CCND2

Chr 12AD

cyclin D2

Also known as: KIAK0002, MPPH3

NCBI Gene: 894ENSG00000118971UniProt: P30279OMIM: 123833

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]

OMIMResearchGenerating clinical summary…
GOFmechanismADLOEUF 0.231 OMIM phenotype
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.
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?
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?
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?
LoF OE?0.00 (0.00–0.23)
0≤0.351.4
Missense OE?0.54 (0.45–0.64)
0≤0.61.4
Synonymous OE?0.89
0≤1.21.6
LoF obs/exp: 0 / 13.0Missense obs/exp: 91 / 169.0Syn Z: 0.78
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveCCND2-related megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndromeGOFAD

This gene — mechanism propensity

DN
0.4190th %ile
GOF
0.4381th %ile
LOF
0.65top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · LOEUF 0.23
GOF1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFThe findings were consistent with a gain-of-function effect of the CCND2 mutations, and Mirzaa et al. (2014) suggested that the expansion of neuronal progenitor populations underlies the megalencephaly as well as the polymicrogyria observed in the disorder.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

  1. 1.PMID 24705253 ↗

ClinVar Variant Classifications

0 submitted variants in ClinVar

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.

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients