Is GPC3 p.Arg199Ter (c.595C>T) pathogenic?

GPC3 p.Arg199Ter (c.595C>T) is classified Pathogenic in GPC3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-07-28). Absent from gnomAD v4.1; Associated with GPC3-related disorders.

What condition is associated with GPC3 p.Arg199Ter (c.595C>T)?

GPC3 p.Arg199Ter (c.595C>T) is associated with GPC3-related disorders, Wilms tumor 1, Simpson-Golabi-Behmel syndrome type 1 (ClinVar).

How common is GPC3 p.Arg199Ter (c.595C>T) in the general population?

GPC3 p.Arg199Ter (c.595C>T) is absent from gnomAD v4.1 (gnomAD).

GPC3 p.Arg199Ter

c.595C>T · rs104894855 · VCV11689

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

GPC3-related disorders

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 3 of 8
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 2.2, phastCons 1
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GPC3
Protein: p.Arg199Ter
Coding: c.595C>T
MANE Select: NM_004484
dbSNP: rs104894855
Type: single nucleotide variant
Location: chrX:133753919 (GRCh38)
Structure: AlphaFold pLDDT 75.60 · 4 PDB
Residue 199: a disulfide bond; an α-helix

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

Disease context

GPC3-related disorders

Also linked: Wilms tumor 1 Simpson-Golabi-Behmel syndrome type 1

Similar variants

GPC3 p.Arg199Gln Uncertain significance ★ ⚠ same residue
GPC3 c.337+2T>A Likely 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 p.Gly556Arg Pathogenic/Likely 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-arg199ter (accessed [today's date]).

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