Is WT1 p.Gln427Pro (c.1280A>C) pathogenic?

WT1 p.Gln427Pro (c.1280A>C) is classified Uncertain significance in WT1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-06-28). Very rare (popmax 0.000848%, nfe); Associated with Inborn genetic diseases.

What condition is associated with WT1 p.Gln427Pro (c.1280A>C)?

WT1 p.Gln427Pro (c.1280A>C) is associated with Inborn genetic diseases, Frasier syndrome, Wilms tumor 1 (ClinVar).

How common is WT1 p.Gln427Pro (c.1280A>C) in the general population?

WT1 p.Gln427Pro (c.1280A>C) is very rare (popmax 0.000848%, nfe) (gnomAD).

WT1 p.Gln427Pro

c.1280A>C · rs1358408901 · VCV963434

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000848%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.347	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	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	26.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000848% European (non-Finnish) · 10/1,179,906 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.00062% 10/1,614,010 alleles · very rare exomes 10/1,461,724 · genomes 0/152,286 · 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.Gln427Pro
Coding: c.1280A>C
MANE Select: NM_024426
dbSNP: rs1358408901
Type: single nucleotide variant
Location: chr11:32392740 (GRCh38)
Gene constraint: LOEUF 0.253 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 52.09 · 31 PDB
Residue 427: a β-strand

Full WT1 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: Frasier syndrome Wilms tumor 1 WAGR syndrome Denys-Drash syndrome

Similar variants

WT1 p.Gln427= Conflicting classifications of pathogenicity ★ same residue
WT1 p.Gln427His Uncertain significance ★ 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-gln427pro (accessed [today's date]).

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