BRAP

Summary

BRAP (BRCA1 associated protein, HGNC:1099) is a protein-coding gene on chromosome 12q24.12, encoding BRCA1-associated protein (Q7Z569). Negatively regulates MAP kinase activation by limiting the formation of Raf/MEK complexes probably by inactivation of the KSR1 scaffold protein. It is a selective cancer dependency (DepMap: 15.0% of cell lines).

The protein encoded by this gene was identified by its ability to bind to the nuclear localization signal of BRCA1 and other proteins. It is a cytoplasmic protein which may regulate nuclear targeting by retaining proteins with a nuclear localization signal in the cytoplasm.

Source: NCBI Gene 8315 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pulmonary arterial hypertension (Limited, GenCC)
• GWAS associations: 60
• Clinical variants (ClinVar): 82 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 15.0% of screened cell lines
• MANE Select transcript: NM_006768

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1099
Approved symbol	BRAP
Name	BRCA1 associated protein
Location	12q24.12
Locus type	gene with protein product
Status	Approved
Aliases	BRAP2, RNF52, IMP
Ensembl gene	ENSG00000089234
Ensembl biotype	protein_coding
OMIM	604986
Entrez	8315

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 11 protein_coding, 1 retained_intron

ENST00000327551, ENST00000419234, ENST00000547043, ENST00000871565, ENST00000871566, ENST00000871567, ENST00000871568, ENST00000871569, ENST00000871570, ENST00000871571, ENST00000930027, ENST00000930028

RefSeq mRNA: 1 — MANE Select: NM_006768 NM_006768

CCDS: CCDS9154

Canonical transcript exons

ENST00000419234 — 12 exons

Exon	Start	End
ENSE00000755201	111679151	111679340
ENSE00001300615	111672661	111672774
ENSE00001355929	111642146	111644562
ENSE00002313575	111685711	111685956
ENSE00002318940	111681637	111681835
ENSE00003480186	111658736	111658845
ENSE00003550797	111660600	111660675
ENSE00003555143	111659207	111659345
ENSE00003597399	111665639	111665787
ENSE00003643182	111649939	111650042
ENSE00003648467	111655566	111655655
ENSE00003677449	111683146	111683307

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 95.33.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.5602 / max 226.2115, expressed in 1823 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
133312	26.6585	1822
133311	0.7440	445
133310	0.1577	46

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	95.33	gold quality
right testis	UBERON:0004534	94.96	gold quality
testis	UBERON:0000473	93.61	gold quality
secondary oocyte	CL:0000655	93.56	gold quality
sperm	CL:0000019	93.12	gold quality
buccal mucosa cell	CL:0002336	92.61	gold quality
male germ cell	CL:0000015	91.80	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.40	gold quality
calcaneal tendon	UBERON:0003701	90.02	gold quality
oocyte	CL:0000023	89.81	gold quality
tendon	UBERON:0000043	87.22	gold quality
gastrocnemius	UBERON:0001388	86.72	gold quality
islet of Langerhans	UBERON:0000006	86.45	gold quality
muscle of leg	UBERON:0001383	86.39	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.71	gold quality
blood	UBERON:0000178	85.38	gold quality
cranial nerve II	UBERON:0000941	85.30	gold quality
stromal cell of endometrium	CL:0002255	85.01	gold quality
hindlimb stylopod muscle	UBERON:0004252	84.97	gold quality
muscle organ	UBERON:0001630	84.51	gold quality
cortical plate	UBERON:0005343	84.44	gold quality
amniotic fluid	UBERON:0000173	84.35	gold quality
ganglionic eminence	UBERON:0004023	84.17	gold quality
middle temporal gyrus	UBERON:0002771	84.03	gold quality
parotid gland	UBERON:0001831	83.95	gold quality
blood vessel layer	UBERON:0004797	83.93	gold quality
monocyte	CL:0000576	83.84	gold quality
palpebral conjunctiva	UBERON:0001812	83.69	gold quality
tendon of biceps brachii	UBERON:0008188	83.64	gold quality
leukocyte	CL:0000738	83.54	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TP53

miRNA regulators (miRDB)

107 targeting BRAP, 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-4262	100.00	73.26	3931
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-3681-3P	99.88	70.46	2254

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 15.0% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 33)

