# NM_007194.4(CHEK2):c.1452G>A (p.Pro484=)

https://sugi.bio/variant/chek2-p-pro484

## Summary

**CHEK2 p.Pro484= (c.1452G>A)** is classified **Conflicting classifications of pathogenicity** in CHEK2 (ClinVar, Conflicting submitters, 14 submitters; last evaluated 2025-12-21). Very rare (popmax 0.0011%, sas); Associated with CHEK2-related cancer predisposition.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs749156425 · 14 submitters · 4 linked conditions · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the CHEK2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 14 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.Pro484= |
| Coding change (HGVS c.) | c.1452G>A |
| MANE Select transcript | [NM_007194](https://www.ncbi.nlm.nih.gov/nuccore/NM_007194) |
| dbSNP | [rs749156425](https://www.ncbi.nlm.nih.gov/snp/rs749156425/) |
| Variant type | single nucleotide variant |
| Location | chr22:28694041-28694041 (GRCh38) |
| ClinVar | [VCV230446](https://www.ncbi.nlm.nih.gov/clinvar/variation/230446/) |

**All HGVS expressions:** `LRG_302:g.52826G>A`, `LRG_302t1:c.1452G>A`, `NC_000022.10:g.29090029C>T`, `NC_000022.11:g.28694041C>T`, `NG_008150.2:g.52826G>A`, `NM_001005735.3:c.1581G>A`, `NM_001257387.3:c.789G>A`, `NM_001349956.3:c.1251G>A`, `NM_007194.4:c.1452G>A`, `NM_145862.3:c.1365G>A`

## 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 -20, GERP -3.33 — fast-evolving / accelerated position
- CADD: **PHRED 0.541**. 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: **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 (gnomAD v4.1): grpmax **0.0011%** (sas) · FAF95 8e-05% · FAF99 5.4e-05% · 1/90,946 in the highest group · 19/1,594,088 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0473% | 2,112 |
| South Asian (grpmax) | 0.0011% | 90,946 |
| European (non-Finnish) | 0.00034% | 294,452 |

Ashkenazi Jewish 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}

**CHEK2** population constraint: LOEUF 1.399, pLI 2.847e-14, missense-Z -0.016674; ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *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 **484** lies in an α-helix; the protein kinase domain.

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.Pro484= 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-12-21.

**Submitter consensus:** conflicting (12 Likely benign, 1 Uncertain significance, 1 Benign).

**Submission history:** 14 submissions (2015–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Mendelics | Likely benign | criteria provided, single submitter | clinical testing | 2019-05-28 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2020-09-25 |
| Sema4, Sema4 | Likely benign | criteria provided, single submitter | curation | 2022-01-06 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2018-11-08 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2015-02-20 |
| Color Diagnostics, LLC DBA Color Health | Likely benign | criteria provided, single submitter | clinical testing | 2016-12-16 |
| Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Likely benign | criteria provided, single submitter | clinical testing | 2023-03-21 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | Likely benign | criteria provided, single submitter | clinical testing | 2023-06-30 |
| Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Likely benign | criteria provided, single submitter | clinical testing | 2025-03-04 |
| Myriad Genetics, Inc. | Benign | criteria provided, single submitter | clinical testing | 2024-10-08 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Likely benign | criteria provided, single submitter | clinical testing | 2024-09-12 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-21 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-05-31 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** CHEK2-related cancer predisposition, Hereditary cancer-predisposing syndrome, not specified, Familial cancer of breast, not provided, Hereditary nonpolyposis colon cancer, none provided, AllHighlyPenetrant, CHEK2-related cancer susceptibility, TUMOR PREDISPOSITION SYNDROME 4.

## Same-residue context {#hotspot}

Residue **484** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CHEK2 p.Pro484fs](/variant/chek2-p-pro484fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CHEK2 variant pages (same residue, condition, or type): [CHEK2 p.Pro484Arg](/variant/chek2-p-pro484arg), [CHEK2 p.Pro484Ser](/variant/chek2-p-pro484ser), [CHEK2 p.Pro484Thr](/variant/chek2-p-pro484thr), [CHEK2 p.Pro484Ala](/variant/chek2-p-pro484ala), [CHEK2 p.Pro484Gln](/variant/chek2-p-pro484gln), [CHEK2 p.Pro484Leu](/variant/chek2-p-pro484leu), [CHEK2 p.Pro484fs](/variant/chek2-p-pro484fs), [CHEK2 p.Pro484_Trp485insGlnArgHisValLeuArgGlnLysLysProTer](/variant/chek2-p-pro484-trp485insglnarghisvalleuargglnlyslysproter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 230446). 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.*