CCNF

Chr 16AD

cyclin F

Also known as: FBX1, FBXO1, FTDALS5

NCBI Gene: 899 ENSG00000162063 UniProt: P41002 OMIM: 600227

This protein functions as a substrate recognition component of SCF E3 ubiquitin ligase complexes that target cell cycle regulatory proteins for degradation, including CP110, RRM2, and CDC6. Mutations cause frontotemporal dementia and/or amyotrophic lateral sclerosis 5 with autosomal dominant inheritance. The gene shows significant constraint against loss-of-function variants (LOEUF 0.419), indicating that such variants are likely pathogenic.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Frontotemporal dementia and/or amyotrophic lateral sclerosis 5MIM #619141

Clinical highlights

Gene–disease validity (ClinGen)

Limited · frontotemporal dementia and/or amyotrophic lateral sclerosis 5 · AD · ClinGen 2022

not for standalone diagnostic reporting

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.42

LOEUF

GOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

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?

0.74Z-score

OE missense 0.90 (0.83–0.98)

424 obs / 469.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.25 (0.15–0.42)

0≤0.351.4

Missense OE?0.90 (0.83–0.98)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 10 / 40.5Missense obs/exp: 424 / 469.2Syn Z: 0.43

Background carrier burden — how many people carry a rare variant somewhere in CCNF?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 72

988 rare PASS variants

Rare truncating (LoF)

1 in 2,700

105 rare PASS variants

Rare synonymous (reference)

1 in 110

466 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CCNF. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 90	1 in 2,300
South Asian	~43k	1 in 35	1 in 3,500
Remaining (unassigned)	~30k	1 in 63	1 in 3,800
European (Finnish)	~27k	1 in 230	1 in 5,200
Admixed American	~22k	1 in 46	≈ 1 in 4,500
African / African American	~21k	1 in 50	1 in 1,900
East Asian	~20k	1 in 56	1 in 3,000
Ashkenazi Jewish	~13k	1 in 480	none seen
Middle Eastern	~2,884	1 in 61	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 15 of 17 coding exons well covered in gnomAD exomes; exons 1, 6 marginal. Genomes: 15 of 17 (exons 4, 13 below).? see exons ↓