• modulates sensitivity of the MAP kinase cascade to stimulus-dependent activation by limiting functional assembly of the core enzymatic components through the inactivation of KSR (PMID:14724641)
• Monocytic differentiation of the promyelomonocytic cell lines U937 and HL60 is associated with the upregulation of Brap2 expression concomitantly with the upregulation and cytoplasmic relocalization of p21. (PMID:15340083)
• the capacity of IMP to inhibit signal propagation through Raf to MEK is a consequence of disrupting KSR1 homooligomerization and B-Raf/c-Raf hetero-oligomerization (PMID:18332145)
• The most current evidence suggests that it may be more beneficial in those with BRCA mutations because tumors associated with these mutations are likely to be estrogen-receptor positive. (PMID:18380995)
• p21 Ras/Imp regulate cytokine production and migration in CD4 T cells [Imp] (PMID:18577512)
• Carriers of mutations in the genes BRCA1/2 may present a specific high risk group for PABC especially at younger ages. (PMID:19009954)
• The authors found that Brap2, which has intrinsic RING domain dependent E3 ligase activity, facilitates HsCdc14A Lys-63 linked ubiquitin modification, indicating that Brap2 may be the ubiquitin E3 Ligase of HsCdc14A. (PMID:19152073)
• SNPs in BRAP associated with risk of myocardial infarction in Asian populations.BRAP knockdown in cultured coronary endothelial cells suppressed activation of NF-kappaB. (PMID:19198608)
• Data indicate that one SNP in BRAP showed(rs11066001) a significant association in allele frequency distribution with CAD in both the Japanese and Korean populations. (PMID:19713974)
• All results are consistent with BRAP2 being a novel, phosphorylation-regulated negative regulator of nuclear import, with potential as an antiviral agent. (PMID:20040518)
• Polymorphism of 270 A > G in BRAP is Associated with Lower Ankle-Brachial Index and peripheral artery disease. (PMID:21301165)
• Data show that BRAP conferred a risk for carotid plaque and intima-medial thickness. (PMID:21670849)
• our approach, which is applicable to any set of interval scale traits that is heritable and exhibits evidence of phenotypic clustering, identified three new loci in or near APOC1, BRAP, and PLCG1, which were associated with multiple phenotype domains. (PMID:22022282)
• Several BRCA1 mutations were observed in Pakistani breast cancer patients with moderate family history. (PMID:22078348)
• BRAP gene is associated with the extent of coronary atherosclerosis and has a synergistic effect with diabetes on the occurrence of significant CAD in the Chinese population (PMID:22085839)
• ANRIL on 9p21 and BRAP were both associated with ankle brachial index in a Taiwanese population. (PMID:22122968)
• genetic association studies in population of Chinese Han young adults in Beijing: Data suggest that 2 SNPs in BRAP (rs11066001; rs3782886) are associated with decreased risk of metabolic syndrome in this population. (PMID:22965072)
• The dominant effect of prolonged USP15 depletion upon signal amplitude is due to a decrease in CRAF levels while allowing for the possibility that USP15 may also function to dampen MAPK signaling through direct stabilization of BRAP. (PMID:23105109)
• The BRAP polymorphism may not play an important role in ischemic stroke in the Taiwanese population. (PMID:23356535)
• BAP1 expression closely correlates with age, clinical stage, pathologic differentiation and histological type in colorectal cancer (CRC). BAP1 may serve as a novel prognostic biomarker for CRC. (PMID:23526420)
• Brap2 regulates temporal control of NF-kappaB localization mediated by inflammatory response. (PMID:23554956)
• ectopic expression of BRAP2 inhibits nuclear localization of HMG20A and NuMA1, and prevents nuclear envelope accumulation of SYNE2. (PMID:23707952)
• BRAP gene may confer vulnerability for schizophrenia in Han Chinese population. (PMID:24454952)
• Together the results indicate for the first time that BRAP2 may play an important NRNI role in germ cells of the testis, with an additional, scaffold/structural role in mature spermatozoa. (PMID:25820252)
• Average dietary energy in lunch, BRAP SNP rs3782886, and GHRL SNP rs696217 were associated with obesity, and BRAP rs3782886 was associated with other metabolic abnormalities (PMID:27245511)
• IMPACT data were consistent with increased risks of onset among BRCA1 and BRCA2 mutation carriers (PMID:27742670)
• Six polymorphisms (rs12229654 at 12q24.1, rs671 of ALDH2, rs11066015 of ACAD10, rs2074356 and rs11066280 of HECTD4, and rs3782886 of BRAP) were found to be associated with both systolic and diastolic blood pressure, with those at 12q24.1 or in ACAD10 or BRAP being novel determinants of blood pressure in Japanese. (PMID:28562329)
• Expression of BRAP is increased in esophageal squamous cell carcinoma samples compared with non-tumor esophageal tissues; increased expression correlates with reduced patient survival time and promotes metastasis of xenograft tumors in mice. (PMID:28780075)
• Mutation in BRAP gene is associated with childhood pulmonary arterial hypertension. (PMID:30703135)
• BRCA1-associated protein inhibits glioma cell proliferation and migration and glioma stem cell self-renewal via the TGF-beta/PI3K/AKT/mTOR signalling pathway. (PMID:31776938)
• Potential mechanisms underlying the association between single nucleotide polymorphism (BRAP and ALDH2) and hypertension among elderly Japanese population. (PMID:32843694)
• CUX2, BRAP and ALDH2 are associated with metabolic traits in people with excessive alcohol consumption. (PMID:33093602)
• BAP1 Loss Is Associated with Higher ASS1 Expression in Epithelioid Mesothelioma: Implications for Therapeutic Stratification. (PMID:36669126)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	brap	ENSDARG00000008560
mus_musculus	Brap	ENSMUSG00000029458
rattus_norvegicus	Brap	ENSRNOG00000046497
drosophila_melanogaster	CG5555	FBGN0038686
caenorhabditis_elegans		WBGENE00017144

