Is WT1 p.Pro381Ser (c.1141C>T) pathogenic?

WT1 p.Pro381Ser (c.1141C>T) is classified Conflicting classifications of pathogenicity in WT1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-08-21). Ultra-rare (popmax 0.0187%, sas); Associated with Wilms tumor 1.

What condition is associated with WT1 p.Pro381Ser (c.1141C>T)?

WT1 p.Pro381Ser (c.1141C>T) is associated with Wilms tumor 1, Frasier syndrome, WAGR syndrome (ClinVar).

How common is WT1 p.Pro381Ser (c.1141C>T) in the general population?

WT1 p.Pro381Ser (c.1141C>T) is ultra-rare (popmax 0.0187%, sas) (gnomAD).

WT1 p.Pro381Ser

c.1141C>T · rs754938612 · VCV1991847

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, sas)

Conditions

Wilms tumor 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.545	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 39 kb · p 0.077 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0187% South Asian · 17/91,082 alleles

Filtering AF 0.0118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00976%

Overall 0.00112% 18/1,613,990 alleles · ultra-rare exomes 17/1,461,816 · genomes 1/152,174 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0187%	5,358
European (non-Finnish)	8.47e-05%	1,180,043

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.Pro381Ser
Coding: c.1141C>T
MANE Select: NM_024426
dbSNP: rs754938612
Type: single nucleotide variant
Location: chr11:32396380 (GRCh38)
Gene constraint: LOEUF 0.253 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 52.09 · 31 PDB
Residue 381: the 'important for interaction with target dna' region

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

Disease context

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

Also linked: Frasier syndrome WAGR syndrome Denys-Drash syndrome

Similar variants

WT1 p.Pro381Leu Uncertain significance ★★ same residue
WT1 p.Pro381= Likely benign ★★ same residue
WT1 p.Pro381Ala Uncertain significance ★ same residue
WT1 p.Pro381fs Likely pathogenic ★ same residue
WT1 p.Pro381Gln 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

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-pro381ser (accessed [today's date]).

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