# NM_001759.4(CCND2):c.841C>T (p.Pro281Ser)

https://sugi.bio/variant/ccnd2-p-pro281ser

## Summary

**CCND2 p.Pro281Ser (c.841C>T)** is classified **Pathogenic/Likely pathogenic** in CCND2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-07-16). AlphaMissense: likely pathogenic (0.9961); Very rare (popmax 0.00134%, afr); Associated with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs587777621 · 5 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00134%, afr)

## For patients & families {#patients}

This is a change in the CCND2 gene that is considered likely disease-causing, submitted by 5 submitters, and is linked to megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3.

*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/0018079/index) · [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.Pro281Ser |
| Coding change (HGVS c.) | c.841C>T |
| MANE Select transcript | [NM_001759](https://www.ncbi.nlm.nih.gov/nuccore/NM_001759) |
| dbSNP | [rs587777621](https://www.ncbi.nlm.nih.gov/snp/rs587777621/) |
| Variant type | single nucleotide variant |
| Location | chr12:4299980-4299980 (GRCh38) |
| ClinVar | [VCV143984](https://www.ncbi.nlm.nih.gov/clinvar/variation/143984/) |

**All HGVS expressions:** `NC_000012.11:g.4409146C>T`, `NC_000012.12:g.4299980C>T`, `NG_034254.1:g.31245C>T`, `NM_001759.4:c.841C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9961) — concordant with the pathogenic call
- REVEL 0.866 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -7.693 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL call this damaging; SaProt does not
- Conservation: phyloP 7.673, GERP 1.86, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 7%** most-pathogenic-predicted substitutions in CCND2 (of 1,696 modeled).
- CADD: **PHRED 26.4**. 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 1.12** across the covering region of the MANE Select transcript (4,299,898–4,300,006), spanning 108 bp. Chi-square p 0.37. 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 (gnomAD v4.1): grpmax **0.00134%** (afr) · FAF95 2.8e-05% · FAF99 1.1e-05% · 1/74,886 in the highest group · 4/1,613,918 alleles overall — very rare (popmax 0.00134%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00134% | 74,886 |
| South Asian | 0.0011% | 91,080 |
| European (non-Finnish) | 0.000169% | 589,995 |

*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}

Residue **281** lies in a UniProt-annotated variant site (in mpph3); the 'disordered' region.

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. p.Pro281Ser falls in the disordered region. 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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-07-16.

**Submitter consensus:** conflicting (3 Pathogenic, 1 not provided, 1 Likely pathogenic).

**Submission history:** 5 submissions (2014–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute of Human Genetics, University of Leipzig Medical Center | Pathogenic | criteria provided, single submitter | clinical testing | 2018-12-11 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2014-05-01 |
| GeneReviews | not provided | no classification provided | literature only |  |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2024-05-08 |
| Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Likely pathogenic | criteria provided, single submitter | clinical testing | 2026-07-16 |

## Associated conditions {#conditions}

[megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3](https://sugi.bio/atlas/disease/megalencephaly-polymicrogyria-polydactyly-hydrocephalus-syndrome-3/).

**Reported phenotype names (ClinVar):** Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3, not provided, none provided.

## Same-residue context {#hotspot}

Residue **281** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [CCND2 p.Pro281Leu](/variant/ccnd2-p-pro281leu), [CCND2 p.Pro281Ala](/variant/ccnd2-p-pro281ala). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CCND2 variant pages (same residue, condition, or type): [CCND2 p.Pro281Leu](/variant/ccnd2-p-pro281leu), [CCND2 p.Pro281Arg](/variant/ccnd2-p-pro281arg), [CCND2 p.Pro281Ala](/variant/ccnd2-p-pro281ala), [CCND2 p.Gln277Ter](/variant/ccnd2-p-gln277ter), [CCND2 p.Ser271Ter](/variant/ccnd2-p-ser271ter), [CCND2 p.Thr280Ala](/variant/ccnd2-p-thr280ala), [CCND2 p.Thr280Asn](/variant/ccnd2-p-thr280asn), [CCND2 p.Thr280Ile](/variant/ccnd2-p-thr280ile).

### 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 143984). 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.*