# NM_024426.6(WT1):c.410del (p.Pro137fs)

https://sugi.bio/variant/wt1-p-pro137fs

## Summary

**WT1 p.Pro137fs (c.410del)** is classified **Pathogenic/Likely pathogenic** in WT1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-04). Very rare (popmax 6.52e-05%); Associated with Denys-Drash syndrome.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs2494480771 · 2 submitters · 4 linked conditions · very rare (popmax 6.52e-05%)

## For patients & families {#patients}

This is a change in the WT1 gene that is considered likely disease-causing, submitted by 2 submitters, 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.Pro137fs |
| Coding change (HGVS c.) | c.410del |
| MANE Select transcript | [NM_024426](https://www.ncbi.nlm.nih.gov/nuccore/NM_024426) |
| dbSNP | [rs2494480771](https://www.ncbi.nlm.nih.gov/snp/rs2494480771/) |
| Variant type | Deletion |
| Location | chr11:32434951-32434951 (GRCh38) |
| ClinVar | [VCV2664749](https://www.ncbi.nlm.nih.gov/clinvar/variation/2664749/) |

**All HGVS expressions:** `LRG_525:g.5591del`, `LRG_525t1:c.391del`, `NC_000011.10:g.32434955del`, `NC_000011.9:g.32456501del`, `NG_009272.1:g.5591del`, `NG_050766.1:g.4208del`, `NG_050766.2:g.4887del`, `NM_000378.6:c.410del`, `NM_001407044.1:c.410del`, `NM_001407045.1:c.410del`, `NM_001407046.1:c.410del`, `NM_001407047.1:c.410del`, `NM_001407048.1:c.410del`, `NM_001407049.1:c.410del`, `NM_001407050.1:c.410del`, `NM_024424.5:c.410del`, `NM_024425.2:c.391delC`, `NM_024426.6:c.410del`, `NM_024426.6:c.410delC`, `NR_160306.1:n.589del`, `NR_176266.1:n.589del`

## 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 -1.041, GERP 0.084, phastCons 0.004 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.253, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 1 of 10**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Repeat context: **simple_repeat** ((GGC)n, GGCGGCGGCGGGGGT). The alignment of this deletion is ambiguous inside a repeating unit, so the same change can be written several ways and a frequency lookup keyed on one representation can miss another. *A qualifier on how reliably this variant can be called and counted — not a pathogenicity signal.*
- Population frequency (gnomAD v4.1): global (via dbSNP) **6.52e-05%** · 1/1,532,618 alleles overall — very rare (popmax 6.52e-05%).

*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}


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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-04-04.

**Submitter consensus:** conflicting (1 Likely pathogenic, 1 Pathogenic).

**Submission history:** 2 submissions (2023–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetics and Molecular Pathology, SA Pathology | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-03-03 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-04-04 |

## 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, Wilms tumor 1, 11p partial monosomy syndrome, Frasier syndrome, NEPHROPATHY, WILMS TUMOR, AND GENITAL ANOMALIES, WILMS TUMOR AND PSEUDO- OR TRUE HERMAPHRODITISM, Wilms tumor, somatic, WAGR Complex, WAGR syndrome, CHROMOSOME 11p13 DELETION SYNDROME.

## Similar variants {#similar}

Related WT1 variant pages (same residue, condition, or type): [WT1 p.Pro137_Pro141del](/variant/wt1-p-pro137-pro141del), [WT1 p.Pro137Ala](/variant/wt1-p-pro137ala), [WT1 p.Pro137=](/variant/wt1-p-pro137), [WT1 c.1354+4_1354+11del](/variant/wt1-c-1354-plus-4-1354-plus-11del), [WT1 c.882_887+3del](/variant/wt1-c-882-887-plus-3del), [WT1 p.Arg476fs](/variant/wt1-p-arg476fs), [WT1 p.Arg500fs](/variant/wt1-p-arg500fs), [WT1 p.Gln457_Cys458insTer](/variant/wt1-p-gln457-cys458inster).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2664749). 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.*