CCNF

Chr 16AD

cyclin F

Also known as: FBX1, FBXO1, FTDALS5

NCBI Gene: 899 ENSG00000162063 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…

GOFmechanismADLOEUF 0.421 OMIM phenotype

Clinical Summary— CCNF

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Gene-Disease Validity (ClinGen)

frontotemporal dementia and/or amyotrophic lateral sclerosis 5 · ADLimited

Limited evidence — not for standalone diagnostic reporting

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.25) despite low pLI — interpret in context.

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ClinVar Variants

3 unique Pathogenic / Likely Pathogenic· 114 VUS of 224 total submissions

Explore recent and relevant literature in Research Assistant →

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

This gene — mechanism propensity

0.5279th %ile

GOF

0.7126th %ile

LOF

0.3940th %ile

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction above median

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.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

224 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic1

VUS114

Likely Benign46

Benign43

Conflicting3

Pathogenic

Likely Pathogenic

114

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	2	0	0	2
Likely Pathogenic	0	1	0	0	1
VUS	2	111	1	0	114
Likely Benign	0	16	6	24	46
Benign	0	4	37	2	43
Conflicting	—				3
Total	2	134	44	26	209

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

View in ClinVar →

30 pathogenic / likely-pathogenic (of 47) ClinVar copy-number / structural variants overlap CCNF — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →