BRD8

Summary

BRD8 (bromodomain containing 8, HGNC:19874) is a protein-coding gene on chromosome 5q31.2, encoding Bromodomain-containing protein 8 (Q9H0E9). May act as a coactivator during transcriptional activation by hormone-activated nuclear receptors (NR). It is a selective cancer dependency (DepMap: 41.4% of cell lines).

The protein encoded by this gene interacts with thyroid hormone receptor in a ligand-dependent manner and enhances thyroid hormone-dependent activation from thyroid response elements. This protein contains a bromodomain and is thought to be a nuclear receptor coactivator. Multiple alternatively spliced transcript variants that encode distinct isoforms have been identified.

Source: NCBI Gene 10902 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 171 total — 3 pathogenic
• Phenotypes (HPO): 1
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 41.4% of screened cell lines
• MANE Select transcript: NM_139199

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19874
Approved symbol	BRD8
Name	bromodomain containing 8
Location	5q31.2
Locus type	gene with protein product
Status	Approved
Aliases	SMAP, p120
Ensembl gene	ENSG00000112983
Ensembl biotype	protein_coding
OMIM	602848
Entrez	10902

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 11 protein_coding, 7 retained_intron, 6 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000230901, ENST00000254900, ENST00000402931, ENST00000411594, ENST00000418329, ENST00000425764, ENST00000427976, ENST00000428808, ENST00000430331, ENST00000432618, ENST00000441656, ENST00000450756, ENST00000453824, ENST00000454473, ENST00000460746, ENST00000463620, ENST00000471437, ENST00000471892, ENST00000472478, ENST00000483805, ENST00000489351, ENST00000506167, ENST00000511898, ENST00000512140, ENST00000515014, ENST00000515254

RefSeq mRNA: 6 — MANE Select: NM_139199 NM_001164326, NM_001300961, NM_001300962, NM_001300966, NM_006696, NM_139199

CCDS: CCDS34241, CCDS4198, CCDS54907

Canonical transcript exons

ENST00000254900 — 27 exons

Exon	Start	End
ENSE00000904341	138145789	138145878
ENSE00000904342	138149640	138149797
ENSE00000904343	138150745	138151008
ENSE00000904344	138152482	138152760
ENSE00001130035	138145177	138145245
ENSE00001312156	138140705	138140882
ENSE00001326398	138139770	138140166
ENSE00001949020	138178596	138178630
ENSE00003461935	138160891	138161068
ENSE00003468851	138164320	138164413
ENSE00003478219	138163130	138163344
ENSE00003523999	138162054	138162146
ENSE00003552523	138170345	138170409
ENSE00003557437	138161796	138161864
ENSE00003564146	138172065	138172134
ENSE00003570720	138171038	138171160
ENSE00003582791	138169222	138169358
ENSE00003593229	138177571	138177667
ENSE00003596543	138159555	138159599
ENSE00003603621	138164714	138165166
ENSE00003615139	138166518	138166727
ENSE00003621939	138170832	138170912
ENSE00003634651	138160069	138160173
ENSE00003644570	138167934	138168078
ENSE00003674288	138165828	138166108
ENSE00003688682	138164087	138164133
ENSE00003785284	138171361	138171410

Expression profiles

Bgee: expression breadth ubiquitous, 300 present calls, max score 98.73.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.4441 / max 559.7910, expressed in 1774 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
63673	12.3070	1746
63674	3.9008	1484
63675	1.2364	666

