CUL1

Chr 7

cullin 1

NCBI Gene: 8454ENSG00000055130UniProt: Q13616

Enables ubiquitin ligase complex scaffold activity and ubiquitin protein ligase binding activity. Involved in SCF-dependent proteasomal ubiquitin-dependent protein catabolic process; positive regulation of canonical NF-kappaB signal transduction; and protein K48-linked ubiquitination. Located in plasma membrane. Part of Parkin-FBXW7-Cul1 ubiquitin ligase complex and SCF ubiquitin ligase complex. [provided by Alliance of Genome Resources, Jul 2025]

96
ClinVar variants
64
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— CUL1
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
64 Pathogenic / Likely Pathogenic· 32 VUS of 96 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.14LOEUF
pLI 1.000
Z-score 6.43
OE 0.06 (0.02–0.14)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

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.
5.70Z-score
OE missense 0.22 (0.18–0.26)
93 obs / 423.0 exp
Constrained

Extremely missense-constrained (top ~0.01%)

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.0.06 (0.02–0.14)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.22 (0.18–0.26)
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.1.02
0≤1.21.6
LoF obs/exp: 3 / 53.9Missense obs/exp: 93 / 423.0Syn Z: -0.21

ClinVar Variant Classifications

96 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic60
Likely Pathogenic4
VUS32
60
Pathogenic
4
Likely Pathogenic
32
VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
60
0
60
Likely Pathogenic
0
0
4
0
4
VUS
0
21
11
0
32
Likely Benign
0
0
0
0
0
Benign
0
0
0
0
0
Total02175096

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

View in ClinVar →

Protein Context — Lollipop Plot

CUL1 · 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
CULLIN 1; CUL1
MIM #603134 · *
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Molecular insights and clinical implications for the tumor suppressor role of SCF(FBXW7) E3 ubiquitin ligase.
Qi Y et al.·Biochim Biophys Acta Rev Cancer
2024Review
FBXL4 suppresses mitophagy by restricting the accumulation of NIX and BNIP3 mitophagy receptors.
Nguyen-Dien GT et al.·EMBO J
2023
CUL1-neddylation contributes to K29-linked ubiquitination on p27 for autophagic degradation in sorafenib-resistant liver cancer.
Xu H et al.·Cell Biol Toxicol
2025
SCF ubiquitin ligase-targeted therapies.
Skaar JR et al.·Nat Rev Drug Discov
2014Review
Dysregulated NUB1 and Neddylation Enhances Rheumatoid Arthritis Fibroblast-Like Synoviocyte Inflammatory Responses.
Sendo S et al.·Arthritis Rheumatol
2024
Omics data integration analysis identified new biological insights into chronic antibody-mediated rejection (CAMR).
Bruschi M et al.·J Transl Med
2025
CUL1 variants cause severe neurodevelopmental disorders: Insights from human genetics and a zebrafish model of microcephaly.
Xu H et al.·HGG Adv
2026Functional
TBL1X: At the crossroads of transcriptional and posttranscriptional regulation.
Pray BA et al.·Exp Hematol
2022Review
FBXO22 deficiency defines a pleiotropic syndrome of growth restriction and multi-system anomalies associated with a unique epigenetic signature.
Ramakrishna NB et al.·Am J Hum Genet
2025
The Role of NEDD4 E3 Ubiquitin-Protein Ligases in Parkinson's Disease.
Conway JA et al.·Genes (Basel)
2022Review
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