Is WT1 p.Arg374= (c.1122A>G) pathogenic?

WT1 p.Arg374= (c.1122A>G) is classified Benign in WT1 (ClinVar, Multiple submitters, 17 submitters; last evaluated 2026-02-04). Common (popmax 67.1%, eas) — too common for a highly-penetrant pathogenic allele; Associated with Wilms tumor 1.

What condition is associated with WT1 p.Arg374= (c.1122A>G)?

WT1 p.Arg374= (c.1122A>G) is associated with Wilms tumor 1, Frasier syndrome, WAGR syndrome (ClinVar).

WT1 p.Arg374=

Q: How common is WT1 p.Arg374= (c.1122A>G) in the general population?

WT1 p.Arg374= (c.1122A>G) is common (popmax 67.1%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1122A>G · rs16754 · VCV198591

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 17 submitters

gnomAD v4.1

Common

common (popmax 67.1%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

Wilms tumor 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.02	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.23	GERP -5.4, phastCons 0.27
Overall
CADD	3.639	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 67.1% East Asian · 30,108/44,860 alleles

Filtering AF 66.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 66.2%

Overall 18% 291,078/1,613,638 alleles · common exomes 263,514/1,461,558 · genomes 27,564/152,080 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	67.1%	1
South Asian	35.4%	3
Admixed American	34.2%	3
Remaining individualsnot grpmax-eligible	20.3%	5
Amishnot grpmax-eligible	19.7%	5
Middle Eastern	18.8%	5
Ashkenazi Jewishnot grpmax-eligible	17.8%	6
Finnishnot grpmax-eligible	17.2%	6
European (non-Finnish)	14.4%	7
African / African-American	11%	9

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.Arg374=
Coding: c.1122A>G
MANE Select: NM_024426
dbSNP: rs16754
Type: single nucleotide variant
Location: chr11:32396399 (GRCh38)
Gene constraint: LOEUF 0.253 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 52.09 · 31 PDB
Residue 374: the 'important for interaction with target dna' region; an α-helix

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 nephrotic syndrome, type 4 Meacham syndrome

Similar variants

WT1 p.Arg374Ter Pathogenic ★★ same residue
WT1 p.Arg374Gly Uncertain significance ★ same residue
WT1 p.Arg374Gln Uncertain significance ★★ same residue
WT1 p.Arg374Trp 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

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-arg374 (accessed [today's date]).

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