NCOA2

Summary

NCOA2 (nuclear receptor coactivator 2, HGNC:7669) is a protein-coding gene on chromosome 8q13.3, encoding Nuclear receptor coactivator 2 (Q15596). Transcriptional coactivator for steroid receptors and nuclear receptors.

The protein encoded by this gene functions as a transcriptional coactivator for nuclear hormone receptors, including steroid, thyroid, retinoid, and vitamin D receptors. The encoded protein acts as an intermediary factor for the ligand-dependent activity of these nuclear receptors, which regulate their target genes upon binding of cognate response elements. This gene has been found to be involved in translocations that result in fusions with other genes in various cancers, including the lysine acetyltransferase 6A (KAT6A) gene in acute myeloid leukemia, the ETS variant 6 (ETV6) gene in acute lymphoblastic leukemia, and the hes related family bHLH transcription factor with YRPW motif 1 (HEY1) gene in mesenchymal chondrosarcoma. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 10499 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Fraser syndrome 3 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 52
• Clinical variants (ClinVar): 1,073 total — 18 pathogenic, 17 likely-pathogenic
• Phenotypes (HPO): 84
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): activating (oncogene-like) across 4 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• Transcription factor: yes — 72 downstream targets (CollecTRI)
• MANE Select transcript: NM_006540

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7669
Approved symbol	NCOA2
Name	nuclear receptor coactivator 2
Location	8q13.3
Locus type	gene with protein product
Status	Approved
Aliases	SRC-2, TIF2, GRIP1, NCoA-2, KAT13C, bHLHe75
Ensembl gene	ENSG00000140396
Ensembl biotype	protein_coding
OMIM	601993
Entrez	10499

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 10 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000452400, ENST00000518287, ENST00000518363, ENST00000519724, ENST00000520416, ENST00000521239, ENST00000522054, ENST00000524223, ENST00000892895, ENST00000892896, ENST00000892897, ENST00000892898, ENST00000892899, ENST00000911542

RefSeq mRNA: 6 — MANE Select: NM_006540 NM_001321703, NM_001321707, NM_001321711, NM_001321712, NM_001321713, NM_006540

CCDS: CCDS47872

Canonical transcript exons

ENST00000452400 — 23 exons

Exon	Start	End
ENSE00000942876	70213903	70214075
ENSE00000942878	70174756	70174859
ENSE00000942880	70170202	70170379
ENSE00000942882	70166566	70166754
ENSE00000942884	70163465	70163566
ENSE00000942885	70162711	70162854
ENSE00000942886	70159505	70159652
ENSE00000942888	70155971	70157240
ENSE00000942889	70148273	70148483
ENSE00000980773	70141184	70141399
ENSE00001090226	70216660	70216764
ENSE00001123295	70121302	70121391
ENSE00001149817	70123884	70124082
ENSE00001149829	70144642	70144848
ENSE00001223764	70296744	70296800
ENSE00002104815	70403700	70403808
ENSE00002134467	70109782	70113643
ENSE00003463687	70128702	70128980
ENSE00003552844	70128433	70128510
ENSE00003568310	70126813	70127047
ENSE00003584510	70124688	70124865
ENSE00003652167	70138203	70138332
ENSE00003678751	70131837	70132002