Protein

Protein identifiers

BRCA1-associated protein — Q7Z569 (reviewed: Q7Z569)

Alternative names: BRAP2, Impedes mitogenic signal propagation, RING finger protein 52, RING-type E3 ubiquitin transferase BRAP2, Renal carcinoma antigen NY-REN-63

All UniProt accessions (2): Q7Z569, J3KNN7

UniProt curated annotations — full annotation on UniProt →

Function. Negatively regulates MAP kinase activation by limiting the formation of Raf/MEK complexes probably by inactivation of the KSR1 scaffold protein. Also acts as a Ras responsive E3 ubiquitin ligase that, on activation of Ras, is modified by auto-polyubiquitination resulting in the release of inhibition of Raf/MEK complex formation. May also act as a cytoplasmic retention protein with a role in regulating nuclear transport.

Subunit / interactions. Interacts with the nuclear localization signal of BRCA1 and with the N-terminal of KSR1. The C-terminal portion of BCRA1 interacts with DDB1.

Subcellular location. Cytoplasm.

Tissue specificity. Expressed in breast epithelial cell lines.

Pathway. Protein modification; protein ubiquitination.

Isoforms (2)

UniProt ID	Names	Canonical?
Q7Z569-1	1	yes
Q7Z569-2	2

RefSeq proteins (1): NP_006759* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001607	Znf_UBP	Domain
IPR001841	Znf_RING	Domain
IPR011422	BRAP2/ETP1_RRM	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR034932	BRAP2_RRM	Domain
IPR035979	RBD_domain_sf	Homologous_superfamily
IPR047243	RING-H2_BRAP2	Domain

Pfam: PF02148, PF07576, PF13639

UniProt features (25 total): binding site 8, modified residue 4, zinc finger region 2, splice variant 2, sequence conflict 2, region of interest 2, compositionally biased region 2, chain 1, mutagenesis site 1, coiled-coil region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7Z569-F1	76.92	0.33

Functional residue map

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

Ligand- & substrate-binding residues (8): 329; 332; 337; 344; 348; 354; 317; 320

Post-translational modifications (4): 52, 97, 117, 119

Mutagenesis-validated functional residues (1):

Position	Phenotype
264	loss of e3 ubiquitin-protein ligase activity.

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-5673000	RAF activation
R-HSA-5675221	Negative regulation of MAPK pathway
R-HSA-6802946	Signaling by moderate kinase activity BRAF mutants
R-HSA-6802955	Paradoxical activation of RAF signaling by kinase inactive BRAF
R-HSA-9649948	Signaling downstream of RAS mutants
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-5683057	MAPK family signaling cascades
R-HSA-5684996	MAPK1/MAPK3 signaling
R-HSA-6802949	Signaling by RAS mutants
R-HSA-6802957	Oncogenic MAPK signaling

MSigDB gene sets: 151 (showing top): TSUNODA_CISPLATIN_RESISTANCE_UP, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, MODULE_255, MODULE_317, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_DN, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_RAS_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, DEBIASI_APOPTOSIS_BY_REOVIRUS_INFECTION_UP, DODD_NASOPHARYNGEAL_CARCINOMA_UP, PUJANA_BREAST_CANCER_LIT_INT_NETWORK, GOBP_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOCC_TRANSFERASE_COMPLEX, LIU_SOX4_TARGETS_UP, MODULE_69

