CCND2

Chr 12AD

cyclin D2

Also known as: KIAK0002, MPPH3

NCBI Gene: 894ENSG00000118971UniProt: P30279

The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance through the cell cycle. Cyclins function as regulators of CDK kinases. Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. This cyclin forms a complex with CDK4 or CDK6 and functions as a regulatory subunit of the complex, whose activity is required for cell cycle G1/S transition. This protein has been shown to interact with and be involved in the phosphorylation of tumor suppressor protein Rb. Knockout studies of the homologous gene in mouse suggest the essential roles of this gene in ovarian granulosa and germ cell proliferation. High level expression of this gene was observed in ovarian and testicular tumors. Mutations in this gene are associated with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3 (MPPH3). [provided by RefSeq, Sep 2014]

Primary Disease Associations & Inheritance

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3MIM #615938
AD
227
ClinVar variants
76
Pathogenic / LP
0.99
pLI score· haploinsufficient
1
Active trials
Clinical Summary— CCND2
🧬
Gene-Disease Validity (ClinGen)
megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
76 Pathogenic / Likely Pathogenic· 77 VUS of 227 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.23LOEUF
pLI 0.987
Z-score 3.35
OE 0.00 (0.00–0.23)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.13Z-score
OE missense 0.54 (0.45–0.64)
91 obs / 169.0 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.00 (0.00–0.23)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.54 (0.45–0.64)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.89
0≤1.21.6
LoF obs/exp: 0 / 13.0Missense obs/exp: 91 / 169.0Syn Z: 0.78

ClinVar Variant Classifications

227 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic63
Likely Pathogenic13
VUS77
Likely Benign55
Benign14
Conflicting5
63
Pathogenic
13
Likely Pathogenic
77
VUS
55
Likely Benign
14
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
4
58
0
63
Likely Pathogenic
1
4
8
0
13
VUS
2
59
14
2
77
Likely Benign
0
4
29
22
55
Benign
0
0
12
2
14
Conflicting
—5
Total47112126227

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

CCND2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

CCND2-related megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome

definitive
ADGain Of FunctionAltered Gene Product Structure
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
CYCLIN D2; CCND2
MIM #123833 · *

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3

MIM #615938

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — CCND2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Molecular Pathogenesis of Multiple Myeloma: Clinical Implications.
Maura F et al.·Hematol Oncol Clin North Am
2024Review
Comprehensive single-cell and bulk transcriptomic analyses to develop an NK cell-derived gene signature for prognostic assessment and precision medicine in breast cancer.
Hou Q et al.·Front Immunol
2024
Cyclin D1-negative mantle cell lymphoma.
Ok CY et al.·Hum Pathol
2025Review
Diagnostic yield and novel candidate genes for neurodevelopmental disorders by exome sequencing in an unselected cohort with microcephaly.
Wang C et al.·BMC Genomics
2023Cohort
The clinical and molecular landscape of diffuse hemispheric glioma, H3 G34-mutant.
Le Rhun E et al.·Neuro Oncol
2025
Proximal variants in CCND2 associated with microcephaly, short stature, and developmental delay: A case series and review of inverse brain growth phenotypes.
Pirozzi F et al.·Am J Med Genet A
2021Review
Interleukin-30 subverts prostate cancer-endothelium crosstalk by fostering angiogenesis and activating immunoregulatory and oncogenic signaling pathways.
Ciummo SL et al.·J Exp Clin Cancer Res
2023
AML1-ETO and CCND2 overexpression cooperate to drive acute myeloid leukemia initiation and progression.
Mou J et al.·J Leukoc Biol
2025
Improving predictive accuracy in multiple myeloma using a plasma cell profile derived from single-cell RNA sequencing.
Liu L et al.·Haematologica
2025
Recent Insights Into Wnt-Related tRNA-Derived Fragments (tRFs) in Human Diseases.
Shen J et al.·J Cell Biochem
2025Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Cancer

Study of the CDK4/6 Inhibitor Abemaciclib in Solid Tumors Harboring Genetic Alterations in Genes Encoding D-Type Cyclins or Amplification of CDK4 or CDK6

RECRUITING
NCT03310879Phase PHASE2Dana-Farber Cancer InstituteStarted 2017-11-21
Abemaciclib

External Resources

Links to major genomics databases and tools