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 97.61.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.5210 / max 378.1115, expressed in 1745 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
93505	11.0090	1657
93504	2.0836	1058
93508	2.0364	691
93506	0.8992	492
93507	0.6043	309
93503	0.3116	141
93500	0.2004	86
93497	0.1932	82
93499	0.0900	38
93492	0.0332	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus epididymis	UBERON:0004359	97.61	gold quality
endothelial cell	CL:0000115	97.60	gold quality
secondary oocyte	CL:0000655	95.97	gold quality
seminal vesicle	UBERON:0000998	95.53	gold quality
jejunal mucosa	UBERON:0000399	95.21	gold quality
amniotic fluid	UBERON:0000173	95.11	gold quality
esophagus squamous epithelium	UBERON:0006920	94.82	gold quality
tibia	UBERON:0000979	94.52	gold quality
buccal mucosa cell	CL:0002336	94.27	gold quality
choroid plexus epithelium	UBERON:0003911	94.27	gold quality
oral cavity	UBERON:0000167	94.18	gold quality
trabecular bone tissue	UBERON:0002483	94.16	gold quality
epithelium of nasopharynx	UBERON:0001951	94.03	gold quality
pigmented layer of retina	UBERON:0001782	93.92	gold quality
caput epididymis	UBERON:0004358	93.78	gold quality
bone marrow cell	CL:0002092	93.53	gold quality
cauda epididymis	UBERON:0004360	93.50	gold quality
parietal pleura	UBERON:0002400	93.35	gold quality
sperm	CL:0000019	93.25	gold quality
oocyte	CL:0000023	93.21	gold quality
upper leg skin	UBERON:0004262	93.11	gold quality
mucosa of paranasal sinus	UBERON:0005030	93.06	gold quality
palpebral conjunctiva	UBERON:0001812	92.97	gold quality
epithelium of mammary gland	UBERON:0003244	92.83	gold quality
pleura	UBERON:0000977	92.73	gold quality
skin of hip	UBERON:0001554	92.56	gold quality
mammary duct	UBERON:0001765	92.36	gold quality
renal medulla	UBERON:0000362	92.34	gold quality
epithelium of esophagus	UBERON:0001976	92.25	gold quality
germinal epithelium of ovary	UBERON:0001304	92.11	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.16
E-MTAB-7606	no	942.95
E-GEOD-124858	no	355.01

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

72 targets.

Target	Regulation
ADIPOQ
AKT1
AP1
AR	Repression
BCAS1
BCL2
BMAL1
BRPF1
CARM1
CASP8AP2
CAV1
CCND1
CD38	Activation
COL2A1	Activation
CREBBP
CXCR4
CYP3A4
DNM1L
DR1
EGF
EGFR
EP300
ERBB2
ESR1
ESRRG
FGB	Activation
FLII
G6PC1	Unknown
GRIA2	Unknown
GRIP1

Upstream regulators (CollecTRI, top): AR, CTNNB1, ESR1, NCOA2

miRNA regulators (miRDB)

291 targeting NCOA2, 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-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4262	100.00	73.26	3931
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-9-5P	100.00	72.28	2361

