CCNF

Chr 16AD

cyclin F

Also known as: FBX1, FBXO1, FTDALS5

NCBI Gene: 899ENSG00000162063UniProt: P41002

This gene encodes a member of the cyclin family. Cyclins are important regulators of cell cycle transitions through their ability to bind and activate cyclin-dependent protein kinases. This member also belongs to the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of the ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbxs class and it was one of the first proteins in which the F-box motif was identified. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Frontotemporal dementia and/or amyotrophic lateral sclerosis 5MIM #619141
AD
268
ClinVar variants
33
Pathogenic / LP
0.13
pLI score
0
Active trials
Clinical Summary— CCNF
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.25) despite low pLI — interpret in context.
📋
ClinVar Variants
33 Pathogenic / Likely Pathogenic· 126 VUS of 268 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.42LOEUF
pLI 0.127
Z-score 4.44
OE 0.25 (0.15–0.42)
Moderately constrained

More LoF-intolerant than ~75% 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.
0.74Z-score
OE missense 0.90 (0.83–0.98)
424 obs / 469.2 exp
Tolerant

Mild missense constraint

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.0.25 (0.15–0.42)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.90 (0.83–0.98)
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.0.96
0≤1.21.6
LoF obs/exp: 10 / 40.5Missense obs/exp: 424 / 469.2Syn Z: 0.43

ClinVar Variant Classifications

268 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic28
Likely Pathogenic5
VUS126
Likely Benign44
Benign45
Conflicting3
28
Pathogenic
5
Likely Pathogenic
126
VUS
44
Likely Benign
45
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
2
26
0
28
Likely Pathogenic
0
1
4
0
5
VUS
1
106
19
0
126
Likely Benign
0
15
6
23
44
Benign
0
5
37
3
45
Conflicting
—3
Total11299226251

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

View in ClinVar →

Protein Context — Lollipop Plot

CCNF · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
CYCLIN F; CCNF
MIM #600227 · *

Frontotemporal dementia and/or amyotrophic lateral sclerosis 5

MIM #619141

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Novel genes associated with amyotrophic lateral sclerosis: diagnostic and clinical implications.
Chia R et al.·Lancet Neurol
2018Review
Genetic and Phenotypic Spectrum of Amyotrophic Lateral Sclerosis Patients with CCNF Variants from a Large Chinese Cohort.
Zhao B et al.·Mol Neurobiol
2023Meta-analysis
ALS-linked CCNF variant disrupts motor neuron ubiquitin homeostasis.
Farrawell NE et al.·Hum Mol Genet
2023
Genetic and clinical landscape of Chinese frontotemporal dementia: dominance of TBK1 and OPTN mutations.
Nan H et al.·Alzheimers Res Ther
2024
Pathogenic mutation in the ALS/FTD gene, CCNF, causes elevated Lys48-linked ubiquitylation and defective autophagy.
Lee A et al.·Cell Mol Life Sci
2018
Investigating CCNF mutations in a Taiwanese cohort with amyotrophic lateral sclerosis.
Tsai PC et al.·Neurobiol Aging
2018Cohort
CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia.
Williams KL et al.·Nat Commun
2016
Recent Updates on the Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.
Kirola L et al.·Mol Neurobiol
2022Review
Exploring the Role of CCNF Variants in Italian ALS Patients.
Bisogni G et al.·Genes (Basel)
2024Cohort
Overexpression of cyclin F/CCNF as an independent prognostic factor for poor survival in clear cell renal cell carcinoma.
Kwiatkowski M et al.·Sci Rep
2024
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools