Is WT1 p.Pro231Ser (c.691C>T) pathogenic?

WT1 p.Pro231Ser (c.691C>T) is classified Uncertain significance in WT1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-22). Very rare (popmax 0.005%, amr); Associated with aniridia 1.

What condition is associated with WT1 p.Pro231Ser (c.691C>T)?

WT1 p.Pro231Ser (c.691C>T) is associated with aniridia 1, malignant mesothelioma, Frasier syndrome (ClinVar).

How common is WT1 p.Pro231Ser (c.691C>T) in the general population?

WT1 p.Pro231Ser (c.691C>T) is very rare (popmax 0.005%, amr) (gnomAD).

WT1 p.Pro231Ser

c.691C>T · rs766425764 · VCV392045

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Conditions

aniridia 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.357	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 1.3, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 39 kb · p 0.077 · regional, not allelic
Overall
CADD	22.3	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/60,024 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.00031% 5/1,613,874 alleles · very rare exomes 5/1,461,594 · genomes 0/152,280 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,008
European (non-Finnish)	0.000169%	590,012

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.Pro231Ser
Coding: c.691C>T
MANE Select: NM_024426
dbSNP: rs766425764
Type: single nucleotide variant
Location: chr11:32428590 (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

aniridia 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

WT1 p.Pro231Ala Uncertain significance ★★ same residue
WT1 p.Pro231= Likely benign ★★ same residue
WT1 p.Pro231Arg 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

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-pro231ser (accessed [today's date]).

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