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Reduction of coactivator expression by antisense oligodeoxynucleotides inhibits ERalpha transcriptional activity and MCF-7 proliferation (PMID:11818499)
• Interaction of transcriptional intermediary factor 2 nuclear receptor box peptides with the coactivator binding site of estrogen receptor alpha (PMID:11937504)
• modulation of nuclear receptor interaction domain by covalent attachment of SUMO-1 (PMID:12060666)
• CAR antagonizes ER-mediated transcriptional activity by squelching limiting amounts of p160 coactivators, such as SRC-1 and GRIP-1. (PMID:12114525)
• Overexpression of SRC-1 (NCOA1) and TIF-2 (NCOA2) increases estrogen-induced gene expression. (PMID:12403846)
• GRIP1 function in different glucocorticoid receptor activation and repression contexts. (PMID:12481024)
• TIF2 complexes with MOZ as a recombinant fusion protein which induces acute myelocytic leukemia. (PMID:12676584)
• FLNa interfered with androgen receptor (AR) interdomain interactions and competed with the coactivator transcriptional intermediary factor 2 to specifically down-regulate AR function. (PMID:12682292)
• wild-type BRCA2, but not a tumor-specific truncated mutant BRCA2, synergizes with the nuclear receptor coactivator p160 GRIP1 to enhance transcriptional activation by androgen receptor (PMID:12756300)
• Tpit, along with NGFI-B and SRC-2, is part of a transcription regulatory complex assembled on the POMC promoter in response to hormonal stimulation. (PMID:12970370)
• TIF2/GRIP1 coactivation of androgen receptor transactivation in recurrent prostate cancer is increased by EGF signaling through MAPK (PMID:14662770)
• Both endogenously and ectopically expressed TIF2 were shown to form foci in the nucleus, and GR could be recruited to the TIF2 foci upon GR agonist but not antagonist treatment. (PMID:15207724)
• TNF-alpha impairs progesterone-stimulated PR-B-mediated transactivation, and these effects appear to be due, in part, to reduced expression of SRC-1 and -2 [SRC-2] (PMID:15231721)
• results demonstrate a rational mechanistic basis for UGT1A1 induction by glucocorticoids and PXR activators, showing that activated glucocorticoid receptor enhances CAR/PXR-mediated UGT1A1 regulation with the transcriptional cofactor GRIP1 (PMID:15557560)
• MOZ-TIF2 oncogenic fusion protein suppresses transcription by nuclear receptors and p53 (PMID:15657427)
• FLASH strongly suppressed thyroid hormone receptor activator molecule 1- and GRIP1-induced enhancement of glucocorticoid receptor-stimulated transactivation of the mouse mammary tumor virus promoter (PMID:15698540)
• coactivator TIF2 greatly enhances binding of T3-occupied Thrb to a subset of thyroid hormone response elements (TREs), suggesting Thrb may activate transcription from these TREs in an RXR-independent manner (PMID:15766871)
• CoCoA uses different combinations of functional domains in its synergistic coactivator function with beta-catenin or GRIP1 (PMID:16344550)
• p160 coactivator glucocorticoid receptor-interacting protein 1 (GRIP1) is phosphorylated and potentiated by the p38 MAPK signaling cascade in vitro and in vivo. (PMID:16410316)
• MOZ-TIF2 associates with the RARbeta2 promoter in vivo, resulting in altered recruitment of CBP/p300, aberrant histone modification, and down-regulation of the RARbeta2 gene (PMID:16613851)
• evidence provided that the GRIP1 C-terminal region may be involved in regulating its own transactivation and nuclear receptor co-activation activities through primary self-association and a repression domain (PMID:16649994)
• Recent detection of SRC-2 in the human endometrium and breast suggests that this coregulator may represent a new clinical target for the future management of female reproductive health and/or breast cancer. (PMID:18174919)
• ETV6-NCOA2 fusion may define a novel subgroup of acute leukemia with T-lymphoid and myeloid features, which is associated with a high prevalence of NOTCH1 mutations. (PMID:18281529)
• The initial stimulation of GRIP1 coactivator function is followed by an increased turnover and subsequent degradation of GRIP1 protein. (PMID:18499756)
• A novel mutation F826L located within the ligand binding domain (LBD) of the human androgen receptor (AR) was investigated. (PMID:18656523)
• important role for androgen receptor-associated coactivators in urothelial carcinoma of the bladder (PMID:18845648)
• VDR and coactivators SRC2 and SRC3, which are also involved in other nuclear receptors as well, are critical for epidermis-specific sphingolipid production and barrier formation (PMID:19052561)
• dissect the GRIP1:Suv4-20h1 interaction in vitro and in vivo and examine its potential involvement in hormone-dependent transcriptional regulation by GR (PMID:19074285)
• The small interfering RNA depletion of SRC-2 inhibited growth of MCF-7 cells, and this was reflected in decreased cell cycle progression and increased apoptosis as well as a reduction in ERalpha transcriptional activity. (PMID:19095746)
• Overexpression of IL-6 increases the resistance of prostate cancer cells to bicalutamide via TIF2. (PMID:19240160)
• cAMP/PKA signaling enhances ERRalpha phosphorylation and nuclear localization, recruitment to the SP-A promoter, and interaction with PKAcat and SRC-2, resulting in the up-regulation of SP-A gene transcription. (PMID:19264843)
• ERbeta1-dependent (genomic and non-genomic) and ER-coregulator-dependent (AIB-1, TIF-2) signal transductions in myofibroblasts may be involved in the initiation and progression of colorectal carcinomas. (PMID:19277704)
• the cellular accumulation of IRF-1 may represent a potential molecular mechanism mediating altered cellular response to GC through the depletion of GRIP-1 from the GR transcriptional regulatory complexes (PMID:19805480)
• To enable recruitment (but not nuclear localization) of GRIP-1 to human glucocorticoid receptor (GR) in vitro, phosphorylation of the GR at serine residues S203, S211, and/or S226 is required. (PMID:20047289)
• Genetic aberrations and dysregulation in expression of p160/SRC coactivators and the ANCCA in breast cancer, prostate cancer, and other nonhormone-responsive cancers, are reviewed. (PMID:20374707)
• The crystal structure of RXRA-ligand binding domain:9-cis-retinoic acid:GRIP1 is reported at 2.05 A. (PMID:21049972)
• Distinctive functions of p160 steroid receptor coactivators in proliferation of an estrogen-independent, tamoxifen-resistant breast cancer cell line. (PMID:21059860)
• the hepatic AMPK-SRC-2 axis as an energy rheostat (PMID:21195347)
• SRC-2 and SRC-3 concomitantly promote human adipocyte differentiation by attenuating phospho-PPARgamma-Serine114 and modulating PPARgamma cellular heterogeneity. (PMID:21220509)
• Treatment of THP-1 cells with coenzyme Q10 significantly decreased expression of NCOA2. (PMID:21370964)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ncoa2	ENSDARG00000017929
mus_musculus	Ncoa2	ENSMUSG00000005886
rattus_norvegicus	Ncoa2	ENSRNOG00000007975
drosophila_melanogaster	tai	FBGN0041092

