Is WT1 p.Arg435Gln (c.1304G>A) pathogenic?

WT1 p.Arg435Gln (c.1304G>A) is classified Uncertain significance in WT1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-09-10). Very rare (popmax 0.00223%, eas); Associated with Denys-Drash syndrome.

What condition is associated with WT1 p.Arg435Gln (c.1304G>A)?

WT1 p.Arg435Gln (c.1304G>A) is associated with Denys-Drash syndrome, Frasier syndrome, Wilms tumor 1 (ClinVar).

How common is WT1 p.Arg435Gln (c.1304G>A) in the general population?

WT1 p.Arg435Gln (c.1304G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Denys-Drash syndrome inherited?

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

WT1 p.Arg435Gln

c.1304G>A · rs144788858 · VCV135456

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

Denys-Drash syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.348	indeterminate
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 2.7, phastCons 1
Regional constraint	o/e 0.16	constrained · MANE · 7,138 bp · p 4.9e-17 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,886 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000991% 16/1,613,940 alleles · very rare exomes 13/1,461,778 · genomes 3/152,162 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
East Asiangrpmax	0.00223%	44,886
South Asian	0.0022%	45,539
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	0.000932%	107,268

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg435Gln
Coding: c.1304G>A
MANE Select: NM_024426
dbSNP: rs144788858
Type: single nucleotide variant
Location: chr11:32392716 (GRCh38)
Gene constraint: LOEUF 0.253 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 52.09 · 31 PDB
Residue 435: an α-helix

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

Disease context

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

Also linked: Frasier syndrome Wilms tumor 1 WAGR syndrome Leber congenital amaurosis 10

For Denys-Drash syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Childhood, Infancy, Neonatal

Similar variants

WT1 p.Arg435Ter Pathogenic ★★ same residue
WT1 p.Arg435= 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

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-arg435gln (accessed [today's date]).

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