Is WT1 p.Pro254Ser (c.760C>T) pathogenic?

WT1 p.Pro254Ser (c.760C>T) is classified Conflicting classifications of pathogenicity in WT1 (ClinVar, Conflicting submitters, 17 submitters; last evaluated 2026-01-31). Ultra-rare (popmax 0.0624%, nfe); Associated with Frasier syndrome.

What condition is associated with WT1 p.Pro254Ser (c.760C>T)?

WT1 p.Pro254Ser (c.760C>T) is associated with Frasier syndrome, Wilms tumor 1, WAGR syndrome (ClinVar).

How common is WT1 p.Pro254Ser (c.760C>T) in the general population?

WT1 p.Pro254Ser (c.760C>T) is ultra-rare (popmax 0.0624%, nfe) (gnomAD).

How is Frasier syndrome inherited?

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

WT1 p.Pro254Ser

c.760C>T · rs2234584 · VCV135453

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 17 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0624%, nfe)

Conditions

Frasier syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.423	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 39 kb · p 0.077 · regional, not allelic
Overall
CADD	22.8	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0624% European (non-Finnish) · 736/1,180,046 alleles

Filtering AF 0.0586% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0571%

Overall 0.0513% 828/1,614,126 alleles · ultra-rare exomes 767/1,461,804 · genomes 61/152,322 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0624%	1,603
Remaining individualsnot grpmax-eligible	0.0512%	1,953
Finnishnot grpmax-eligible	0.0422%	2,369
Admixed American	0.0416%	2,401
African / African-American	0.00933%	10,722
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.Pro254Ser
Coding: c.760C>T
MANE Select: NM_024426
dbSNP: rs2234584
Type: single nucleotide variant
Location: chr11:32428521 (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: Wilms tumor 1 WAGR syndrome Denys-Drash syndrome nephrotic syndrome, type 4 Meacham syndrome hereditary neoplastic syndrome

For Frasier syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

WT1 p.Pro254Leu Uncertain significance ★★ same residue
WT1 p.Pro254Thr Benign/Likely benign ★★ same residue
WT1 p.Pro254His 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-pro254ser (accessed [today's date]).

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