Is GPC3 p.Phe248Ser (c.743T>C) pathogenic?

GPC3 p.Phe248Ser (c.743T>C) is classified Uncertain significance in GPC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-06). AlphaMissense: likely pathogenic (0.8508); Very rare (popmax 0.00295%, eas); Associated with Wilms tumor 1.

What condition is associated with GPC3 p.Phe248Ser (c.743T>C)?

GPC3 p.Phe248Ser (c.743T>C) is associated with Wilms tumor 1 (ClinVar).

How common is GPC3 p.Phe248Ser (c.743T>C) in the general population?

GPC3 p.Phe248Ser (c.743T>C) is very rare (popmax 0.00295%, eas) (gnomAD).

What do computational predictors say about GPC3 p.Phe248Ser (c.743T>C)?

AlphaMissense predicts likely pathogenic (score 0.8508) — an in-silico prediction, not a clinical call.

GPC3 p.Phe248Ser

c.743T>C · rs2521355358 · VCV2717111

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8508 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00295%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Wilms tumor 1

Computational evidence

Protein change
AlphaMissense	0.8508	likely pathogenic
REVEL	0.265	benign-leaning
SaProt	LLR -10.48	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 2.2, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 449 kb · p 7.5e-06 · regional, not allelic
Overall
CADD	23.0	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

Grpmax group 0.00295% East Asian · 1/33,850 alleles

Overall 9.11e-05% 1/1,098,029 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.Phe248Ser
Coding: c.743T>C
MANE Select: NM_004484
dbSNP: rs2521355358
Type: single nucleotide variant
Location: chrX:133753771 (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 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 c.1292+6C>T Uncertain significance ★★ same condition
GPC3 p.Ala141Thr Uncertain significance ★★ ⚠ 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-phe248ser (accessed [today's date]).

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