# NM_001237.5(CCNA2):c.1225A>G (p.Ile409Val)

https://sugi.bio/variant/ccna2-p-ile409val

## Summary

**CCNA2 p.Ile409Val (c.1225A>G)** is classified **Uncertain significance** in CCNA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-25). AlphaMissense: likely benign (0.0724); Ultra-rare (popmax 0.012%, afr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.012%, afr)

## For patients & families {#patients}

This is a change in the CCNA2 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 | [CCNA2](https://sugi.bio/atlas/gene/CCNA2/) |
| Protein change (HGVS p.) | p.Ile409Val |
| Coding change (HGVS c.) | c.1225A>G |
| MANE Select transcript | [NM_001237](https://www.ncbi.nlm.nih.gov/nuccore/NM_001237) |
| Variant type | single nucleotide variant |
| Location | chr4:121818069-121818069 (GRCh38) |
| ClinVar | [VCV4222025](https://www.ncbi.nlm.nih.gov/clinvar/variation/4222025/) |

**All HGVS expressions:** `NC_000004.11:g.122739224T>C`, `NC_000004.12:g.121818069T>C`, `NG_029848.1:g.21753T>C`, `NG_052974.1:g.10933A>G`, `NG_052974.2:g.10814A>G`, `NM_001237.5:c.1225A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0724)
- REVEL 0.102 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.461 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor gain** (Δ 0.46) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 2.906, GERP 1.99, phastCons 0.999 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 21.9**. 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 0.54** across the covering region of the MANE Select transcript (121,817,641–121,821,007), spanning 3,366 bp. Chi-square p 4.5e-15. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.46**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.46**.
- Population frequency (gnomAD v4.1): grpmax **0.012%** (afr) · FAF95 0.00623% · FAF99 0.00467% · 9/75,026 in the highest group · 52/1,613,706 alleles overall — ultra-rare (popmax 0.012%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.012% | 8,336 |
| Remaining individuals (not grpmax-eligible) | 0.008% | 12,498 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,588 |
| European (non-Finnish) | 0.00297% | 33,709 |
| East Asian | 0.00223% | 44,878 |
| Admixed American | 0.00167% | 59,910 |

*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}

**CCNA2** population constraint: LOEUF 0.183, pLI 1, missense-Z 2.5241. *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 **409** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 73.80, 59% of residues very-high.

**115 experimental structure(s)** (PDB): [11GV](https://www.rcsb.org/structure/11GV), [1E9H](https://www.rcsb.org/structure/1E9H), [1FIN](https://www.rcsb.org/structure/1FIN), [1FVV](https://www.rcsb.org/structure/1FVV), [1GY3](https://www.rcsb.org/structure/1GY3), [1H1P](https://www.rcsb.org/structure/1H1P) — incl. mutant structure 2IW8.

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

*Describes the biological roles of CCNA2 (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:** CCNA2's established molecular role includes cyclin-dependent protein serine/threonine kinase regulator activity.


### Pathways affected {#pathways}

CCNA2 participates in **21 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [CDK-mediated phosphorylation and removal of Cdc6](https://reactome.org/content/detail/R-HSA-69017) | curated |
| [Cdc20:Phospho-APC/C mediated degradation of Cyclin A](https://reactome.org/content/detail/R-HSA-174184) | curated |
| [Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex](https://reactome.org/content/detail/R-HSA-75035) | 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 |
| [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 |
| [G2/M DNA replication checkpoint](https://reactome.org/content/detail/R-HSA-69478) | curated |
| [Orc1 removal from chromatin](https://reactome.org/content/detail/R-HSA-68949) | 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 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 |
| [Ub-specific processing proteases](https://reactome.org/content/detail/R-HSA-5689880) | curated |
| [p53-Dependent G1 DNA Damage Response](https://reactome.org/content/detail/R-HSA-69563) | curated |
| [Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1](https://reactome.org/content/detail/R-HSA-1362300) | electronic |

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

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

**Biological process:** G2/M transition of mitotic cell cycle, regulation of DNA replication, Ras protein signal transduction, post-translational protein modification, cell cycle G1/S phase transition.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-25.

**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 | 2025-08-25 |

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

## Similar variants {#similar}

Related CCNA2 variant pages (same residue, condition, or type): [EXOSC9 p.Ala438Val](/variant/exosc9-p-ala438val), [CCN1 c.277+50G>C](/variant/ccn1-c-277-plus-50g-c), [CCN1 c.64-124G>A](/variant/ccn1-c-64-minus-124g-a), [CCN1 c.-107C>A](/variant/ccn1-c-minus-107c-a), [CCN1 p.Ser316Cys](/variant/ccn1-p-ser316cys), [CCN1 p.Tyr300=](/variant/ccn1-p-tyr300), [CCNA2 c.*828C>G](/variant/ccna2-c-star-828c-g), [CCNA2 p.Leu126=](/variant/ccna2-p-leu126).

### 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 4222025). 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.*