CUL3

Chr 2

cullin 3

Also known as: CUL-3, NEDAUS, PHA2E

NCBI Gene: 8452 ENSG00000036257 UniProt: Q13618

The protein functions as the core scaffold component of an E3 ubiquitin ligase complex that mediates polyubiquitination and degradation of specific protein substrates. Mutations cause autosomal dominant neurodevelopmental disorder with or without autism or seizures, as well as pseudohypoaldosteronism type IIE. The pathogenic mechanism involves loss of function, which disrupts normal protein degradation pathways essential for neuronal development and electrolyte regulation.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.23

Clinical Summary— CUL3

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Gene-Disease Validity (ClinGen)

pseudohypoaldosteronism type 2E · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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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.

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ClinVar Variants

120 unique Pathogenic / Likely Pathogenic· 295 VUS of 688 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — CUL3

Authoritative clinical overview · Recommended first read

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

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?

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?

LoF OE?0.10 (0.05–0.23)

0≤0.351.4

Missense OE?0.35 (0.30–0.40)

0≤0.61.4

Synonymous OE?1.12

0≤1.21.6

LoF obs/exp: 4 / 40.1Missense obs/exp: 145 / 418.7Syn Z: -1.10

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveCUL3-related developmental disorderLOFAD

This gene — mechanism propensity

0.4586th %ile

GOF

0.4085th %ile

LOF

0.66top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 75% of P/LP variants are LoF · LOEUF 0.23

DN1 literature citation

Literature Evidence

DNIn conclusion, deletion of exon 9 from Cul3 generates a protein that is itself ubiquitin-ligase defective but also capable of enhanced autophagocytic KLHL3 degradation, thereby exerting dominant-negative effects on the WT allele.1

LOFAutism-linked Cullin3 germline haploinsufficiency impacts cytoskeletal dynamics and cortical neurogenesis through RhoA signaling2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

688 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic65

Likely Pathogenic55

VUS295

Likely Benign151

Benign78

Conflicting19

Pathogenic

Likely Pathogenic

295

VUS

151

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	50	7	7	1	65
Likely Pathogenic	40	12	1	2	55
VUS	17	185	85	8	295
Likely Benign	1	9	70	71	151
Benign	0	1	71	6	78
Conflicting	—				19
Total	108	214	234	88	663

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

View in ClinVar →

29 pathogenic / likely-pathogenic (of 35) ClinVar copy-number / structural variants overlap CUL3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →