Is WT1 p.Arg463Ter (c.1387C>T) pathogenic?

WT1 p.Arg463Ter (c.1387C>T) is classified Pathogenic in WT1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-11). Very rare (popmax 8.47e-05%, nfe); Associated with Frasier syndrome.

What condition is associated with WT1 p.Arg463Ter (c.1387C>T)?

WT1 p.Arg463Ter (c.1387C>T) is associated with Frasier syndrome, malignant mesothelioma, Wilms tumor 1 (ClinVar).

How common is WT1 p.Arg463Ter (c.1387C>T) in the general population?

WT1 p.Arg463Ter (c.1387C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Frasier syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

WT1 p.Arg463Ter

c.1387C>T · rs121907909 · VCV3494

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

Frasier syndrome

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 9 of 10
REVEL	0.074	moderately benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.3	GERP 2.7, phastCons 1
Overall
CADD	45.0	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,966 alleles

Overall 6.2e-05% 1/1,613,764 alleles · very rare exomes 0/1,461,868 · genomes 1/151,896 · 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: WT1
Protein: p.Arg463Ter
Coding: c.1387C>T
MANE Select: NM_024426
dbSNP: rs121907909
Type: single nucleotide variant
Location: chr11:32392032 (GRCh38)
Gene constraint: LOEUF 0.253 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 52.09 · 31 PDB

Full WT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Frasier syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: malignant mesothelioma Wilms tumor 1 WAGR syndrome Denys-Drash syndrome nephrotic syndrome, type 4 Meacham syndrome focal segmental glomerulosclerosis

For Frasier syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

WT1 p.Arg463Gln Conflicting classifications of pathogenicity ★ same residue
WT1 p.Arg463Pro Conflicting classifications of pathogenicity ★ same residue
WT1 p.Arg463= Likely benign ★ same residue
WT1 c.1354+2T>C Pathogenic/Likely pathogenic ★★ same condition
WT1 c.1447+2T>C Pathogenic ★★ same condition
WT1 c.1447+4C>T Pathogenic/Likely pathogenic ★★ same condition
WT1 c.1447+5G>A Pathogenic/Likely pathogenic ★★ same condition
WT1 c.1448-1G>A Pathogenic/Likely pathogenic ★★ 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/wt1-p-arg463ter (accessed [today's date]).

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