Paralogs (2): NCOA1 (ENSG00000084676), NCOA3 (ENSG00000124151)

Protein

Protein identifiers

Nuclear receptor coactivator 2 — Q15596 (reviewed: Q15596)

Alternative names: Class E basic helix-loop-helix protein 75, Transcriptional intermediary factor 2

All UniProt accessions (5): Q15596, A0A1D5RMT0, E5RFN9, E7EWM1, H0YBB6

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional coactivator for steroid receptors and nuclear receptors. Coactivator of the steroid binding domain (AF-2) but not of the modulating N-terminal domain (AF-1). Required with NCOA1 to control energy balance between white and brown adipose tissues. Critical regulator of glucose metabolism regulation, acts as a RORA coactivator to specifically modulate G6PC1 expression. Involved in the positive regulation of the transcriptional activity of the glucocorticoid receptor NR3C1 by sumoylation enhancer RWDD3. Positively regulates the circadian clock by acting as a transcriptional coactivator for the CLOCK-BMAL1 heterodimer.

Subunit / interactions. Present in a complex containing NCOA3, IKKA, IKKB, IKBKG and CREBBP. Present in a complex containing CARM1 and EP300/P300. Interacts (via C-terminus) with CREBBP. Interacts (via LXXLL 1, 2 and 3 motifs) with RORA (via AF-2 motif). Interacts (via LXXLL 1, 2 and 3 motifs) with RORC (via AF-2 motif). Interacts with APEX1. Interacts with BMAL1. Interacts with CARM1. Interacts with CASP8AP2. Interacts with CLOCK. Interacts with DDX5. Interacts with ESR1. Interacts with HIF1A. Interacts with NCOA1. Interacts with NR4A1/Nur77. Interacts with NR4A3; potentiates the activity of the NR4A3. Interacts with NR1H3. Interacts with NR3C1. Interacts with NR3C2. Interacts with PSMB9. Interacts with RARA. Interacts with RXRA. Interacts with RWDD3. Interacts with TTLL5/STAMP. Interacts with NR5A2.

Subcellular location. Nucleus.

Post-translational modifications. Acetylated. Deacetylation at Lys-780 by SIRT6 stimulates its ability to coactivate PPARA.

Disease relevance. Chromosomal aberrations involving NCOA2 may be a cause of acute myeloid leukemias. Inversion inv(8)(p11;q13) generates the KAT6A-NCOA2 oncogene, which consists of the N-terminal part of KAT6A and the C-terminal part of NCOA2/TIF2. KAT6A-NCOA2 binds to CREBBP and disrupts its function in transcription activation.

