.4705); Absent from gnomAD v4.1; Associated with Wilms tumor 1.

What condition is associated with GPC3 p.Pro363Arg (c.1088C>G)?

GPC3 p.Pro363Arg (c.1088C>G) is associated with Wilms tumor 1, Simpson-Golabi-Behmel syndrome type 1 (ClinVar).

How common is GPC3 p.Pro363Arg (c.1088C>G) in the general population?

GPC3 p.Pro363Arg (c.1088C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GPC3 p.Pro363Arg (c.1088C>G)?

AlphaMissense predicts ambiguous (score 0.4705) — an in-silico prediction, not a clinical call.

GPC3 p.Pro363Arg

c.1088C>G · VCV3598037

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4705 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Wilms tumor 1

Computational evidence

Protein change
AlphaMissense	0.4705	ambiguous
REVEL	0.22	benign-leaning
SaProt	LLR -6.77	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 449 kb · p 7.5e-06 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

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: GPC3
Protein: p.Pro363Arg
Coding: c.1088C>G
MANE Select: NM_004484
Type: single nucleotide variant
Location: chrX:133699973 (GRCh38)
Structure: AlphaFold pLDDT 75.60 · 4 PDB

Full GPC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Wilms tumor 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Simpson-Golabi-Behmel syndrome type 1

Similar variants

GPC3 p.Pro363Ser Uncertain significance ★ ⚠ same residue
GPC3 c.337+2T>A Likely pathogenic ★★ same condition
GPC3 p.Arg199Ter Pathogenic ★★ same condition
GPC3 p.Arg254Ter Pathogenic ★★ same condition
GPC3 p.Arg387Ter Pathogenic ★★ same condition
GPC3 p.Arg86Ter Pathogenic ★★ same condition
GPC3 p.Glu298Ter Pathogenic ★★ same condition
GPC3 p.Gly556Arg Pathogenic/Likely 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/gpc3-p-pro363arg (accessed [today's date]).

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