GO Biological Process (4): MAPK cascade (GO:0000165), Ras protein signal transduction (GO:0007265), negative regulation of signal transduction (GO:0009968), protein ubiquitination (GO:0016567)

GO Molecular Function (9): nucleic acid binding (GO:0003676), ubiquitin-protein transferase activity (GO:0004842), nuclear localization sequence binding (GO:0008139), zinc ion binding (GO:0008270), identical protein binding (GO:0042802), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (5): ubiquitin ligase complex (GO:0000151), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), nuclear membrane (GO:0031965)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Oncogenic MAPK signaling	3
RAF/MAP kinase cascade	2
Signaling by RAS mutants	1
Disease	1
MAPK1/MAPK3 signaling	1
Signal Transduction	1
MAPK family signaling cascades	1
Diseases of signal transduction by growth factor receptors and second messengers	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
binding	2
intracellular signaling cassette	1
small GTPase-mediated signal transduction	1
signal transduction	1
regulation of signal transduction	1
negative regulation of cell communication	1
negative regulation of signaling	1
negative regulation of response to stimulus	1
protein modification by small protein conjugation	1
ubiquitin-like protein transferase activity	1
signal sequence receptor activity	1
transition metal ion binding	1
protein binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
catalytic activity	1
cation binding	1
intracellular protein-containing complex	1
transferase complex	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
nucleus	1
nuclear envelope	1
organelle membrane	1

Protein interactions and networks

STRING

840 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BRAP	BRCA1	P38398	995
BRAP	BARD1	Q99728	712
BRAP	BRAT1	Q6PJG6	664
BRAP	RBBP8	Q99708	662
BRAP	UIMC1	Q96RL1	658
BRAP	KSR1	Q8IVT5	612
BRAP	BRCC3	P46736	609
BRAP	ABRAXAS1	Q6UWZ7	591
BRAP	CDKN1A	P38936	544
BRAP	ATM	Q13315	520
BRAP	HCFC1	P51610	518
BRAP	BABAM2	Q9NXR7	510
BRAP	CENPF	P49454	510
BRAP	MDC1	Q14676	510
BRAP	CSTF1	Q05048	504

IntAct

69 interactions, top by confidence:

A	B	Type	Score
BRAP	EFHC1	psi-mi:“MI:0915”(physical association)	0.660
EFHC1	BRAP	psi-mi:“MI:0914”(association)	0.660
BRAP	BRAP	psi-mi:“MI:0915”(physical association)	0.570
BRAP	YJU2	psi-mi:“MI:0915”(physical association)	0.560
KLHDC3	DPYSL4	psi-mi:“MI:0914”(association)	0.530
SERPINB13	TTC4	psi-mi:“MI:0914”(association)	0.530
KLHDC3	CLUH	psi-mi:“MI:0914”(association)	0.530
BRAP	HRAS	psi-mi:“MI:0915”(physical association)	0.520
HRAS	BRAP	psi-mi:“MI:0915”(physical association)	0.520
BRAP	AKAP3	psi-mi:“MI:0915”(physical association)	0.510
BRCA1	BRAP	psi-mi:“MI:0915”(physical association)	0.510
BRAP	BRCA1	psi-mi:“MI:0915”(physical association)	0.510
PHLPP1	BRAP	psi-mi:“MI:0403”(colocalization)	0.440
BRAP	PHLPP1	psi-mi:“MI:0915”(physical association)	0.440
TNFAIP3	LRRIQ3	psi-mi:“MI:2364”(proximity)	0.420
PHLPP1	BRAP	psi-mi:“MI:0915”(physical association)	0.400
BRAP	Dnmt1	psi-mi:“MI:0915”(physical association)	0.400
BRAP	KSR1	psi-mi:“MI:0915”(physical association)	0.400
BRAP	UBB	psi-mi:“MI:0915”(physical association)	0.370
BRAP	UBC	psi-mi:“MI:0915”(physical association)	0.370
BRAP	APOA1	psi-mi:“MI:0915”(physical association)	0.370
BRAP	NUMA1	psi-mi:“MI:0915”(physical association)	0.370
BRAP	SYNE2	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (141): BRAP (Affinity Capture-MS), BRAP (Affinity Capture-MS), BRAP (Affinity Capture-MS), BRAP (Affinity Capture-MS), BRAP (Affinity Capture-MS), BRAP (Affinity Capture-MS), BRAP (Affinity Capture-MS), BRAP (Affinity Capture-MS), EFHC1 (Two-hybrid), UBB (Two-hybrid), UBC (Two-hybrid), APOA1 (Two-hybrid), NUMA1 (Two-hybrid), SYNE2 (Two-hybrid), BRK1 (Two-hybrid)