Top tissues by expression

300 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	98.73	gold quality
left testis	UBERON:0004533	98.67	gold quality
ventricular zone	UBERON:0003053	98.52	gold quality
pituitary gland	UBERON:0000007	97.87	gold quality
testis	UBERON:0000473	97.70	gold quality
adenohypophysis	UBERON:0002196	97.70	gold quality
right lobe of thyroid gland	UBERON:0001119	97.55	gold quality
right uterine tube	UBERON:0001302	97.36	gold quality
left lobe of thyroid gland	UBERON:0001120	97.34	gold quality
middle temporal gyrus	UBERON:0002771	97.09	gold quality
thyroid gland	UBERON:0002046	97.07	gold quality
buccal mucosa cell	CL:0002336	97.04	gold quality
cerebellar hemisphere	UBERON:0002245	97.04	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.97	gold quality
cerebellar cortex	UBERON:0002129	96.94	gold quality
body of pancreas	UBERON:0001150	96.92	gold quality
left ovary	UBERON:0002119	96.87	gold quality
ganglionic eminence	UBERON:0004023	96.83	gold quality
metanephros cortex	UBERON:0010533	96.78	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.74	gold quality
right ovary	UBERON:0002118	96.71	gold quality
body of uterus	UBERON:0009853	96.68	gold quality
mucosa of stomach	UBERON:0001199	96.64	gold quality
tibial nerve	UBERON:0001323	96.57	gold quality
endocervix	UBERON:0000458	96.55	gold quality
cerebellum	UBERON:0002037	96.33	gold quality
embryo	UBERON:0000922	96.31	gold quality
primary visual cortex	UBERON:0002436	96.24	gold quality
lower esophagus mucosa	UBERON:0035834	96.22	gold quality
ovary	UBERON:0000992	96.12	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-100618	yes	451.39
E-ANND-3	yes	11.29

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): STAT1

miRNA regulators (miRDB)

18 targeting BRD8, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-18A-3P	99.56	65.68	1092
HSA-MIR-7849-3P	99.47	68.17	1224
HSA-MIR-3182	99.40	68.15	2454
HSA-MIR-877-3P	99.09	68.10	1637
HSA-MIR-6738-3P	99.03	67.14	1326
HSA-MIR-876-3P	98.76	68.23	945
HSA-MIR-3145-5P	98.57	67.83	900
HSA-MIR-653-3P	98.31	67.71	1542
HSA-MIR-18B-3P	98.05	65.55	595
HSA-MIR-4456	97.50	64.88	1678
HSA-MIR-3157-3P	95.86	67.08	454

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 41.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 9)

• SMAP gene family constitutes an important ArfGAP subfamily, with each SMAP member exerting both common and distinct functions in vesicle trafficking. (PMID:16571680)
• BRD8 expression is associated with tumor progression toward advanced stages (PMID:19787264)
• incorporation of the histone variant H2A.Z at the promoter regions of PPARgamma target genes by p400/Brd8 is essential to allow fat cell differentiation (PMID:23064015)
• miR-185 can attenuate androgen receptor function indirectly by suppressing BRD8 ISO2 (PMID:26940039)
• Taken together, our results suggest that BRD8 is involved not only in p53-dependent gene suppression, but also in the maintenance of genome stability. (PMID:30237520)
• BRD8, which is negatively regulated by miR-876-3p, promotes the proliferation and apoptosis resistance of hepatocellular carcinoma cells via KAT5. (PMID:32860757)
• The Bromodomain Containing 8 (BRD8) transcriptional network in human lung epithelial cells. (PMID:33476703)
• BRD8 maintains glioblastoma by epigenetic reprogramming of the p53 network. (PMID:36544023)
• Understanding the role of BRD8 in human carcinogenesis. (PMID:38965933)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	brd8b	ENSDARG00000025071
danio_rerio	brd8a	ENSDARG00000055999
mus_musculus	Brd8	ENSMUSG00000003778
rattus_norvegicus	Brd8	ENSRNOG00000020340
drosophila_melanogaster	Brd8	FBGN0039654
caenorhabditis_elegans		WBGENE00019118

Protein

Protein identifiers

Bromodomain-containing protein 8 — Q9H0E9 (reviewed: Q9H0E9)

Alternative names: Skeletal muscle abundant protein, Skeletal muscle abundant protein 2, Thyroid hormone receptor coactivating protein of 120 kDa, p120

All UniProt accessions (15): Q9H0E9, B5MCW3, C9JV05, D6RID0, F8WBH2, F8WCS7, F8WDX5, H0Y8F9, H0YA84, H0YAH7, H7C026, H7C127, H7C128, H7C179, H7C2P4

