Is WT1 p.Cys355Arg (c.1063T>C) pathogenic?

WT1 p.Cys355Arg (c.1063T>C) is classified Conflicting classifications of pathogenicity in WT1 (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-01-26). Ultra-rare (popmax 0.0965%, nfe); Associated with Hereditary cancer.

What condition is associated with WT1 p.Cys355Arg (c.1063T>C)?

WT1 p.Cys355Arg (c.1063T>C) is associated with Hereditary cancer, Frasier syndrome, Wilms tumor 1 (ClinVar).

How common is WT1 p.Cys355Arg (c.1063T>C) in the general population?

WT1 p.Cys355Arg (c.1063T>C) is ultra-rare (popmax 0.0965%, nfe) (gnomAD).

WT1 p.Cys355Arg

c.1063T>C · rs142059681 · VCV41847

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0965%, nfe)

Conditions

Hereditary cancer

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.807	moderately pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 39 kb · p 0.077 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0965% European (non-Finnish) · 1,139/1,180,054 alleles

Filtering AF 0.0918% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0899%

Overall 0.078% 1,259/1,614,120 alleles · ultra-rare exomes 1,198/1,461,892 · genomes 61/152,228 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0965%	1,036
Admixed American	0.0933%	1,072
Remaining individualsnot grpmax-eligible	0.0848%	1,179
African / African-American	0.0133%	7,494
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608

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.Cys355Arg
Coding: c.1063T>C
MANE Select: NM_024426
dbSNP: rs142059681
Type: single nucleotide variant
Location: chr11:32399998 (GRCh38)
Gene constraint: LOEUF 0.253 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 52.09 · 31 PDB
Residue 355: a UniProt-annotated variant site (in wt1); a UniProt-annotated variant site (in dds)

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

Disease context

Hereditary cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Frasier syndrome Wilms tumor 1 WAGR syndrome Denys-Drash syndrome hereditary neoplastic syndrome

Similar variants

WT1 p.Cys355= 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
WT1 p.Arg374Ter Pathogenic ★★ same condition
WT1 p.Arg435Ter 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-cys355arg (accessed [today's date]).

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