Is GPC3 p.Ser220= (c.660C>T) pathogenic?

GPC3 p.Ser220= (c.660C>T) is classified Conflicting classifications of pathogenicity in GPC3 (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-01-21). Rare (popmax 0.109%, nfe); Associated with Inborn genetic diseases.

What condition is associated with GPC3 p.Ser220= (c.660C>T)?

GPC3 p.Ser220= (c.660C>T) is associated with Inborn genetic diseases, Wilms tumor 1 (ClinVar).

How common is GPC3 p.Ser220= (c.660C>T) in the general population?

GPC3 p.Ser220= (c.660C>T) is rare (popmax 0.109%, nfe) (gnomAD).

GPC3 p.Ser220=

c.660C>T · rs138450923 · VCV239945

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

gnomAD v4.1

Rare

rare (popmax 0.109%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP 0.41, phastCons 1
Overall
CADD	9.261	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.109% European (non-Finnish) · 978/894,866 alleles

Filtering AF 0.104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.101%

Overall 0.0832% 1,006/1,209,627 alleles · rare exomes 953/1,097,792 · genomes 53/111,835 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.109%	915
Remaining individualsnot grpmax-eligible	0.0441%	2,267
African / African-American	0.0105%	9,528
Finnishnot grpmax-eligible	0.00215%	46,612

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.Ser220=
Coding: c.660C>T
MANE Select: NM_004484
dbSNP: rs138450923
Type: single nucleotide variant
Location: chrX:133753854 (GRCh38)
Structure: AlphaFold pLDDT 75.60 · 4 PDB
Residue 220: an α-helix

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.Ser220Pro 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-ser220 (accessed [today's date]).

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