UniProt curated annotations — full annotation on UniProt →

Function. May act as a coactivator during transcriptional activation by hormone-activated nuclear receptors (NR). Isoform 2 stimulates transcriptional activation by AR/DHTR, ESR1/NR3A1, RXRA/NR2B1 and THRB/ERBA2. At least isoform 1 and isoform 2 are components of the NuA4 histone acetyltransferase (HAT) complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A. This modification may both alter nucleosome - DNA interactions and promote interaction of the modified histones with other proteins which positively regulate transcription. This complex may be required for the activation of transcriptional programs associated with oncogene and proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest and replicative senescence, apoptosis, and DNA repair. NuA4 may also play a direct role in DNA repair when recruited to sites of DNA damage. Component of a SWR1-like complex that specifically mediates the removal of histone H2A.Z/H2AZ1 from the nucleosome.

Subunit / interactions. Component of the NuA4 histone acetyltransferase complex which contains the catalytic subunit KAT5/TIP60 and the subunits EP400, TRRAP/PAF400, BRD8/SMAP, EPC1, DMAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, ING3, actin, ACTL6A/BAF53A, MORF4L1/MRG15, MORF4L2/MRGX, MRGBP, YEATS4/GAS41, VPS72/YL1 and MEAF6. The NuA4 complex interacts with MYC and the adenovirus E1A protein. Component of a NuA4-related complex which contains EP400, TRRAP/PAF400, SRCAP, BRD8/SMAP, EPC1, DMAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, actin, ACTL6A/BAF53A, VPS72 and YEATS4/GAS41. BRD8 isoform 2 interacts with RXRA/NR2B1 and THRB/ERBA2. Component of a SWR1-like complex.

Subcellular location. Nucleus.

Tissue specificity. Expressed in adipose tissue, brain, heart, kidney, liver, lung, pancreas, placenta and skeletal muscle.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9H0E9-1	1	yes
Q9H0E9-2	2
Q9H0E9-3	3
Q9H0E9-4	4

RefSeq proteins (6): NP_001157798, NP_001287890, NP_001287891, NP_001287895, NP_006687, NP_631938* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001487	Bromodomain	Domain
IPR036427	Bromodomain-like_sf	Homologous_superfamily
IPR037966	Brd8_Bromo_dom	Domain

Pfam: PF00439

UniProt features (53 total): modified residue 18, splice variant 11, cross-link 6, region of interest 6, compositionally biased region 3, sequence variant 3, domain 2, sequence conflict 2, chain 1, coiled-coil region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H0E9-F1	53.92	0.22

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (24): 85, 383, 387, 481, 579, 621, 637, 641, 469, 481, 481, 509, 575, 612, 264, 268, 284, 924, 124, 128 …

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-3214847	HATs acetylate histones
R-HSA-3247509	Chromatin modifying enzymes
R-HSA-4839726	Chromatin organization

MSigDB gene sets: 245 (showing top): GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, GOBP_REGULATION_OF_DNA_RECOMBINATION, CROONQUIST_NRAS_SIGNALING_DN, MORF_SNRP70, MORF_UBE2I, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, TATTATA_MIR374, AACYNNNNTTCCS_UNKNOWN, GENTILE_RESPONSE_CLUSTER_D3, GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR_VIA_HOMOLOGOUS_RECOMBINATION, FOXO4_01, GOBP_REGULATION_OF_DNA_REPAIR, AACWWCAANK_UNKNOWN

GO Biological Process (9): chromatin organization (GO:0006325), cell surface receptor signaling pathway (GO:0007166), regulation of apoptotic process (GO:0042981), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of cell cycle (GO:0051726), cellular response to thyroid hormone stimulus (GO:0097067), positive regulation of double-strand break repair via homologous recombination (GO:1905168), regulation of double-strand break repair (GO:2000779)

GO Molecular Function (3): transcription coactivator activity (GO:0003713), nuclear thyroid hormone receptor binding (GO:0046966), protein binding (GO:0005515)