ESM2 similar proteins: A0A1L8G016, A1A5Q0, B3DH20, D3Z8X7, D4A1F2, E1BTG2, F1MF74, F1RA39, O14730, O60308, O88978, O94851, O95801, P51432, P70566, Q1RMR5, Q1RMT7, Q28FY0, Q2YDM7, Q3UHZ5, Q3UM18, Q4KLT3, Q4R3F0, Q4R8L2, Q5BJT6, Q5EA11, Q5ZJD3, Q6AZN0, Q6P5Q4, Q7Z569, Q80V31, Q863A4, Q863A5, Q863A6, Q863A7, Q86X45, Q8BML1, Q8CCP0, Q8R368, Q8R3H9

Diamond homologs: A0A8I6GM68, D2HBJ8, F1QCV2, O17323, O27262, O30107, P28606, P38748, P53973, P56523, P56524, P72702, P83038, Q09440, Q0V9G5, Q20296, Q2QWU2, Q3JUN4, Q54QE6, Q569C4, Q57955, Q5A960, Q5R902, Q5XGZ2, Q613L4, Q6NTR6, Q6NZM9, Q6P3E7, Q6P9L4, Q70CQ1, Q70I53, Q7Z569, Q7ZUM8, Q80ZH1, Q8C2B3, Q8C2S0, Q8GXJ1, Q8LRK8, Q8RX28, Q8WUI4

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	BRAP	ubiquitination
BRAP	“up-regulates activity”	CDC14A	polyubiquitination
BRAP	“down-regulates quantity by destabilization”	BRAP	ubiquitination
BRAP	“down-regulates quantity by destabilization”	KSR1	ubiquitination
BRAP	“down-regulates quantity by destabilization”	USP15	ubiquitination
USP15	“up-regulates quantity by stabilization”	BRAP	deubiquitination
USP4	“up-regulates quantity by stabilization”	BRAP	deubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 64 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
Negative regulation of MAPK pathway	5	36.9×	1e-04
Neddylation	5	6.6×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	62
Likely benign	1
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

1666 predictions. Top by Δscore:

Variant	Effect	Δscore
12:111644558:TGCAC:T	acceptor_gain	1.0000
12:111644560:CAC:C	acceptor_gain	1.0000
12:111644562:CCTTT:C	acceptor_gain	1.0000
12:111644563:C:CC	acceptor_gain	1.0000
12:111644566:T:C	acceptor_gain	1.0000
12:111644566:T:TC	acceptor_gain	1.0000
12:111649934:CCTA:C	donor_gain	1.0000
12:111649937:A:AC	donor_gain	1.0000
12:111649937:AC:A	donor_loss	1.0000
12:111649938:C:CC	donor_gain	1.0000
12:111649938:CT:C	donor_gain	1.0000
12:111649938:CTT:C	donor_gain	1.0000
12:111649938:CTTT:C	donor_gain	1.0000
12:111649941:T:A	donor_gain	1.0000
12:111650038:TTAAT:T	acceptor_gain	1.0000
12:111650039:TAAT:T	acceptor_gain	1.0000
12:111650039:TAATC:T	acceptor_loss	1.0000
12:111650040:AAT:A	acceptor_gain	1.0000
12:111650041:AT:A	acceptor_gain	1.0000
12:111650042:TCTG:T	acceptor_loss	1.0000
12:111650043:C:CC	acceptor_gain	1.0000
12:111650043:C:CG	acceptor_loss	1.0000
12:111655564:A:AC	donor_gain	1.0000
12:111655564:ACTT:A	donor_gain	1.0000
12:111655565:C:CC	donor_gain	1.0000
12:111655565:CTT:C	donor_gain	1.0000
12:111655565:CTTC:C	donor_gain	1.0000
12:111655567:T:TA	donor_gain	1.0000
12:111655568:C:A	donor_gain	1.0000
12:111655651:GAATA:G	acceptor_gain	1.0000

