Is GPC3 p.Phe577Leu (c.1729T>C) pathogenic?

GPC3 p.Phe577Leu (c.1729T>C) is classified Uncertain significance in GPC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-23). AlphaMissense: likely benign (0.1797); Very rare (popmax 0.000224%, nfe); Associated with Wilms tumor 1.

What condition is associated with GPC3 p.Phe577Leu (c.1729T>C)?

GPC3 p.Phe577Leu (c.1729T>C) is associated with Wilms tumor 1 (ClinVar).

How common is GPC3 p.Phe577Leu (c.1729T>C) in the general population?

GPC3 p.Phe577Leu (c.1729T>C) is very rare (popmax 0.000224%, nfe) (gnomAD).

What do computational predictors say about GPC3 p.Phe577Leu (c.1729T>C)?

AlphaMissense predicts likely benign (score 0.1797) — an in-silico prediction, not a clinical call.

GPC3 p.Phe577Leu

c.1729T>C · rs755635706 · VCV657490

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1797 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000224%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Wilms tumor 1

Computational evidence

Protein change
AlphaMissense	0.1797	likely benign
REVEL	0.06	moderately benign-leaning
SaProt	LLR -5.19	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.69	GERP 0.12, phastCons 0.96
Regional constraint	o/e 0.79	unconstrained · MANE · 449 kb · p 7.5e-06 · regional, not allelic
Overall
CADD	9.59	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000224% European (non-Finnish) · 2/891,799 alleles

Filtering AF 3.7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.000183% 2/1,093,139 alleles · very rare

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: GPC3
Protein: p.Phe577Leu
Coding: c.1729T>C
MANE Select: NM_004484
dbSNP: rs755635706
Type: single nucleotide variant
Location: chrX:133536138 (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

Similar variants

GPC3 p.Phe577= Likely benign ★ same residue
GPC3 p.Phe577del 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

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-phe577leu (accessed [today's date]).

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