GO Cellular Component (6): nucleosome (GO:0000786), Swr1 complex (GO:0000812), nucleus (GO:0005634), nucleoplasm (GO:0005654), mitochondrion (GO:0005739), NuA4 histone acetyltransferase complex (GO:0035267)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Chromatin modifying enzymes	1
Chromatin organization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of DNA-templated transcription	2
intracellular membrane-bounded organelle	2
cellular component organization	1
signal transduction	1
apoptotic process	1
regulation of programmed cell death	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
cell cycle	1
regulation of cellular process	1
cellular response to hormone stimulus	1
response to thyroid hormone	1
double-strand break repair via homologous recombination	1
regulation of double-strand break repair via homologous recombination	1
positive regulation of DNA recombination	1
positive regulation of double-strand break repair	1
regulation of DNA repair	1
double-strand break repair	1
transcription coregulator activity	1
nuclear receptor binding	1
binding	1
chromatin	1
protein-DNA complex	1
histone deacetylase complex	1
nuclear chromosome	1
INO80-type complex	1
nuclear lumen	1
cellular anatomical structure	1
cytoplasm	1
H4/H2A histone acetyltransferase complex	1

Protein interactions and networks

STRING

1843 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BRD8	DMAP1	Q9NPF5	970
BRD8	EP400	Q96L91	949
BRD8	TRRAP	Q9Y4A5	934
BRD8	ING3	Q9NXR8	912
BRD8	MEAF6	Q9HAF1	911
BRD8	YEATS4	O95619	908
BRD8	RUVBL2	Q9Y230	869
BRD8	EPC2	Q52LR7	860
BRD8	KAT5	Q92993	853
BRD8	MORF4L1	Q9UBU8	849
BRD8	ACTL6A	O96019	841
BRD8	MRGBP	Q9NV56	804
BRD8	RUVBL1	P82276	781
BRD8	VPS72	Q15906	775
BRD8	MORF4L2	Q15014	762

IntAct

95 interactions, top by confidence:

A	B	Type	Score
RUVBL1	ZNHIT1	psi-mi:“MI:0914”(association)	0.860
CDK8	MED19	psi-mi:“MI:2364”(proximity)	0.850
MRGBP	YEATS4	psi-mi:“MI:0914”(association)	0.840
RUVBL2	ZNHIT1	psi-mi:“MI:0914”(association)	0.810
YEATS4	ZNHIT1	psi-mi:“MI:0914”(association)	0.790
H2AZ1	ZNHIT1	psi-mi:“MI:0914”(association)	0.770
MRGBP	ACTL6A	psi-mi:“MI:0914”(association)	0.760
TRRAP	ATXN7	psi-mi:“MI:0914”(association)	0.740
MBTD1	YEATS4	psi-mi:“MI:0914”(association)	0.730
MBTD1	MORF4L2	psi-mi:“MI:0914”(association)	0.730
MORF4L1	SIN3B	psi-mi:“MI:0914”(association)	0.730
ACTL6A	ZNHIT1	psi-mi:“MI:0914”(association)	0.720
VPS72	ZNHIT1	psi-mi:“MI:0914”(association)	0.690
BRD8	MORF4L2	psi-mi:“MI:0915”(physical association)	0.670
H2BC1	PPM1G	psi-mi:“MI:0914”(association)	0.640
FOXR1	YEATS4	psi-mi:“MI:0914”(association)	0.640
EPC2	YEATS4	psi-mi:“MI:0914”(association)	0.640
RUVBL1	POLR3A	psi-mi:“MI:0914”(association)	0.640
RUVBL2	POLR3A	psi-mi:“MI:0914”(association)	0.640
EP400	MORF4L2	psi-mi:“MI:0914”(association)	0.640
ACTL6A	MORF4L2	psi-mi:“MI:0915”(physical association)	0.560
KAT5	YEATS4	psi-mi:“MI:0914”(association)	0.530
EPC1	YEATS4	psi-mi:“MI:0914”(association)	0.530