AlphaMissense

3934 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:111655618:C:G	R420P	1.000
12:111655621:T:G	Q419P	1.000
12:111655630:A:G	L416P	1.000
12:111655642:A:G	L412P	1.000
12:111658827:A:G	L377P	1.000
12:111658827:A:T	L377Q	1.000
12:111658830:C:G	R376P	1.000
12:111658831:G:C	R376G	1.000
12:111658833:T:C	H375R	1.000
12:111658836:A:T	V374D	1.000
12:111658839:T:C	Y373C	1.000
12:111658840:A:C	Y373D	1.000
12:111658845:T:A	D371V	1.000
12:111658845:T:C	D371G	1.000
12:111658845:T:G	D371A	1.000
12:111659207:C:A	D371Y	1.000
12:111659207:C:G	D371H	1.000
12:111659215:T:C	Y368C	1.000
12:111659216:A:C	Y368D	1.000
12:111659216:A:G	Y368H	1.000
12:111659217:G:C	D367E	1.000
12:111659217:G:T	D367E	1.000
12:111659218:T:A	D367V	1.000
12:111659218:T:C	D367G	1.000
12:111659218:T:G	D367A	1.000
12:111659219:C:G	D367H	1.000
12:111659220:C:A	W366C	1.000
12:111659220:C:G	W366C	1.000
12:111659221:C:A	W366L	1.000
12:111659221:C:G	W366S	1.000

dbSNP variants (sampled 300 via entrez): RS1000008753 (12:111679679 T>C,G), RS1000161614 (12:111656594 A>C), RS1000183865 (12:111654667 C>A,T), RS1000196871 (12:111653161 T>C), RS1000375282 (12:111667124 G>C), RS1000420709 (12:111661713 G>T), RS1000466985 (12:111641857 C>T), RS1000473791 (12:111659929 T>C), RS1000569384 (12:111684480 T>A,C), RS1000694933 (12:111648066 G>A), RS1000806139 (12:111686417 C>A), RS1000832603 (12:111671590 G>A), RS1000874038 (12:111666728 G>A), RS1000918031 (12:111684162 G>A), RS1000962351 (12:111677647 C>T)

Disease associations

OMIM: gene MIM:604986 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
pulmonary arterial hypertension	Limited	Autosomal dominant

Mondo (1): pulmonary arterial hypertension (MONDO:0015924)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

60 associations (top):

Study	Trait	p-value
GCST000466_1	Esophageal cancer	3.000000e-24
GCST000583_16	Hematological and biochemical traits	5.000000e-09
GCST000759_8	LDL cholesterol	2.000000e-09
GCST000760_40	Cholesterol, total	7.000000e-12
GCST000994_1	Drinking behavior	4.000000e-211
GCST001474_12	Hypothyroidism	3.000000e-12
GCST002221_11	Cholesterol, total	2.000000e-16
GCST002222_21	LDL cholesterol	1.000000e-11
GCST002783_437	Body mass index	1.000000e-06
GCST002783_512	Body mass index	1.000000e-06
GCST003017_10	Colorectal cancer	2.000000e-08
GCST003017_5	Colorectal cancer	2.000000e-08
GCST003679_13	C-reactive protein levels or LDL-cholesterol levels (pleiotropy)	3.000000e-08
GCST004131_54	Inflammatory bowel disease	2.000000e-09
GCST004132_84	Crohn’s disease	7.000000e-07
GCST004346_54	Psoriasis	2.000000e-08
GCST004603_118	Platelet count	3.000000e-31
GCST004607_55	Plateletcrit	2.000000e-35
GCST005329_1	Coffee consumption	2.000000e-16
GCST005439_1	Response to alcohol consumption (flushing response)	2.000000e-14
GCST005440_17	Alcohol dependence symptom count	6.000000e-10
GCST005441_8	Alcohol consumption (max-drinks)	2.000000e-12
GCST005581_9	Primary biliary cirrhosis	3.000000e-09
GCST005951_1	Body mass index	4.000000e-12
GCST006137_1	Serum folate levels	2.000000e-07
GCST006166_34	Diastolic blood pressure x alcohol consumption interaction (2df test)	2.000000e-45
GCST006167_31	Mean arterial pressure x alcohol consumption interaction (2df test)	2.000000e-14
GCST006167_63	Mean arterial pressure x alcohol consumption interaction (2df test)	1.000000e-11
GCST006169_1	Diastolic blood pressure x alcohol consumption (light vs heavy) interaction (2df test)	4.000000e-21
GCST006172_26	Mean arterial pressure x alcohol consumption (light vs heavy) interaction (2df test)	1.000000e-16

EFO canonical traits (26, from GWAS)

