Is GPC3 p.Pro58Ser (c.172C>T) pathogenic?

GPC3 p.Pro58Ser (c.172C>T) is classified Conflicting classifications of pathogenicity in GPC3 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-11-10). AlphaMissense: likely benign (0.1093); Ultra-rare (popmax 0.0324%, nfe); Associated with Inborn genetic diseases.

What condition is associated with GPC3 p.Pro58Ser (c.172C>T)?

GPC3 p.Pro58Ser (c.172C>T) is associated with Inborn genetic diseases, Wilms tumor 1 (ClinVar).

How common is GPC3 p.Pro58Ser (c.172C>T) in the general population?

GPC3 p.Pro58Ser (c.172C>T) is ultra-rare (popmax 0.0324%, nfe) (gnomAD).

What do computational predictors say about GPC3 p.Pro58Ser (c.172C>T)?

AlphaMissense predicts likely benign (score 0.1093) — an in-silico prediction, not a clinical call.

GPC3 p.Pro58Ser

c.172C>T · rs147231796 · VCV239941

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1093 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0324%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1093	likely benign
REVEL	0.038	moderately benign-leaning
SaProt	LLR -3.41	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 5.2	GERP 0.69, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 449 kb · p 7.5e-06 · regional, not allelic
Overall
CADD	18.01	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 0.0324% European (non-Finnish) · 290/894,537 alleles

Filtering AF 0.0293% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0281%

Overall 0.0247% 299/1,209,394 alleles · ultra-rare exomes 283/1,096,696 · genomes 16/112,698 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0324%	3,085
Remaining individualsnot grpmax-eligible	0.0168%	5,942
African / African-American	0.00174%	57,377

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.Pro58Ser
Coding: c.172C>T
MANE Select: NM_004484
dbSNP: rs147231796
Type: single nucleotide variant
Location: chrX:133985278 (GRCh38)
Structure: AlphaFold pLDDT 75.60 · 4 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Wilms tumor 1

Similar variants

GPC3 p.Pro58= 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-pro58ser (accessed [today's date]).

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