BRD4

Chr 19AD

bromodomain containing 4

NCBI Gene: 23476ENSG00000141867UniProt: O60885

Chromatin reader protein that recognizes and binds acetylated histones and plays a key role in transmission of epigenetic memory across cell divisions and transcription regulation (PubMed:20871596, PubMed:23086925, PubMed:23317504, PubMed:29176719, PubMed:29379197). Remains associated with acetylated chromatin throughout the entire cell cycle and provides epigenetic memory for postmitotic G1 gene transcription by preserving acetylated chromatin status and maintaining high-order chromatin structure (PubMed:22334664, PubMed:23317504, PubMed:23589332). During interphase, plays a key role in regulating the transcription of signal-inducible genes by associating with the P-TEFb complex and recruiting it to promoters (PubMed:16109376, PubMed:16109377, PubMed:19596240, PubMed:23589332, PubMed:24360279). Also recruits P-TEFb complex to distal enhancers, so called anti-pause enhancers in collaboration with JMJD6 (PubMed:16109376, PubMed:16109377, PubMed:19596240, PubMed:23589332, PubMed:24360279). BRD4 and JMJD6 are required to form the transcriptionally active P-TEFb complex by displacing negative regulators such as HEXIM1 and 7SKsnRNA complex from P-TEFb, thereby transforming it into an active form that can then phosphorylate the C-terminal domain (CTD) of RNA polymerase II (PubMed:16109376, PubMed:16109377, PubMed:19596240, PubMed:23589332, PubMed:24360279). Regulates differentiation of naive CD4(+) T-cells into T-helper Th17 by promoting recruitment of P-TEFb to promoters (By similarity). Promotes phosphorylation of 'Ser-2' of the C-terminal domain (CTD) of RNA polymerase II (PubMed:23086925). According to a report, directly acts as an atypical protein kinase and mediates phosphorylation of 'Ser-2' of the C-terminal domain (CTD) of RNA polymerase II; these data however need additional evidences in vivo (PubMed:22509028). In addition to acetylated histones, also recognizes and binds acetylated RELA, leading to further recruitment of the P-TEFb complex and subsequent activation of NF-kappa-B (PubMed:19103749). Also acts as a regulator of p53/TP53-mediated transcription: following phosphorylation by CK2, recruited to p53/TP53 specific target promoters (PubMed:23317504)

Primary Disease Associations & Inheritance

Cornelia de Lange syndrome 6MIM #620568
AD
985
ClinVar variants
16
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— BRD4
⚡
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.
📋
ClinVar Variants
16 Pathogenic / Likely Pathogenic· 244 VUS of 985 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.00 (0.00–0.05)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.64 (0.60–0.69)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.25
0≤1.21.6
LoF obs/exp: 0 / 61.5Missense obs/exp: 519 / 805.3Syn Z: -3.62

ClinVar Variant Classifications

985 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5
Likely Pathogenic11
VUS244
Likely Benign200
Benign9
Conflicting7
5
Pathogenic
11
Likely Pathogenic
244
VUS
200
Likely Benign
9
Benign
7
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
4
0
1
0
5
Likely Pathogenic
9
1
1
0
11
VUS
1
207
34
2
244
Likely Benign
0
7
51
142
200
Benign
0
1
2
6
9
Conflicting
—7
Total1421689150476

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

View in ClinVar →

Protein Context — Lollipop Plot

BRD4 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

BRD4-related Cornelia de Lange-like syndrome

strong
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Cornelia de Lange syndrome 6

MIM #620568

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
BRD4 and Cancer: going beyond transcriptional regulation.
Donati B et al.·Mol Cancer
2018Review
BET proteins: Biological functions and therapeutic interventions.
Guo J et al.·Pharmacol Ther
2023Review
Opposing Functions of BRD4 Isoforms in Breast Cancer.
Wu SY et al.·Mol Cell
2020
Genomic analyses in Cornelia de Lange Syndrome and related diagnoses: Novel candidate genes, genotype-phenotype correlations and common mechanisms.
Kaur M et al.·Am J Med Genet A
2023Functional
BET inhibitor suppresses melanoma progression via the noncanonical NF-κB/SPP1 pathway.
Deng G et al.·Theranostics
2020Meta-analysis
LSD1 Inhibition Disrupts Super-Enhancer-Driven Oncogenic Transcriptional Programs in Castration-Resistant Prostate Cancer.
Li M et al.·Cancer Res
2023
BRD4 contributes to LPS-induced macrophage senescence and promotes progression of atherosclerosis-associated lipid uptake.
Wang H et al.·Aging (Albany NY)
2020
PROTACs as Therapeutic Modalities for Drug Discovery in Castration-Resistant Prostate Cancer.
Wang LY et al.·Annu Rev Pharmacol Toxicol
2025Review
Circular RNA circBCBM1 promotes breast cancer brain metastasis by modulating miR-125a/BRD4 axis.
Fu B et al.·Int J Biol Sci
2021
A novel ROR1-targeting antibody-PROTAC conjugate promotes BRD4 degradation for solid tumor treatment.
Wang L et al.·Theranostics
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Advanced NUT CarcinomaMetastatic NUT CarcinomaUnresectable NUT Carcinoma

Testing the Safety and Efficacy of the Addition of a New Anti-cancer Drug, ZEN003694, to Chemotherapy Treatment (Cisplatin and Etoposide or Carboplatin and Paclitaxel) for Adult and Pediatric Patients (12-17 Years) With NUT Carcinoma

RECRUITING
NCT05019716Phase PHASE1, PHASE2National Cancer Institute (NCI)Started 2022-07-13
BET Bromodomain Inhibitor ZEN-3694Biopsy ProcedureBiospecimen Collection

External Resources

Links to major genomics databases and tools