BioGRID (274): MIS18A (Two-hybrid), FSD2 (Two-hybrid), BRD8 (Affinity Capture-MS), BRD8 (Affinity Capture-MS), BRD8 (Affinity Capture-MS), BRD8 (Affinity Capture-MS), BRD8 (Affinity Capture-MS), BRD8 (Affinity Capture-MS), BRD8 (Affinity Capture-MS), BRD8 (Co-fractionation), BRD8 (Proximity Label-MS), BRD8 (Proximity Label-MS), BRD8 (Two-hybrid), BRD8 (Affinity Capture-MS), BRD8 (Affinity Capture-MS)

ESM2 similar proteins: A0A1L8GR68, A2CG63, A2VE56, D3ZHS6, E6ZGB4, F7AQ22, O75376, O88974, P0C6S7, P57768, P57769, Q15047, Q2YDJ8, Q2YDW7, Q4KKX4, Q4LE39, Q52L14, Q5F3F2, Q5F3N6, Q5FWF5, Q5R6Q7, Q5VVJ2, Q60974, Q66JB6, Q68FE8, Q69Z61, Q69Z66, Q69Z69, Q6N043, Q6NXK2, Q7Z6G8, Q86YI8, Q8BIZ1, Q8C080, Q8K2W6, Q8QFX1, Q92560, Q96N64, Q98925, Q99PU7

Diamond homologs: A0A0R4IXF6, A0A7U2QYM2, A1YVX4, A2AUY4, A6H619, B7ZS37, D4A7T3, E9Q2Z1, F1QW93, F1R5H6, F7DRV9, G5E8P1, O15164, O60885, O95696, P13709, P21675, P25440, P29375, P34545, P35817, P41229, P41230, P51123, Q03330, Q07442, Q08D75, Q12830, Q15059, Q1LUC3, Q23541, Q32S26, Q338B9, Q38JA7, Q3UXZ9, Q4R8Y1, Q54BA2, Q54UW4, Q58F21, Q5A4W8

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
BRD8	“form complex”	“NuA4 complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 95 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
HATs acetylate histones	20	23.3×	6e-20
Nuclear Receptor transcription pathway	5	14.7×	1e-03
Chromatin organization	12	14.4×	7e-09
Chromatin modifying enzymes	12	12.8×	2e-08
Formation of the beta-catenin:TCF transactivating complex	7	12.4×	1e-04
DNA Damage/Telomere Stress Induced Senescence	5	12.0×	2e-03
Deposition of new CENPA-containing nucleosomes at the centromere	5	11.7×	2e-03
Deubiquitination	6	10.9×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
regulation of double-strand break repair	17	111.0×	1e-29
positive regulation of double-strand break repair via homologous recombination	17	73.2×	7e-26
regulation of DNA replication	8	32.9×	7e-09
cellular response to estradiol stimulus	5	23.1×	9e-05
regulation of DNA repair	7	21.7×	2e-06
positive regulation of DNA repair	5	20.1×	2e-04
regulation of apoptotic process	19	17.8×	8e-17
regulation of cell cycle	20	16.8×	4e-17

Disease & clinical

Clinical variants and AI predictions

ClinVar

171 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	120
Likely benign	4
Benign	3

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1047869	GRCh37/hg19 5q31.2(chr5:136409875-137739167)	Pathogenic
144268	GRCh38/hg38 5q31.1-31.3(chr5:135297294-140106003)x3	Pathogenic
58361	GRCh38/hg38 5q31.1-31.2(chr5:133401565-138437038)x1	Pathogenic

SpliceAI

4314 predictions. Top by Δscore:

