Is GPC3 p.Ser397Phe (c.1190C>T) pathogenic?

GPC3 p.Ser397Phe (c.1190C>T) is classified Uncertain significance in GPC3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-11). AlphaMissense: likely benign (0.2074); Very rare (popmax 0.000225%, nfe); Associated with Wilms tumor 1.

What condition is associated with GPC3 p.Ser397Phe (c.1190C>T)?

GPC3 p.Ser397Phe (c.1190C>T) is associated with Wilms tumor 1 (ClinVar).

How common is GPC3 p.Ser397Phe (c.1190C>T) in the general population?

GPC3 p.Ser397Phe (c.1190C>T) is very rare (popmax 0.000225%, nfe) (gnomAD).

What do computational predictors say about GPC3 p.Ser397Phe (c.1190C>T)?

AlphaMissense predicts likely benign (score 0.2074) — an in-silico prediction, not a clinical call.

GPC3 p.Ser397Phe

c.1190C>T · rs2071074547 · VCV839100

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2074 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000225%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Wilms tumor 1

Computational evidence

Protein change
AlphaMissense	0.2074	likely benign
REVEL	0.201	benign-leaning
SaProt	LLR -9.89	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 9.8	GERP 1, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 449 kb · p 7.5e-06 · regional, not allelic
Overall
CADD	23.2	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 0.000225% European (non-Finnish) · 2/888,922 alleles

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

Overall 0.000166% 2/1,204,781 alleles · very rare exomes 2/1,090,812 · genomes 0/113,969 · 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: GPC3
Protein: p.Ser397Phe
Coding: c.1190C>T
MANE Select: NM_004484
dbSNP: rs2071074547
Type: single nucleotide variant
Location: chrX:133692471 (GRCh38)
Structure: AlphaFold pLDDT 75.60 · 4 PDB
Residue 397: a turn

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.Ser397Cys 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 c.1292+6C>T 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-ser397phe (accessed [today's date]).

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