# NM_003390.4(WEE1):c.1262C>T (p.Ser421Phe)

https://sugi.bio/variant/wee1-p-ser421phe

## Summary

**WEE1 p.Ser421Phe (c.1262C>T)** is classified **Uncertain significance** in WEE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-02). AlphaMissense: ambiguous (0.4157); Very rare (popmax 0.00133%, afr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense ambiguous · very rare (popmax 0.00133%, afr)

## For patients & families {#patients}

This is a change in the WEE1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [WEE1](https://sugi.bio/atlas/gene/WEE1/) |
| Protein change (HGVS p.) | p.Ser421Phe |
| Coding change (HGVS c.) | c.1262C>T |
| MANE Select transcript | [NM_003390](https://www.ncbi.nlm.nih.gov/nuccore/NM_003390) |
| Variant type | single nucleotide variant |
| Location | chr11:9581652-9581652 (GRCh38) |
| ClinVar | [VCV4605031](https://www.ncbi.nlm.nih.gov/clinvar/variation/4605031/) |

**All HGVS expressions:** `NC_000011.10:g.9581652C>T`, `NC_000011.9:g.9603199C>T`, `NM_001143976.2:c.620C>T`, `NM_003390.4:c.1262C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL are indeterminate here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.4157) — no call either way
- REVEL 0.336 (indeterminate)
- SaProt LLR -10.431 (damaging)
- SpliceAI predicts **donor loss** (Δ 0.22) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 3.298, GERP 1.85, phastCons 1 — highly conserved
- CADD: **PHRED 25.5**. 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 0.67** across the covering region of the MANE Select transcript (9,581,542–9,585,504), spanning 3,962 bp. Chi-square p 0.0002. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.22**, acceptor gain **0.00**, donor gain **0.15**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.22**, acceptor gain **0.00**, donor gain **0.15**.
- Population frequency (gnomAD v4.1): grpmax **0.00133%** (afr) · FAF95 0.000763% · FAF99 0.000605% · 1/74,976 in the highest group · 17/1,612,914 alleles overall — very rare (popmax 0.00133%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,444 |
| African / African-American (grpmax) | 0.00133% | 74,976 |
| European (non-Finnish) | 0.00127% | 78,648 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**WEE1** population constraint: LOEUF 0.405, pLI 0.99985, missense-Z 1.8732. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **421** lies in the protein kinase domain.

AlphaFold model confidence (whole protein): pLDDT 65.90, 37% of residues very-high.

**29 experimental structure(s)** (PDB): [1X8B](https://www.rcsb.org/structure/1X8B), [2IN6](https://www.rcsb.org/structure/2IN6), [2IO6](https://www.rcsb.org/structure/2IO6), [2Z2W](https://www.rcsb.org/structure/2Z2W), [3BI6](https://www.rcsb.org/structure/3BI6), [3BIZ](https://www.rcsb.org/structure/3BIZ).

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

*Describes the biological roles of WEE1 (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:** WEE1's established molecular role includes protein tyrosine kinase activity. p.Ser421Phe falls in the protein kinase domain.


### Pathways affected {#pathways}

WEE1 participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cyclin A/B1/B2 associated events during G2/M transition](https://reactome.org/content/detail/R-HSA-69273) | curated |
| [Cyclin A:Cdk2-associated events at S phase entry](https://reactome.org/content/detail/R-HSA-69656) | curated |
| [Cyclin E associated events during G1/S transition ](https://reactome.org/content/detail/R-HSA-69202) | curated |
| [G2/M DNA replication checkpoint](https://reactome.org/content/detail/R-HSA-69478) | curated |
| [Polo-like kinase mediated events](https://reactome.org/content/detail/R-HSA-156711) | curated |
| [Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex](https://reactome.org/content/detail/R-HSA-75035) | electronic |
| [Factors involved in megakaryocyte development and platelet production](https://reactome.org/content/detail/R-HSA-983231) | electronic |

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

**Molecular function:** protein tyrosine kinase activity.

**Biological process:** negative regulation of G2/M transition of mitotic cell cycle.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-02.

**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 | 2025-12-02 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related WEE1 variant pages (same residue, condition, or type): [WEE1 p.Gly210Cys](/variant/wee1-p-gly210cys), [WEE1 p.Ala130Val](/variant/wee1-p-ala130val), [WEE1 p.Ala156Thr](/variant/wee1-p-ala156thr), [WEE1 p.Ala15Ser](/variant/wee1-p-ala15ser), [WEE1 p.Ala387Ser](/variant/wee1-p-ala387ser), [WEE1 p.Ala510Thr](/variant/wee1-p-ala510thr), [WEE1 p.Arg13Cys](/variant/wee1-p-arg13cys), [WEE1 p.Arg223Gly](/variant/wee1-p-arg223gly).

### 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 4605031). 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.*