Variant	Effect	Δscore
5:138140701:GTA:G	donor_loss	1.0000
5:138140702:TACCT:T	donor_loss	1.0000
5:138140703:A:T	donor_loss	1.0000
5:138140704:C:CA	donor_loss	1.0000
5:138140878:TGGGT:T	acceptor_gain	1.0000
5:138140879:GGGT:G	acceptor_gain	1.0000
5:138140880:GGT:G	acceptor_gain	1.0000
5:138140881:GT:G	acceptor_gain	1.0000
5:138140882:TC:T	acceptor_loss	1.0000
5:138140883:C:CC	acceptor_gain	1.0000
5:138140883:C:CG	acceptor_loss	1.0000
5:138140886:C:CT	acceptor_gain	1.0000
5:138140887:A:T	acceptor_gain	1.0000
5:138140889:G:C	acceptor_gain	1.0000
5:138140889:G:GC	acceptor_gain	1.0000
5:138140894:C:CT	acceptor_gain	1.0000
5:138140894:C:T	acceptor_gain	1.0000
5:138140895:A:T	acceptor_gain	1.0000
5:138145784:CCTA:C	donor_loss	1.0000
5:138145785:CTACC:C	donor_loss	1.0000
5:138145786:TACCT:T	donor_loss	1.0000
5:138145787:ACCTG:A	donor_loss	1.0000
5:138145788:C:A	donor_loss	1.0000
5:138145874:CAGTC:C	acceptor_gain	1.0000
5:138145877:TC:T	acceptor_gain	1.0000
5:138145877:TCC:T	acceptor_loss	1.0000
5:138145878:CC:C	acceptor_gain	1.0000
5:138145879:C:CC	acceptor_gain	1.0000
5:138145879:CT:C	acceptor_loss	1.0000
5:138145880:T:G	acceptor_loss	1.0000

AlphaMissense

8150 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:138160168:G:C	F811L	1.000
5:138160168:G:T	F811L	1.000
5:138160169:A:C	F811C	1.000
5:138160169:A:G	F811S	1.000
5:138160170:A:G	F811L	1.000
5:138160907:A:T	V804D	1.000
5:138160913:C:G	R802P	1.000
5:138160916:T:G	Q801P	1.000
5:138160918:C:A	M800I	1.000
5:138160918:C:G	M800I	1.000
5:138160918:C:T	M800I	1.000
5:138160919:A:C	M800R	1.000
5:138160919:A:G	M800T	1.000
5:138160919:A:T	M800K	1.000
5:138160928:G:T	A797E	1.000
5:138160929:C:G	A797P	1.000
5:138160930:C:A	M796I	1.000
5:138160930:C:G	M796I	1.000
5:138160930:C:T	M796I	1.000
5:138160931:A:C	M796R	1.000
5:138160931:A:G	M796T	1.000
5:138160940:A:T	V793D	1.000
5:138160957:A:C	N787K	1.000
5:138160957:A:T	N787K	1.000
5:138160959:T:C	N787D	1.000
5:138160961:T:C	Y786C	1.000
5:138160962:A:C	Y786D	1.000
5:138160962:A:G	Y786H	1.000
5:138160970:G:T	A783D	1.000
5:138160971:C:G	A783P	1.000

dbSNP variants (sampled 300 via entrez): RS1000059901 (5:138156296 C>T), RS1000117998 (5:138167254 C>A), RS1000256846 (5:138155999 C>T), RS1000341427 (5:138159701 C>T), RS1000431641 (5:138148958 T>C), RS1000451041 (5:138161742 A>G), RS1000479801 (5:138165763 T>G), RS1000565412 (5:138172222 T>C,G), RS1000568832 (5:138165649 C>T), RS1000791706 (5:138158212 A>AC), RS1000807625 (5:138143791 G>A), RS1001042088 (5:138179912 G>A), RS1001063629 (5:138158232 C>T), RS1001171202 (5:138159202 TGTTAAAA>T), RS1001354845 (5:138152070 G>A,T)

Disease associations

OMIM: gene MIM:602848 | disease phenotypes: MIM:615934

GenCC curated gene-disease

Mondo (2): microcephaly (MONDO:0001149), STING-associated vasculopathy with onset in infancy (MONDO:0014405)

Orphanet (1): STING-associated vasculopathy with onset in infancy (Orphanet:425120)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000252	Microcephaly

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002541_16	Menarche (age at onset)	9.000000e-14
GCST004521_66	Autism spectrum disorder or schizophrenia	1.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004703	age at menarche

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3588731 (SINGLE PROTEIN), CHEMBL5291946 (SELECTIVITY GROUP)

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Bromodomain kinase (BRDK) family

