# NM_024426.6(WT1):c.796_797dup (p.Ser267fs)

https://sugi.bio/variant/wt1-p-ser267fs

## Summary

**WT1 p.Ser267fs (c.796_797dup)** is classified **Pathogenic** in WT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-22). No gnomAD frequency available for this variant; Associated with WT1-related disorder.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2494426569 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the WT1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to WT1-related disorder.

*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.*

**Support & next steps:** [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.Ser267fs |
| Coding change (HGVS c.) | c.796_797dup |
| MANE Select transcript | [NM_024426](https://www.ncbi.nlm.nih.gov/nuccore/NM_024426) |
| dbSNP | [rs2494426569](https://www.ncbi.nlm.nih.gov/snp/rs2494426569/) |
| Variant type | Duplication |
| Location | chr11:32428045-32428046 (GRCh38) |
| ClinVar | [VCV2633663](https://www.ncbi.nlm.nih.gov/clinvar/variation/2633663/) |

**All HGVS expressions:** `LRG_525:g.12495_12496dup`, `LRG_525t1:c.781_782dup`, `LRG_525t2:c.145_146dup`, `NC_000011.10:g.32428046_32428047dup`, `NC_000011.9:g.32449592_32449593dup`, `NG_009272.1:g.12495_12496dup`, `NG_122166.1:g.229_230dup`, `NM_000378.6:c.796_797dup`, `NM_001198551.2:c.145_146dup`, `NM_001198552.2:c.145_146dup`, `NM_001407044.1:c.796_797dup`, `NM_001407045.1:c.796_797dup`, `NM_001407046.1:c.796_797dup`, `NM_001407047.1:c.673_674dup`, `NM_001407048.1:c.796_797dup`, `NM_001407049.1:c.796_797dup`, `NM_001407050.1:c.673_674dup`, `NM_001407051.1:c.34_35dup`, `NM_024424.5:c.796_797dup`, `NM_024425.2:c.781_782dup`, `NM_024426.6:c.796_797dup`, `NR_160306.1:n.975_976dup`, `NR_176266.1:n.975_976dup`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 4.476, GERP 1.26, phastCons 1 — highly conserved position (PP3-type support)
- 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 3 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 duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-03-22.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Pathogenic | criteria provided, single submitter | clinical testing | 2023-03-22 |

## Associated conditions {#conditions}

[WT1-related disorder](https://sugi.bio/atlas/disease/wt1-related-disorder/).

**Reported phenotype names (ClinVar):** WT1-related disorder, WT1-related disorders.

## Similar variants {#similar}

Related WT1 variant pages (same residue, condition, or type): [WT1 p.Ser267=](/variant/wt1-p-ser267), [WT1 p.Ala387fs](/variant/wt1-p-ala387fs), [WT1 p.Pro278fs](/variant/wt1-p-pro278fs), [WT1 p.Thr363fs](/variant/wt1-p-thr363fs), [WT1 p.Tyr294fs](/variant/wt1-p-tyr294fs), [WT1 p.Ser267Ala](/variant/wt1-p-ser267ala), [WT1 p.Ser267Leu](/variant/wt1-p-ser267leu), [WT1 p.Ser267Pro](/variant/wt1-p-ser267pro).

### 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 2633663). 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.*