# NM_001798.5(CDK2):c.571T>C (p.Cys191Arg)

https://sugi.bio/variant/cdk2-p-cys191arg

## Summary

**CDK2 p.Cys191Arg (c.571T>C)** is classified **Uncertain significance** in CDK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-02). AlphaMissense: likely pathogenic (0.9988); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CDK2 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 | [CDK2](https://sugi.bio/atlas/gene/CDK2/) |
| Protein change (HGVS p.) | p.Cys191Arg |
| Coding change (HGVS c.) | c.571T>C |
| MANE Select transcript | [NM_001798](https://www.ncbi.nlm.nih.gov/nuccore/NM_001798) |
| Variant type | single nucleotide variant |
| Location | chr12:55969559-55969559 (GRCh38) |
| ClinVar | [VCV3999620](https://www.ncbi.nlm.nih.gov/clinvar/variation/3999620/) |

**All HGVS expressions:** `NC_000012.11:g.56363343T>C`, `NC_000012.12:g.55969559T>C`, `NG_028086.1:g.2154A>G`, `NG_034014.1:g.7791T>C`, `NM_001290230.2:c.408+611T>C`, `NM_001798.5:c.571T>C`, `NM_052827.4:c.486+611T>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** (0.9988)
- REVEL 0.584 (indeterminate)
- SaProt LLR -14.552 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP 7.917, GERP 2.32, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 32.0**. 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 0.13** across the covering region of the MANE Select transcript (55,968,933–55,969,559), spanning 626 bp — the region is depleted of missense variation. Chi-square p 4.1e-08. 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}

**CDK2** population constraint: LOEUF 0.39, pLI 0.99867, missense-Z 2.9267. *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 **191** lies in the protein kinase domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 88.55, 69% of residues very-high.

**523 experimental structure(s)** (PDB): [11GV](https://www.rcsb.org/structure/11GV), [1AQ1](https://www.rcsb.org/structure/1AQ1), [1B38](https://www.rcsb.org/structure/1B38), [1B39](https://www.rcsb.org/structure/1B39), [1BUH](https://www.rcsb.org/structure/1BUH), [1CKP](https://www.rcsb.org/structure/1CKP) — incl. mutant structure 2IW8.

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

*Describes the biological roles of CDK2 (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:** CDK2's established molecular role includes protein serine/threonine kinase activity. p.Cys191Arg falls in the protein kinase domain. In Reactome, CDK2 is annotated in disease pathway(s) including **Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)**.

**Disease mechanism (Reactome):** CDK2 loss or alteration is curated in [Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)](https://reactome.org/content/detail/R-HSA-9661069).

### Pathways affected {#pathways}

CDK2 participates in **27 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)](https://reactome.org/content/detail/R-HSA-9661069) | curated |
| [Activation of ATR in response to replication stress](https://reactome.org/content/detail/R-HSA-176187) | curated |
| [Activation of the pre-replicative complex](https://reactome.org/content/detail/R-HSA-68962) | curated |
| [CDK-mediated phosphorylation and removal of Cdc6](https://reactome.org/content/detail/R-HSA-69017) | curated |
| [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 D associated events in G1](https://reactome.org/content/detail/R-HSA-69231) | curated |
| [Cyclin E associated events during G1/S transition ](https://reactome.org/content/detail/R-HSA-69202) | curated |
| [DNA Damage/Telomere Stress Induced Senescence](https://reactome.org/content/detail/R-HSA-2559586) | curated |
| [G0 and Early G1](https://reactome.org/content/detail/R-HSA-1538133) | curated |
| [G2 Phase](https://reactome.org/content/detail/R-HSA-68911) | curated |
| [Orc1 removal from chromatin](https://reactome.org/content/detail/R-HSA-68949) | curated |
| [PTK6 Regulates Cell Cycle](https://reactome.org/content/detail/R-HSA-8849470) | curated |
| [Phosphorylation of proteins involved in G1/S transition by active Cyclin E:Cdk2 complexes](https://reactome.org/content/detail/R-HSA-69200) | curated |
| [Processing of DNA double-strand break ends](https://reactome.org/content/detail/R-HSA-5693607) | curated |
| [Regulation of APC/C activators between G1/S and early anaphase](https://reactome.org/content/detail/R-HSA-176408) | curated |
| [Regulation of MITF-M-dependent genes involved in cell cycle and proliferation](https://reactome.org/content/detail/R-HSA-9825892) | 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 |
| [SCF(Skp2)-mediated degradation of p27/p21](https://reactome.org/content/detail/R-HSA-187577) | curated |
| [Senescence-Associated Secretory Phenotype (SASP)](https://reactome.org/content/detail/R-HSA-2559582) | curated |
| [TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest](https://reactome.org/content/detail/R-HSA-6804116) | curated |
| [Telomere Extension By Telomerase](https://reactome.org/content/detail/R-HSA-171319) | curated |
| [Transcriptional regulation of granulopoiesis](https://reactome.org/content/detail/R-HSA-9616222) | curated |
| [p53-Dependent G1 DNA Damage Response](https://reactome.org/content/detail/R-HSA-69563) | curated |
| [Factors involved in megakaryocyte development and platelet production](https://reactome.org/content/detail/R-HSA-983231) | electronic |
| [Meiotic recombination](https://reactome.org/content/detail/R-HSA-912446) | electronic |

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

**Molecular function:** protein serine/threonine kinase activity, cyclin-dependent protein serine/threonine kinase activity, protein domain specific binding, cyclin binding, cyclin-dependent protein kinase activity.

**Biological process:** protein phosphorylation, centriole replication, Ras protein signal transduction, positive regulation of cell population proliferation, peptidyl-serine phosphorylation, positive regulation of heterochromatin formation.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-04-02.

**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 | 2025-04-02 |

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

## Similar variants {#similar}

Related CDK2 variant pages (same residue, condition, or type): [CDK2 p.Arg199His](/variant/cdk2-p-arg199his), [CDK2 p.Arg200Gln](/variant/cdk2-p-arg200gln), [CDK2 p.Arg200Trp](/variant/cdk2-p-arg200trp), [CDK2 p.Arg214Gln](/variant/cdk2-p-arg214gln), [CDK2 p.Asp288His](/variant/cdk2-p-asp288his), [CDK2 p.Glu57Ala](/variant/cdk2-p-glu57ala), [CDK2 p.His268Leu](/variant/cdk2-p-his268leu), [CDK2 p.Ile10Leu](/variant/cdk2-p-ile10leu).

### 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 3999620). 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.*