# NM_024426.6(WT1):c.1388G>C (p.Arg463Pro)

https://sugi.bio/variant/wt1-p-arg463pro

## Summary

**WT1 p.Arg463Pro (c.1388G>C)** is classified **Conflicting classifications of pathogenicity** in WT1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-07-11). Absent from gnomAD v4.1; Associated with acute myeloid leukemia.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs1037084691 · 2 submitters · 2 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the WT1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to acute myeloid leukemia.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 2278 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012757/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.Arg463Pro |
| Coding change (HGVS c.) | c.1388G>C |
| MANE Select transcript | [NM_024426](https://www.ncbi.nlm.nih.gov/nuccore/NM_024426) |
| dbSNP | [rs1037084691](https://www.ncbi.nlm.nih.gov/snp/rs1037084691/) |
| Variant type | single nucleotide variant |
| Location | chr11:32392031-32392031 (GRCh38) |
| ClinVar | [VCV625171](https://www.ncbi.nlm.nih.gov/clinvar/variation/625171/) |

**All HGVS expressions:** `LRG_525:g.48511G>C`, `LRG_525t1:c.1373G>C`, `LRG_525t2:c.737G>C`, `NC_000011.10:g.32392031C>G`, `NC_000011.9:g.32413577C>G`, `NG_009272.1:g.48511G>C`, `NM_000378.6:c.1337G>C`, `NM_001198551.2:c.737G>C`, `NM_001198552.2:c.686G>C`, `NM_001367854.1:c.200G>C`, `NM_001407044.1:c.1382G>C`, `NM_001407045.1:c.1337G>C`, `NM_001407047.1:c.1265G>C`, `NM_001407048.1:c.1247G>C`, `NM_001407050.1:c.1214G>C`, `NM_001407051.1:c.626G>C`, `NM_024424.5:c.1388G>C`, `NM_024425.2:c.1322G>C`, `NM_024426.6:c.1388G>C`, `NR_160306.1:n.1720G>C`, `NR_176266.1:n.1669G>C`

## 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 7.719, GERP 2.71, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 33.0**. 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.*
- Regional missense constraint: **o/e 0.16** across the covering region of the MANE Select transcript (32,389,165–32,396,303), spanning 7,138 bp — the region is depleted of missense variation. Chi-square p 4.9e-17. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-07-11.

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

**Submission history:** 2 submissions (2018–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory Oncology Unit, Dr.B.R.A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences | Uncertain significance | criteria provided, single submitter | research | 2018-12-06 |
| 3billion | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-07-11 |

## Associated conditions {#conditions}

[acute myeloid leukemia](https://sugi.bio/atlas/disease/acute-myeloid-leukemia/), [nephrotic syndrome, type 4](https://sugi.bio/atlas/disease/nephrotic-syndrome-type-4/).

**Reported phenotype names (ClinVar):** Acute myeloid leukemia, Nephrotic syndrome, type 4, CEBPA-Associated Familial Acute Myeloid Leukemia (AML), Leukemia, acute myeloid, somatic, Acute myeloid leukemia, adult, AML adult, Acute non-lymphocytic leukemia, Acute granulocytic leukemia, Leukemia, acute myelogenous, somatic, Familial mesangial sclerosis.

## Same-residue context {#hotspot}

Residue **463** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [WT1 p.Arg463Ter](/variant/wt1-p-arg463ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related WT1 variant pages (same residue, condition, or type): [WT1 p.Arg463Ter](/variant/wt1-p-arg463ter), [WT1 p.Arg463Gln](/variant/wt1-p-arg463gln), [WT1 p.Arg463=](/variant/wt1-p-arg463), [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 p.Arg435Ter](/variant/wt1-p-arg435ter).

### 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 625171). 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.*