EFO ID	Trait name
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004574	total cholesterol measurement
EFO:0004315	drinking behavior
EFO:0004340	body mass index
EFO:0004458	C-reactive protein measurement
EFO:0004309	platelet count
EFO:0007985	platelet crit
EFO:0006782	cups of coffee per day measurement
EFO:0007835	alcohol dependence measurement
EFO:0004329	alcohol drinking
EFO:0006336	diastolic blood pressure
EFO:0006340	mean arterial pressure
EFO:0006335	systolic blood pressure
EFO:0004847	age at onset
EFO:0004761	uric acid measurement
EFO:0007645	longitudinal alcohol consumption measurement
EFO:0009458	alcohol use disorder measurement
EFO:0007796	parental longevity
EFO:1001504	small vessel stroke
EFO:0010139	fish consumption measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0004338	body weight
EFO:0010091	tea consumption measurement
EFO:0009473	hemolysis
EFO:0007986	reticulocyte count
EFO:0010701	mean reticulocyte volume

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D000081029	Pulmonary Arterial Hypertension	C08.381.423.847

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5291566 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	increases expression	2
Tobacco Smoke Pollution	increases expression	2
Cyclosporine	increases expression	2
FR900359	affects phosphorylation	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
zinc chromate	increases abundance, increases expression	1
coumarin	increases phosphorylation	1
chromium hexavalent ion	increases abundance, increases expression	1
K 7174	increases expression	1
abrine	increases expression	1
asparanin A	decreases expression	1
PCI 5002	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Glyphosate	decreases expression, increases expression	1
Caffeine	decreases phosphorylation	1
Dimethyl Sulfoxide	increases expression	1
Drugs, Chinese Herbal	increases expression	1
Ethyl Methanesulfonate	increases expression	1
Methyl Methanesulfonate	increases expression	1
Naphthoquinones	increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Testosterone	decreases expression	1
Urethane	increases expression	1
Valproic Acid	affects expression	1
Zinc	affects cotreatment, increases expression	1
Cadmium Chloride	increases expression	1
Lactic Acid	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5228945	Binding	Binding affinity to biotinylated BRAP zinc finger ubiquitin binding domain (304 to 390 residues) (unknown origin) expressed in Escherichia coli incubated for 120 secs by Biolayer Interferometry assay	Structure-Activity Relationship of USP5 Inhibitors. — J Med Chem

