CUL3

Chr 2AD

cullin 3

Also known as: CUL-3, NEDAUS, PHA2E

NCBI Gene: 8452 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.

GeneReviews OMIM 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 OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Neurodevelopmental disorder with or without autism or seizuresMIM #619239

Pseudohypoaldosteronism, type IIEMIM #614496

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

127

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.23

LOEUF· LoF intol.

LOF

Mechanism· G2P

📖

GeneReview available — CUL3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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

Background carrier burden — how many people carry a rare variant somewhere in CUL3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 130

545 rare PASS variants

Rare truncating (LoF)

1 in 1,700

62 rare PASS variants

Rare synonymous (reference)

1 in 150

390 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CUL3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 210	1 in 2,100
South Asian	~43k	1 in 310	1 in 4,000
Remaining (unassigned)	~30k	1 in 110	1 in 930
European (Finnish)	~27k	1 in 410	≈ 1 in 6,500
Admixed American	~22k	1 in 160	1 in 3,100
African / African American	~21k	1 in 330	1 in 1,100
East Asian	~20k	1 in 240	1 in 1,800
Ashkenazi Jewish	~13k	1 in 840	1 in 2,100
Middle Eastern	~2,884	1 in 480	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 14 of 16 coding exons well covered in gnomAD exomes; exons 1, 2 marginal. Genomes: 15 of 16 (exon 2 below).? see exons ↓