# NM_001105558.1(WEE2):c.1221G>A (p.Glu407=)

https://sugi.bio/variant/wee2-p-glu407

## Summary

**WEE2 p.Glu407= (c.1221G>A)** is classified **Pathogenic** in WEE2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-04-10). Very rare (popmax 0.00223%, eas); Associated with oocyte maturation defect 5.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs1380657460 · 1 submitter · 1 linked condition · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the WEE2 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to oocyte maturation defect 5.

*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 | [WEE2](https://sugi.bio/atlas/gene/WEE2/) |
| Protein change (HGVS p.) | p.Glu407= |
| Coding change (HGVS c.) | c.1221G>A |
| MANE Select transcript | [NM_001105558](https://www.ncbi.nlm.nih.gov/nuccore/NM_001105558) |
| dbSNP | [rs1380657460](https://www.ncbi.nlm.nih.gov/snp/rs1380657460/) |
| Variant type | single nucleotide variant |
| Location | chr7:141724275-141724275 (GRCh38) |
| ClinVar | [VCV977296](https://www.ncbi.nlm.nih.gov/clinvar/variation/977296/) |

**All HGVS expressions:** `NC_000007.13:g.141424075G>A`, `NC_000007.14:g.141724275G>A`, `NM_001105558.1:c.1220_1392delinsA[NC_000007.14:g.141724275_141724850]`, `NM_001105558.1:c.1221G>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.93) — consistent with the pathogenic call
- Conservation: phyloP 8.515, GERP 5.46, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 24.1**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.93**, acceptor gain **0.00**, donor gain **0.34**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.93**, acceptor gain **0.00**, donor gain **0.34**.
- Pangolin: Δ**0.80** (loss), gain 0.15 / loss 0.80. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00223%** (eas) · 1/44,860 in the highest group · 1/152,098 alleles overall — very rare (popmax 0.00223%, eas).

*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}

**WEE2** population constraint: LOEUF 1.031, pLI 7.9709e-14, missense-Z 1.2451. *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 **407** lies in the protein kinase domain.

AlphaFold model confidence (whole protein): pLDDT 67.50, 41% of residues very-high.

**1 experimental structure(s)** (PDB): [5VDK](https://www.rcsb.org/structure/5VDK).

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2023-04-10.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2023-04-10 |

## Associated conditions {#conditions}

[oocyte maturation defect 5](https://sugi.bio/atlas/disease/oocyte-maturation-defect-5/).

**Reported phenotype names (ClinVar):** Oocyte maturation defect 5, OOCYTE/ZYGOTE/EMBRYO MATURATION ARREST 5.

## Similar variants {#similar}

Related WEE2 variant pages (same residue, condition, or type): [WEE2 p.Tyr163His](/variant/wee2-p-tyr163his), [WEE2 p.Arg200Ter](/variant/wee2-p-arg200ter), [WEE2 p.Arg410Trp](/variant/wee2-p-arg410trp), [WEE2 p.Asp234His](/variant/wee2-p-asp234his), [WEE2 p.Glu75fs](/variant/wee2-p-glu75fs), [WEE2 p.His337fs](/variant/wee2-p-his337fs), [WEE2 p.Thr493fs](/variant/wee2-p-thr493fs), [WEE2 p.Gly357Arg](/variant/wee2-p-gly357arg).

### 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 2026-07-14); 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 977296). 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.*