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2SW	Abcam HEK293T BRAP KO	Transformed cell line	Female
CVCL_E1S7	HAP1 BRAP (-) 1	Cancer cell line	Male
CVCL_E1S8	HAP1 BRAP (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00058929	PHASE4	COMPLETED	A Transition Study From Flolan® to Remodulin® in Patients With Pulmonary Arterial Hypertension
NCT00303459	PHASE4	COMPLETED	Effects of the Combination of Bosentan and Sildenafil Versus Sildenafil Monotherapy on Pulmonary Arterial Hypertension (PAH)
NCT00323297	PHASE4	COMPLETED	Assess the Efficacy and Safety of Sildenafil When Added to Bosentan in the Treatment of Pulmonary Arterial Hypertension
NCT00367770	PHASE4	COMPLETED	BREATHE 5-OL: Tracleer (Bosentan) in Patients With Pulmonary Arterial Hypertension Related to Eisenmenger Physiology
NCT00403650	PHASE4	COMPLETED	Inhaled Iloprost for Sarcoidosis-associated Pulmonary Hypertension
NCT00430716	PHASE4	TERMINATED	To Assess The Efficacy and Safety Of Oral Sildenafil in the Treatment of Pulmonary Arterial Hypertension.
NCT00433329	PHASE4	COMPLETED	Combination Therapy in Pulmonary Arterial Hypertension
NCT00439946	PHASE4	TERMINATED	Safety, Efficacy, and Treatment Satisfaction Switching From Flolan to Remodulin Using the Crono Five Ambulatory Pump in Patients With PAH
NCT00483626	PHASE4	UNKNOWN	Hemodynamic Response After Six Months of Sildenafil
NCT00494533	PHASE4	TERMINATED	Study of Intravenous Remodulin in Patients in India With Pulmonary Arterial Hypertension
NCT00617305	PHASE4	COMPLETED	Study of Add-on Ambrisentan Therapy to Background Phosphodiesterase Type-5 Inhibitor (PDE5i) Therapy in Pulmonary Arterial Hypertension (ATHENA-1)
NCT00625079	PHASE4	WITHDRAWN	Pulmonary Hypertension Secondary to Idiopathic Pulmonary Fibrosis And Treatment With Sildenafil
NCT00625469	PHASE4	WITHDRAWN	Pulmonary Arterial Hypertension Secondary to Idiopathic Pulmonary Fibrosis and Treatment With Bosentan
NCT00705588	PHASE4	UNKNOWN	Long Acting Phosphodiesterase 5 Inhibitors as Add-on Therapy for Patients With Pulmonary Hypertension Treated With Prostanoids.
NCT00741819	PHASE4	COMPLETED	Safety Evaluation of Inhaled Treprostinil Administration Following Transition From Inhaled Ventavis in Pulmonary Arterial Hypertension (PAH) Subjects
NCT01042158	PHASE4	COMPLETED	A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis
NCT01105091	PHASE4	COMPLETED	Epoprostenol for Injection in Pulmonary Arterial Hypertension
NCT01105117	PHASE4	COMPLETED	Epoprostenol for Injection in Pulmonary Arterial Hypertension - Extension of AC-066A401
NCT01268553	PHASE4	COMPLETED	Transition From Injectable Prostacyclin Medication to Inhaled Prostacyclin Medication
NCT01302444	PHASE4	TERMINATED	Treprostinil Combined With Tadalafil for Pulmonary Hypertension
NCT01330108	PHASE4	COMPLETED	Safely Change From Bosentan to Ambrisentan in Pulmonary Hypertension
NCT01433328	PHASE4	TERMINATED	Lidocaine Subcutaneous Infusion for Control of Treprostinil Related Site Pain
NCT01508780	PHASE4	WITHDRAWN	Combined Use of Angiography, Optical Coherence Tomography and Intravascular Ultrasound in Evaluation of Pulmonary Vascular Structure and Function in Patients With Pulmonary Arterial Hypertension Treated With Oral Bosentan
NCT01615627	PHASE4	WITHDRAWN	Hypotonic Treprostinil Subcutaneous Infusion for Control of Treprostinil Related Site Pain
NCT01642407	PHASE4	COMPLETED	Safety And Efficacy Of Sildenafil In Children With Pulmonary Arterial Hypertension
NCT01649739	PHASE4	UNKNOWN	Vardenafil as add-on Therapy for Patients With Pulmonary Hypertension Treated With Inhaled Iloprost
NCT02060487	PHASE4	TERMINATED	Effects of Oral Sildenafil on Mortality in Adults With PAH
NCT02253394	PHASE4	TERMINATED	The Combination Ambrisentan Plus Spironolactone in Pulmonary Arterial Hypertension Study
NCT02284737	PHASE4	TERMINATED	A Study to Investigate the Efficacy of PADN to Improved Functional Capacity and Hemodynamics in Patients With PAH
NCT02310672	PHASE4	COMPLETED	REPAIR: Right vEntricular Remodeling in Pulmonary ArterIal hypeRtension
NCT02847260	PHASE4	COMPLETED	Safety and Tolerability of Rapid Dose Titration of Subcutaneous Remodulin® Therapy in PAH Subjects (RAPID)
NCT02882126	PHASE4	WITHDRAWN	An Open Label Extension Study to Evaluate the Safety of Continued Therapy of Subcutanous Remodulin® in Pulmonary Arterial Hypertension
NCT02885012	PHASE4	TERMINATED	Crossover Study From Macitentan or Bosentan Over to Ambrisentan
NCT02891850	PHASE4	COMPLETED	Riociguat rEplacing PDE-5i Therapy evaLuated Against Continued PDE-5i thErapy
NCT02893995	PHASE4	WITHDRAWN	Safety, Tolerability, Pharmacokinetics and Efficacy of Two Different Rates of Subcutanous Remodulin® Dose Titration in Pulmonary Arterial Hypertension
NCT02968901	PHASE4	TERMINATED	Clinical Study Evaluating the Effects of First-line Oral cOmbination theraPy of maciTentan and tadalafIl in Patients With Newly Diagnosed pulMonary Arterial Hypertension (OPTIMA)
NCT03055221	PHASE4	COMPLETED	TRUST-2: Safety and Efficacy of Intravenous Remodulin® in Patients in India With Pulmonary Arterial Hypertension (PAH)
NCT03078907	PHASE4	COMPLETED	Effect of Selexipag on Daily Life Physical Activity of Patients With Pulmonary Arterial Hypertension.
NCT03236818	PHASE4	UNKNOWN	Goal Oriented Strategy to Preserve Ejection Fraction Trial
NCT03344159	PHASE4	COMPLETED	Spironolactone Therapy in Chronic Stable Right HF Trial