# NM_007194.4(CHEK2):c.1282T>C (p.Ser428Pro)

https://sugi.bio/variant/chek2-p-ser428pro

## Summary

**CHEK2 p.Ser428Pro (c.1282T>C)** is classified **Uncertain significance** in CHEK2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-02-13). AlphaMissense: likely pathogenic (0.9449); Very rare (popmax 0.00134%, afr); Associated with CHEK2-related cancer predisposition.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1182200321 · 4 submitters · 5 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.00134%, afr)

## For patients & families {#patients}

This is a change in the CHEK2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 4 submitters, and is linked to CHEK2-related cancer predisposition.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0026411/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CHEK2](https://sugi.bio/atlas/gene/CHEK2/) |
| Protein change (HGVS p.) | p.Ser428Pro |
| Coding change (HGVS c.) | c.1282T>C |
| MANE Select transcript | [NM_007194](https://www.ncbi.nlm.nih.gov/nuccore/NM_007194) |
| dbSNP | [rs1182200321](https://www.ncbi.nlm.nih.gov/snp/rs1182200321/) |
| Variant type | single nucleotide variant |
| Location | chr22:28695220-28695220 (GRCh38) |
| ClinVar | [VCV653464](https://www.ncbi.nlm.nih.gov/clinvar/variation/653464/) |

**All HGVS expressions:** `LRG_302:g.51647T>C`, `LRG_302t1:c.1282T>C`, `NC_000022.10:g.29091208A>G`, `NC_000022.11:g.28695220A>G`, `NG_008150.2:g.51647T>C`, `NM_001005735.3:c.1411T>C`, `NM_001257387.3:c.619T>C`, `NM_001349956.3:c.1081T>C`, `NM_007194.4:c.1282T>C`, `NM_145862.3:c.1195T>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9449)
- REVEL 0.345 (indeterminate)
- SaProt LLR -13.525 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL is indeterminate
- SpliceAI predicts **acceptor loss** (Δ 0.31) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 9.104, GERP 1.71, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 28.4**. 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 1.02** across the covering region of the MANE Select transcript (28,687,900–28,734,721), spanning 46,821 bp. Chi-square p 0.57. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.31**, donor loss **0.00**, acceptor gain **0.04**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.31**, donor loss **0.00**, acceptor gain **0.04**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.00134%** (afr) · 1/74,846 in the highest group · 1/1,610,400 alleles overall — very rare (popmax 0.00134%, afr).

*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}

**CHEK2** population constraint: LOEUF 1.399, pLI 2.847e-14, missense-Z -0.016674; 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):

- **CHEK2-related cancer predisposition** — Definitive (AD)
- **familial ovarian cancer** — Refuted (AD)
- **hereditary nonpolyposis colon cancer** — Limited (AD)

## Protein context {#protein}

Residue **428** lies in the protein kinase domain; a UniProt-annotated variant site (may increase breast cancer risk).

AlphaFold model confidence (whole protein): pLDDT 77.64, 49% of residues very-high.

**38 experimental structure(s)** (PDB): [1GXC](https://www.rcsb.org/structure/1GXC), [2CN5](https://www.rcsb.org/structure/2CN5), [2CN8](https://www.rcsb.org/structure/2CN8), [2W0J](https://www.rcsb.org/structure/2W0J), [2W7X](https://www.rcsb.org/structure/2W7X), [2WTC](https://www.rcsb.org/structure/2WTC).

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

*Describes the biological roles of CHEK2 (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:** CHEK2's established molecular role includes protein serine/threonine kinase activity. p.Ser428Pro falls in the protein kinase domain.


### Pathways affected {#pathways}

CHEK2 participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex](https://reactome.org/content/detail/R-HSA-75035) | curated |
| [G2/M DNA damage checkpoint](https://reactome.org/content/detail/R-HSA-69473) | curated |
| [Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks](https://reactome.org/content/detail/R-HSA-5693565) | curated |
| [Regulation of TP53 Activity through Methylation](https://reactome.org/content/detail/R-HSA-6804760) | curated |
| [Regulation of TP53 Activity through Phosphorylation](https://reactome.org/content/detail/R-HSA-6804756) | curated |
| [Regulation of TP53 Degradation](https://reactome.org/content/detail/R-HSA-6804757) | curated |
| [Stabilization of p53](https://reactome.org/content/detail/R-HSA-69541) | curated |
| [Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A](https://reactome.org/content/detail/R-HSA-69601) | curated |

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

**Molecular function:** protein serine/threonine kinase activity, protein kinase binding, ubiquitin protein ligase binding, identical protein binding, protein homodimerization activity.

**Biological process:** G2/M transition of mitotic cell cycle, double-strand break repair, regulation of DNA-templated transcription, protein phosphorylation, DNA damage response, intrinsic apoptotic signaling pathway in response to DNA damage.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-02-13.

**Submitter consensus:** unanimous (4/4 Uncertain significance).

**Submission history:** 4 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-02-18 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-03-19 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-02-13 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-04-24 |

## Associated conditions {#conditions}

[CHEK2-related cancer predisposition](https://sugi.bio/atlas/disease/chek2-related-cancer-predisposition/), [bone osteosarcoma](https://sugi.bio/atlas/disease/bone-osteosarcoma/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [hereditary breast carcinoma](https://sugi.bio/atlas/disease/hereditary-breast-carcinoma/), [prostate cancer, hereditary](https://sugi.bio/atlas/disease/prostate-cancer-hereditary/).

**Reported phenotype names (ClinVar):** CHEK2-related cancer predisposition, Familial cancer of breast, Hereditary cancer-predisposing syndrome, Bone osteosarcoma, Familial prostate cancer, CHEK2-related cancer susceptibility, TUMOR PREDISPOSITION SYNDROME 4, CANCER PREDISPOSITION SYNDROME, CHEK2-RELATED, Osteosarcoma, somatic, Hereditary Prostate Cancer.

## Same-residue context {#hotspot}

Residue **428** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CHEK2 p.Ser428fs](/variant/chek2-p-ser428fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CHEK2 variant pages (same residue, condition, or type): [CHEK2 p.Ser428=](/variant/chek2-p-ser428), [CHEK2 p.Ser428Cys](/variant/chek2-p-ser428cys), [CHEK2 p.Ser428Phe](/variant/chek2-p-ser428phe), [CHEK2 p.Ser428fs](/variant/chek2-p-ser428fs), [CDS1 p.Gln428His](/variant/cds1-p-gln428his), [CHEK2 c.1008+1G>A](/variant/chek2-c-1008-plus-1g-a), [CHEK2 c.1008+1G>T](/variant/chek2-c-1008-plus-1g-t), [CHEK2 c.1008+2T>A](/variant/chek2-c-1008-plus-2t-a).

### 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 653464). 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.*