ChEMBL bioactivities

5 potent at pChembl≥5 of 13 total, top 5 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.52	Kd	30	nM	CHEMBL6143758
6.01	IC50	970	nM	CHEMBL3823101
5.31	Kd	4900	nM	CHEMBL4648912
5.23	Kd	5900	nM	CHEMBL3926851
5.10	Kd	7943	nM	CHEMBL3590405

PubChem BioAssay actives

3 with measured affinity, of 35 total; 3 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-[1-(1,1-dipyridin-2-ylethyl)-6-(1-methyl-7-oxo-6H-pyrrolo[2,3-c]pyridin-3-yl)indol-4-yl]ethanesulfonamide	1652252: Binding affinity to human partial length BRD8 BD1 (S700 to F854 residues) expressed in mammalian expression system BROMOscan assay	kd	4.9000	uM
4-[2-cyclopropyl-7-(6-methylquinolin-5-yl)-3H-benzimidazol-5-yl]-3,5-dimethyl-1,2-oxazole	1535669: Binding affinity to BRD8 bromodomain 1 (unknown origin) after 1 hr by bromoscan assay	kd	5.9000	uM
8-[[(3R,4R)-3-[(1,1-dioxothian-4-yl)methoxy]piperidin-4-yl]amino]-3-methyl-5-(5-methyl-3-pyridinyl)-1H-quinolin-2-one	1234399: Binding affinity to BRD8 in human HUT78 cells incubated for 45 mins by mass spectrometry based bromosphere chemoproteomic assay	kd	7.9433	uM

CTD chemical–gene interactions

42 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases expression, decreases methylation	4
Estradiol	affects binding, increases reaction, decreases expression	3
Cadmium Chloride	decreases expression, increases abundance	3
Air Pollutants	affects cotreatment, decreases expression, increases abundance, increases oxidation	2
Formaldehyde	decreases expression, increases expression	2
FR900359	affects phosphorylation	1
TAK-243	decreases sumoylation	1
alpha-pinene	affects cotreatment, decreases expression, increases oxidation, increases abundance	1
bisphenol A	affects binding, affects folding, decreases reaction	1
beta-lapachone	decreases expression	1
arsenite	affects binding, decreases reaction	1
methacrylaldehyde	affects cotreatment, decreases expression, increases oxidation, increases abundance	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	decreases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases expression, increases response to substance	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	decreases expression	1
bisphenol AF	decreases reaction, affects binding, affects folding	1
Troglitazone	increases response to substance, decreases reaction	1
Leflunomide	decreases expression	1
Acetaminophen	increases expression	1
Acrolein	decreases expression, increases oxidation, increases abundance, affects cotreatment	1
Air Pollutants, Occupational	decreases expression	1
Arsenic	affects methylation	1
Cadmium	increases abundance, decreases expression	1
Caffeine	affects phosphorylation	1
Carbamazepine	affects expression	1
Ethyl Methanesulfonate	increases expression	1
Hydralazine	increases expression, affects cotreatment	1
Hydrogen Peroxide	affects expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	increases expression	1

ChEMBL screening assays

40 unique, capped per target: 40 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3591393	Binding	Binding affinity to BRD8 in human HUT78 cells incubated for 45 mins by mass spectrometry based bromosphere chemoproteomic assay	Structure-Based Optimization of Naphthyridones into Potent ATAD2 Bromodomain Inhibitors. — J Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_SF65	HAP1 BRD8 (-) 1	Cancer cell line	Male
CVCL_SF66	HAP1 BRD8 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

19 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.
NCT04517253	PHASE2/PHASE3	TERMINATED	A Study of Baricitinib (LY3009104) in Adult and Pediatric Japanese Participants With NNS/CANDLE, SAVI, and AGS
NCT02974595	Not specified	RECRUITING	Natural History, Pathogenesis, and Outcome of Autoinflammatory Diseases (NOMID/CAPS, DIRA, CANDLE, SAVI, NLRC4-MAS, Still’S-like Diseases, and Other Undifferentiated Autoinflammatory Diseases)