# NM_024426.6(WT1):c.1122_1124delinsGCC (p.Arg375Pro)

https://sugi.bio/variant/wt1-p-arg375pro

## Summary

**WT1 p.Arg375Pro (c.1122_1124delinsGCC)** is classified **Uncertain significance** in WT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-15). Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the WT1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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.Arg375Pro |
| Coding change (HGVS c.) | c.1122_1124delinsGCC |
| MANE Select transcript | [NM_024426](https://www.ncbi.nlm.nih.gov/nuccore/NM_024426) |
| Variant type | Indel |
| Location | chr11:32396397-32396399 (GRCh38) |
| ClinVar | [VCV3982437](https://www.ncbi.nlm.nih.gov/clinvar/variation/3982437/) |

**All HGVS expressions:** `LRG_525:g.44143_44145delinsGCC`, `LRG_525t1:c.1107_1109delACGinsGCC`, `LRG_525t2:c.471_473delACGinsGCC`, `NC_000011.10:g.32396397_32396399delinsGGC`, `NC_000011.9:g.32417943_32417945delinsGGC`, `NG_009272.1:g.44143_44145delinsGCC`, `NM_000378.6:c.1071_1073delinsGCC`, `NM_001198551.2:c.471_473delinsGCC`, `NM_001198552.2:c.420_422delinsGCC`, `NM_001367854.1:c.-67_-65delinsGCC`, `NM_001407044.1:c.1116_1118delinsGCC`, `NM_001407045.1:c.1071_1073delinsGCC`, `NM_001407046.1:c.1122_1124delinsGCC`, `NM_001407047.1:c.999_1001delinsGCC`, `NM_001407048.1:c.1071_1073delinsGCC`, `NM_001407049.1:c.1071_1073delinsGCC`, `NM_001407050.1:c.948_950delinsGCC`, `NM_001407051.1:c.360_362delinsGCC`, `NM_001429031.1:c.903_905delinsGCC`, `NM_001429032.1:c.903_905delinsGCC`, `NM_001429033.1:c.852_854delinsGCC`, `NM_001429034.1:c.852_854delinsGCC`, `NM_024424.5:c.1122_1124delinsGCC`, `NM_024426.6:c.1122_1124delinsGCC`, `NR_160306.1:n.1454_1456delinsGCC`, `NR_176266.1:n.1403_1405delinsGCC`

## 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 7.663, GERP 2.71, phastCons 1 — highly conserved position (PP3-type support)
- Regional missense constraint: **o/e 0.93** across the covering region of the MANE Select transcript (32,396,304–32,435,360), spanning 39,056 bp. Chi-square p 0.077. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no indel variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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 **375** lies in the 'important for interaction with target dna' region; 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. p.Arg375Pro falls in the important for interaction with target dna region.


### 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-04-15.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-04-15 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Same-residue context {#hotspot}

Residue **375** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [WT1 p.Arg375fs](/variant/wt1-p-arg375fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related WT1 variant pages (same residue, condition, or type): [WT1 p.Arg375=](/variant/wt1-p-arg375), [WT1 p.Arg375His](/variant/wt1-p-arg375his), [WT1 p.Arg375Tyr](/variant/wt1-p-arg375tyr), [WT1 p.Arg375Cys](/variant/wt1-p-arg375cys), [WT1 p.Arg375Leu](/variant/wt1-p-arg375leu), [WT1 p.Arg375fs](/variant/wt1-p-arg375fs), [WT1 c.1016+4A>C](/variant/wt1-c-1016-plus-4a-c), [WT1 c.1113+5G>A](/variant/wt1-c-1113-plus-5g-a).

### 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 3982437). 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.*