# NM_001759.4(CCND2):c.*1_*3del (p.Ter290=)

https://sugi.bio/variant/ccnd2-p-ter290

## Summary

**CCND2 p.Ter290= (c.*1_*3del)** is classified **Uncertain significance** in CCND2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-31). Very rare (popmax 0.00334%, amr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · very rare (popmax 0.00334%, amr)

## For patients & families {#patients}

This is a change in the CCND2 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 | [CCND2](https://sugi.bio/atlas/gene/CCND2/) |
| Protein change (HGVS p.) | p.Ter290= |
| Coding change (HGVS c.) | c.*1_*3del |
| MANE Select transcript | [NM_001759](https://www.ncbi.nlm.nih.gov/nuccore/NM_001759) |
| Variant type | Deletion |
| Location | chr12:4300008-4300010 (GRCh38) |
| ClinVar | [VCV4698461](https://www.ncbi.nlm.nih.gov/clinvar/variation/4698461/) |

**All HGVS expressions:** `NC_000012.11:g.4409176_4409178del`, `NC_000012.12:g.4300010_4300012del`, `NG_034254.1:g.31275_31277del`, `NG_034254.2:g.31250_31252del`, `NM_001759.4:c.*1_*3del`

## 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 7.892, GERP 1.86, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **stop-loss** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.385, pLI 0.99932), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00334%** (amr) · FAF95 0.000554% · FAF99 0.000207% · 2/59,934 in the highest group · 3/1,613,234 alleles overall — very rare (popmax 0.00334%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00334% | 29,967 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,460 |

*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}

**CCND2** population constraint: LOEUF 0.385, pLI 0.99932, missense-Z 2.8824. *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):

- **megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 87.98, 72% of residues very-high.

**1 experimental structure(s)** (PDB): [6EI2](https://www.rcsb.org/structure/6EI2).

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

*Describes the biological roles of CCND2 (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:** CCND2's established molecular role includes protein kinase binding. In Reactome, CCND2 is annotated in disease pathway(s) including **Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)**.

**Disease mechanism (Reactome):** CCND2 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}

CCND2 participates in **4 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 |
| [Cyclin D associated events in G1](https://reactome.org/content/detail/R-HSA-69231) | curated |
| [Drug-mediated inhibition of CDK4/CDK6 activity](https://reactome.org/content/detail/R-HSA-9754119) | curated |
| [Regulation of RUNX1 Expression and Activity](https://reactome.org/content/detail/R-HSA-8934593) | curated |

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

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

**Biological process:** G1/S transition of mitotic cell cycle, positive regulation of cell population proliferation, negative regulation of apoptotic process, positive regulation of G1/S transition of mitotic cell cycle.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-01-31.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-01-31 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related CCND2 variant pages (same residue, condition, or type): [CCND2 c.196-205_250del](/variant/ccnd2-c-196-minus-205-250del), [CCND2 c.720+195del](/variant/ccnd2-c-720-plus-195del).

### 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 4698461). 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.*