# NM_024426.6(WT1):c.1305A>G (p.Arg435=)

https://sugi.bio/variant/wt1-p-arg435

## Summary

**WT1 p.Arg435= (c.1305A>G)** is classified **Likely benign** in WT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-02). Very rare (popmax 0.000932%, nfe); Associated with Denys-Drash syndrome.

**At a glance:** Likely benign · review: Single submitter · rsID rs2132920648 · 1 submitter · 4 linked conditions · very rare (popmax 0.000932%, nfe)

## For patients & families {#patients}

This is a change in the WT1 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to Denys-Drash syndrome.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Adolescent, Childhood, Infancy, Neonatal |
| Clinical trials | 4 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | WT1 is a diagnostic-grade gene on 12 Genomics England panels |

**Commonly reported features of Denys-Drash syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Male pseudohermaphroditism — Very frequent (99-80%)
- Proteinuria — Very frequent (99-80%)
- Nephrotic syndrome — Very frequent (99-80%)
- Nephropathy — Very frequent (99-80%)
- Nephroblastoma — Very frequent (99-80%)
- Hypertension — Frequent (79-30%)
- Gonadal dysgenesis — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005576/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [WT1](https://sugi.bio/atlas/gene/WT1/) |
| Protein change (HGVS p.) | p.Arg435= |
| Coding change (HGVS c.) | c.1305A>G |
| MANE Select transcript | [NM_024426](https://www.ncbi.nlm.nih.gov/nuccore/NM_024426) |
| dbSNP | [rs2132920648](https://www.ncbi.nlm.nih.gov/snp/rs2132920648/) |
| Variant type | single nucleotide variant |
| Location | chr11:32392715-32392715 (GRCh38) |
| ClinVar | [VCV2017747](https://www.ncbi.nlm.nih.gov/clinvar/variation/2017747/) |

**All HGVS expressions:** `LRG_525:g.47827A>G`, `LRG_525t1:c.1290A>G`, `LRG_525t2:c.654A>G`, `NC_000011.10:g.32392715T>C`, `NC_000011.9:g.32414261T>C`, `NG_009272.1:g.47827A>G`, `NM_000378.6:c.1254A>G`, `NM_001198551.2:c.654A>G`, `NM_001198552.2:c.603A>G`, `NM_001367854.1:c.117A>G`, `NM_001407044.1:c.1299A>G`, `NM_001407045.1:c.1254A>G`, `NM_001407046.1:c.1305A>G`, `NM_001407047.1:c.1182A>G`, `NM_001407048.1:c.1214-651A>G`, `NM_001407049.1:c.1254A>G`, `NM_001407050.1:c.1131A>G`, `NM_001407051.1:c.543A>G`, `NM_024424.5:c.1305A>G`, `NM_024425.2:c.1239A>G`, `NM_024426.6:c.1305A>G`, `NR_160306.1:n.1637A>G`, `NR_176266.1:n.1586A>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 1.161, GERP -0.634, phastCons 1 — weakly conserved position
- CADD: **PHRED 10.82**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (T>A, Δ0.25 donor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.000932%** (nfe) · FAF95 0.0005% · FAF99 0.000366% · 11/1,179,952 in the highest group · 11/1,614,072 alleles overall — very rare (popmax 0.000932%, nfe).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**WT1** population constraint: LOEUF 0.253, pLI 1, missense-Z 1.4207; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Wilms tumor 1** — Definitive (AD)
- **Denys-Drash syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **435** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 52.09, 11% of residues very-high.

**31 experimental structure(s)** (PDB): [1XF7](https://www.rcsb.org/structure/1XF7), [2JP9](https://www.rcsb.org/structure/2JP9), [2JPA](https://www.rcsb.org/structure/2JPA), [2PRT](https://www.rcsb.org/structure/2PRT), [3HPJ](https://www.rcsb.org/structure/3HPJ), [3MYJ](https://www.rcsb.org/structure/3MYJ) — incl. mutant structure 3MYJ.

## What this gene does {#gene-function}

*Describes the biological roles of WT1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** WT1's established molecular role includes transcription cis-regulatory region binding.


### Pathways affected {#pathways}

WT1 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Negative Regulation of CDH1 Gene Transcription](https://reactome.org/content/detail/R-HSA-9764725) | curated |
| [Nephron development](https://reactome.org/content/detail/R-HSA-9831926) | electronic |
| [Transcriptional regulation of testis differentiation](https://reactome.org/content/detail/R-HSA-9690406) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** transcription cis-regulatory region binding, RNA polymerase II cis-regulatory region sequence-specific DNA binding, DNA-binding transcription activator activity, RNA polymerase II-specific, zinc ion binding, double-stranded methylated DNA binding, sequence-specific DNA binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, branching involved in ureteric bud morphogenesis, kidney development, heart development, sex determination, negative regulation of cell population proliferation.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-03-02.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-03-02 |

## Associated conditions {#conditions}

[Denys-Drash syndrome](https://sugi.bio/atlas/disease/denys-drash-syndrome/), [Frasier syndrome](https://sugi.bio/atlas/disease/frasier-syndrome/), [Wilms tumor 1](https://sugi.bio/atlas/disease/wilms-tumor-1/), [WAGR syndrome](https://sugi.bio/atlas/disease/wagr-syndrome/).

**Reported phenotype names (ClinVar):** Drash syndrome, 11p partial monosomy syndrome, Frasier syndrome, Wilms tumor 1, NEPHROPATHY, WILMS TUMOR, AND GENITAL ANOMALIES, WILMS TUMOR AND PSEUDO- OR TRUE HERMAPHRODITISM, Wilms tumor, somatic, WAGR Complex, CHROMOSOME 11p13 DELETION SYNDROME, WAGR Spectrum Disorder.

## Same-residue context {#hotspot}

Residue **435** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [WT1 p.Arg435Ter](/variant/wt1-p-arg435ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related WT1 variant pages (same residue, condition, or type): [WT1 p.Arg435Ter](/variant/wt1-p-arg435ter), [WT1 p.Arg435Gln](/variant/wt1-p-arg435gln), [WT1 c.1354+2T>C](/variant/wt1-c-1354-plus-2t-c), [WT1 c.1447+2T>C](/variant/wt1-c-1447-plus-2t-c), [WT1 c.1447+4C>T](/variant/wt1-c-1447-plus-4c-t), [WT1 c.1447+5G>A](/variant/wt1-c-1447-plus-5g-a), [WT1 c.1448-1G>A](/variant/wt1-c-1448-minus-1g-a), [WT1 p.Arg374Ter](/variant/wt1-p-arg374ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 2017747). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*