CUL3

Chr 2AD

cullin 3

Also known as: CUL-3, NEDAUS, PHA2E

NCBI Gene: 8452ENSG00000036257UniProt: Q13618

This gene encodes a member of the cullin protein family. The encoded protein plays a critical role in the polyubiquitination and subsequent degradation of specific protein substrates as the core component and scaffold protein of an E3 ubiquitin ligase complex. Complexes including the encoded protein may also play a role in late endosome maturation. Mutations in this gene are a cause of type 2E pseudohypoaldosteronism. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Mar 2012]

Primary Disease Associations & Inheritance

Neurodevelopmental disorder with or without autism or seizuresMIM #619239
AD
Pseudohypoaldosteronism, type IIEMIM #614496
AD
599
ClinVar variants
111
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— CUL3
🧬
Gene-Disease Validity (ClinGen)
pseudohypoaldosteronism type 2E · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡
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
111 Pathogenic / Likely Pathogenic· 259 VUS of 599 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

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.
0.23LOEUF
pLI 1.000
Z-score 5.28
OE 0.10 (0.05–0.23)
Highly constrained

Highly LoF-intolerant (top ~10% 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.
4.75Z-score
OE missense 0.35 (0.30–0.40)
145 obs / 418.7 exp
Constrained

Highly missense-constrained (top ~0.1%)

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.0.10 (0.05–0.23)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.35 (0.30–0.40)
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.1.12
0≤1.21.6
LoF obs/exp: 4 / 40.1Missense obs/exp: 145 / 418.7Syn Z: -1.10

ClinVar Variant Classifications

599 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic74
Likely Pathogenic37
VUS259
Likely Benign132
Benign78
Conflicting19
74
Pathogenic
37
Likely Pathogenic
259
VUS
132
Likely Benign
78
Benign
19
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
24
6
43
1
74
Likely Pathogenic
19
9
8
1
37
VUS
13
142
97
7
259
Likely Benign
0
7
61
64
132
Benign
0
1
71
6
78
Conflicting
—19
Total5616528079599

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

View in ClinVar →

Protein Context — Lollipop Plot

CUL3 · protein map & ClinVar variants

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

Gene2Phenotype Curations

CUL3-related developmental disorder

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
CULLIN 3; CUL3
MIM #603136 · *

Neurodevelopmental disorder with or without autism or seizures

MIM #619239

Molecular basis of disorder known

Autosomal dominant

Pseudohypoaldosteronism, type IIE

MIM #614496

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — CUL3
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
De novo genic mutations among a Chinese autism spectrum disorder cohort.
Wang T et al.·Nat Commun
2016Cohort
Familial Hyperkalemic Hypertension.
Cornelius RJ et al.·Compr Physiol
2024Review
Integrated molecular analysis of clear-cell renal cell carcinoma.
Sato Y et al.·Nat Genet
2013
Penetrance, variable expressivity and monogenic neurodevelopmental disorders.
de Masfrand S et al.·Eur J Med Genet
2024
DDRGK1 Enhances Osteosarcoma Chemoresistance via Inhibiting KEAP1-Mediated NRF2 Ubiquitination.
Wang X et al.·Adv Sci (Weinh)
2023
The integrated landscape of driver genomic alterations in glioblastoma.
Frattini V et al.·Nat Genet
2013
De novo missense variants in the E3 ubiquitin ligase adaptor KLHL20 cause a developmental disorder with intellectual disability, epilepsy, and autism spectrum disorder.
Sleyp Y et al.·Genet Med
2022
Insights into the diverse mechanisms and effects of variant CUL3-induced familial hyperkalemic hypertension.
Sharma P et al.·Cell Commun Signal
2023Review
LZTR1 Mutation Mediates Oncogenesis through Stabilization of EGFR and AXL.
Ko A et al.·Cancer Discov
2023
Isoform-specific function of NSD3 in DNA replication stress confers resistance to PARP inhibitors in prostate cancer.
Zhu S et al.·Mol Cell
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
CUL3LRB E3 ubiquitin ligases control thermosensory growth in Arabidopsis by differentially regulating HY5 and PIF4 protein stability.
Singhal C et al.·Sci Adv
2026🔓 Open Access
CUL3-Related Neurodevelopmental Disorder: Expanding the Prenatal Phenotype.
Gofin Y et al.·Prenat Diagn
2026
PF protects retinal pigment epithelial cells from oxidative injury by enhancing mitophagy through a CUL3-dependent AMPK/ULK1 pathway.
Chen X et al.·Arch Pharm Res
2026
Emerging roles of artificial intelligence/machine learning (AI/ML) towards new understandings in molecular crosstalk between circRNA-CUL3-TKI to resensitize chemoresistant cancers.
Dutta P et al.·Mol Cell Probes
2026
Targeted modification of cis-elements in the CUL3 gene to restore exon 9 inclusion for treating Gordon syndrome.
Shi X et al.·Hum Genomics
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10

External Resources

Links to major genomics databases and tools