CUL4A

Chr 13

cullin 4A

NCBI Gene: 8451 ENSG00000139842 UniProt: Q13619 OMIM: 603137

CUL4A encodes a scaffold protein that serves as the core component of multiple cullin-RING-based E3 ubiquitin-protein ligase complexes, which target specific proteins for degradation and regulate processes including DNA repair, cell cycle progression, and circadian rhythms. Mutations cause X-linked intellectual disability with growth retardation and malformations in males, with an X-linked inheritance pattern. The gene is highly intolerant to loss-of-function variants, reflecting its essential cellular functions.

OMIM ResearchSummary from RefSeq, UniProt

CUL4A is the ubiquitin ligase component of a multimeric complex involved in the degradation of DNA damage-response proteins (Liu et al., 2009 [PubMed 19481525]).[supplied by OMIM, Oct 2009]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.12

LOEUF· LoF intol.

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.12LOEUF

pLI 1.000

Z-score 5.59

OE 0.03 (0.01–0.12)

Highly constrained

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

Missense Constraint?

2.81Z-score

OE missense 0.60 (0.54–0.67)

231 obs / 386.1 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.03 (0.01–0.12)

0≤0.351.4

Missense OE?0.60 (0.54–0.67)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 1 / 38.3Missense obs/exp: 231 / 386.1Syn Z: -1.01

Background carrier burden — how many people carry a rare variant somewhere in CUL4A?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 130

668 rare PASS variants

Rare truncating (LoF)

1 in 1,300

42 rare PASS variants

Rare synonymous (reference)

1 in 130

409 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CUL4A. 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 120	1 in 2,500
South Asian	~43k	1 in 120	1 in 460
Remaining (unassigned)	~30k	1 in 100	1 in 690
European (Finnish)	~27k	1 in 370	1 in 5,300
Admixed American	~22k	1 in 100	1 in 1,600
African / African American	~21k	1 in 120	1 in 1,900
East Asian	~20k	1 in 150	1 in 590
Ashkenazi Jewish	~13k	1 in 230	≈ 1 in 5,600
Middle Eastern	~2,884	1 in 110	≈ 1 in 1,300

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): 15 of 20 coding exons well covered in gnomAD exomes; exons 1, 2, 7, 16, 20 marginal. Genomes: 19 of 20 (exon 1 below).? see exons ↓