BRD4

Chr 19AD

bromodomain containing 4

Also known as: CAP, CDLS6, FSHRG4, HUNK1, HUNKI, MCAP

NCBI Gene: 23476 ENSG00000141867 UniProt: O60885 OMIM: 608749

The protein is a chromatin regulator that contains two bromodomains and associates with chromosomes during mitosis. Loss-of-function mutations cause Cornelia de Lange syndrome 6, an autosomal dominant disorder. The gene is highly intolerant to loss-of-function variation, consistent with haploinsufficiency as the disease mechanism.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The protein encoded by this gene is homologous to the murine protein MCAP, which associates with chromosomes during mitosis, and to the human RING3 protein, a serine/threonine kinase. Each of these proteins contains two bromodomains, a conserved sequence motif which may be involved in chromatin targeting. This gene has been implicated as the chromosome 19 target of translocation t(15;19)(q13;p13.1), which defines an upper respiratory tract carcinoma in young people. Two alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Cornelia de Lange syndrome 6MIM #620568

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · syndromic intellectual disability · AD · ClinGen 2025

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

731

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.05

LOEUF· LoF intol.

LOF

Mechanism· G2P

📖

GeneReview available — BRD4

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?

0.05LOEUF

pLI 1.000

Z-score 7.27

OE 0.00 (0.00–0.05)

Highly constrained

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

Missense Constraint?

3.59Z-score

OE missense 0.64 (0.60–0.69)

519 obs / 805.3 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.05)

0≤0.351.4

Missense OE?0.64 (0.60–0.69)

0≤0.61.4

Synonymous OE?1.25

0≤1.21.6

LoF obs/exp: 0 / 61.5Missense obs/exp: 519 / 805.3Syn Z: -3.62

Background carrier burden — how many people carry a rare variant somewhere in BRD4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 39

1,705 rare PASS variants

Rare truncating (LoF)

1 in 500

95 rare PASS variants

Rare synonymous (reference)

1 in 30

967 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for BRD4. 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 51	1 in 410
South Asian	~43k	1 in 36	1 in 1,400
Remaining (unassigned)	~30k	1 in 35	1 in 830
European (Finnish)	~27k	1 in 100	1 in 640
Admixed American	~22k	1 in 40	1 in 580
African / African American	~21k	1 in 48	1 in 1,100
East Asian	~20k	1 in 38	1 in 870
Ashkenazi Jewish	~13k	1 in 130	1 in 1,600
Middle Eastern	~2,884	1 in 31	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): 18 of 19 coding exons well covered in gnomAD exomes; exon 14 marginal. Genomes: 17 of 19 (exons 13, 14 below).? see exons ↓