# NM_007194.4(CHEK2):c.49G>T (p.Ala17Ser)

https://sugi.bio/variant/chek2-p-ala17ser

## Summary

**CHEK2 p.Ala17Ser (c.49G>T)** is classified **Pathogenic** in CHEK2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2002-01-01). AlphaMissense: likely benign (0.0617); Absent from gnomAD v4.1; Associated with bone osteosarcoma.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs137853008 · 1 submitter · 1 linked condition · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CHEK2 gene that is reported as disease-causing, though the computational evidence is not fully concordant, submitted by 1 submitter, and is linked to bone osteosarcoma.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Not applicable |
| Age of onset (of this condition) | Childhood |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CHEK2 is a diagnostic-grade gene on 3 Genomics England panels |

**Commonly reported features of Osteosarcoma** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Osteolysis — Very frequent (99-80%)
- Abnormality of the femoral metaphysis — Very frequent (99-80%)
- Abnormal metaphysis morphology — Frequent (79-30%)
- Joint swelling — Frequent (79-30%)
- Elevated circulating alkaline phosphatase concentration — Frequent (79-30%)
- Abnormality of the tibial metaphysis — Frequent (79-30%)
- Pain — Frequent (79-30%)
- Increased circulating lactate dehydrogenase concentration — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007284/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.Ala17Ser |
| Coding change (HGVS c.) | c.49G>T |
| MANE Select transcript | [NM_007194](https://www.ncbi.nlm.nih.gov/nuccore/NM_007194) |
| dbSNP | [rs137853008](https://www.ncbi.nlm.nih.gov/snp/rs137853008/) |
| Variant type | single nucleotide variant |
| Location | chr22:28734673-28734673 (GRCh38) |
| ClinVar | [VCV5595](https://www.ncbi.nlm.nih.gov/clinvar/variation/5595/) |

**All HGVS expressions:** `LRG_302:g.12194G>T`, `LRG_302t1:c.49G>T`, `NC_000022.10:g.29130661C>A`, `NC_000022.11:g.28734673C>A`, `NG_008150.2:g.12194G>T`, `NM_001005735.3:c.49G>T`, `NM_001257387.3:c.-729G>T`, `NM_001349956.3:c.49G>T`, `NM_007194.4:c.49G>T`, `NM_145862.3:c.49G>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — AlphaMissense predicts likely-benign.

- AlphaMissense **likely benign** (0.0617) — ⚠ discordant with the pathogenic call
- REVEL 0.058 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -3.601 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- CADD: **PHRED 0.003**. 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: **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}

**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 **17** lies in the 'disordered' region; a UniProt-annotated variant site (found in an osteogenic sarcoma sample; somatic mutation; might influence susceptibility to breast cancer).

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.Ala17Ser falls in the disordered region.


### 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}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2002-01-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2002-01-01 |

## Associated conditions {#conditions}

[bone osteosarcoma](https://sugi.bio/atlas/disease/bone-osteosarcoma/).

**Reported phenotype names (ClinVar):** Bone osteosarcoma, Osteosarcoma, somatic.

## Similar variants {#similar}

Related CHEK2 variant pages (same residue, condition, or type): [CHEK2 p.Ala17=](/variant/chek2-p-ala17), [CHEK2 p.Ala17Gly](/variant/chek2-p-ala17gly), [CHEK2 p.Ala17Val](/variant/chek2-p-ala17val), [CHEK2 c.1008+2T>G](/variant/chek2-c-1008-plus-2t-g), [CHEK2 c.1461+1G>A](/variant/chek2-c-1461-plus-1g-a), [CHEK2 c.319+1G>A](/variant/chek2-c-319-plus-1g-a), [CHEK2 c.319+2T>A](/variant/chek2-c-319-plus-2t-a), [CHEK2 c.444+1G>A](/variant/chek2-c-444-plus-1g-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 5595). 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.*