CUL3

Chr 2AD

cullin 3

ENSG00000036257 UniProt: Q13618 OMIM: 603136

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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

LOFmechanismADLOEUF 0.232 OMIM phenotypes

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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Clinical Trials

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

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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 OE0.10 (0.05–0.23)

0≤0.351.4

Missense OE0.35 (0.30–0.40)

0≤0.61.4

Synonymous OE1.12

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

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 · 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.PMID:29897280

LOFAutism-linked Cullin3 germline haploinsufficiency impacts cytoskeletal dynamics and cortical neurogenesis through RhoA signalingPMID:33727673

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