Domain organisation. Contains four Leu-Xaa-Xaa-Leu-Leu (LXXLL) motifs. The LXXLL motifs are essential for the association with nuclear receptors and are, at least in part, functionally redundant. The LLXXLXXXL motif is involved in transcriptional coactivation and CREBBP/CBP binding. Contains 2 C-terminal transcription activation domains (AD1 and AD2) that can function independently.

Similarity. Belongs to the SRC/p160 nuclear receptor coactivator family.

RefSeq proteins (6): NP_001308632, NP_001308636, NP_001308640, NP_001308641, NP_001308642, NP_006531* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000014	PAS	Domain
IPR009110	Nuc_rcpt_coact	Homologous_superfamily
IPR010011	NCO_DUF1518	Domain
IPR011598	bHLH_dom	Domain
IPR013767	PAS_fold	Domain
IPR014920	Nuc_rcpt_coact_Ncoa-typ	Domain
IPR014935	SRC/p160_LXXLL	Domain
IPR017426	Nuclear_rcpt_coactivator	Family
IPR028822	NCOA2_bHLH	Domain
IPR032565	NCOA2/3_DUF4927	Domain
IPR035965	PAS-like_dom_sf	Homologous_superfamily
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily
IPR037077	Nuc_rcpt_coact_Ncoa_int_sf	Homologous_superfamily
IPR056193	bHLH_NCOA1-3	Domain

Pfam: PF00989, PF07469, PF08815, PF08832, PF14598, PF16279, PF16665, PF23172

UniProt features (73 total): modified residue 27, region of interest 10, compositionally biased region 8, cross-link 6, short sequence motif 5, mutagenesis site 5, helix 4, domain 2, strand 2, initiator methionine 1, chain 1, site 1, sequence variant 1

Structure

Experimental structures (PDB)

381 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
3UP3	X-RAY DIFFRACTION	1.25
7NFB	X-RAY DIFFRACTION	1.33
7NEL	X-RAY DIFFRACTION	1.45
9QX6	X-RAY DIFFRACTION	1.46
5DXE	X-RAY DIFFRACTION	1.5
6LB4	X-RAY DIFFRACTION	1.5
7A77	X-RAY DIFFRACTION	1.5
5APH	X-RAY DIFFRACTION	1.54
6R7K	X-RAY DIFFRACTION	1.54
7RKE	X-RAY DIFFRACTION	1.55
7RAF	X-RAY DIFFRACTION	1.55
7PDQ	X-RAY DIFFRACTION	1.58
6HL1	X-RAY DIFFRACTION	1.6
3UP0	X-RAY DIFFRACTION	1.6
5KCT	X-RAY DIFFRACTION	1.6
7OFK	X-RAY DIFFRACTION	1.61
9RMR	X-RAY DIFFRACTION	1.65
1T65	X-RAY DIFFRACTION	1.66
6VC2	X-RAY DIFFRACTION	1.7
6KKB	X-RAY DIFFRACTION	1.7
5G42	X-RAY DIFFRACTION	1.72
7A78	X-RAY DIFFRACTION	1.72
3L0L	X-RAY DIFFRACTION	1.74
3PLZ	X-RAY DIFFRACTION	1.75
4PLD	X-RAY DIFFRACTION	1.75
4PLE	X-RAY DIFFRACTION	1.75
5G46	X-RAY DIFFRACTION	1.76
7W3P	X-RAY DIFFRACTION	1.77
4ZNV	X-RAY DIFFRACTION	1.77
2B1Z	X-RAY DIFFRACTION	1.78

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15596-F1	48.53	0.11

Functional residue map

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

Catalytic / active sites (1): 869–870 (breakpoint for translocation to form kat6a-ncoa2)

Post-translational modifications (33): 2, 29, 338, 487, 493, 499, 554, 565, 636, 640, 682, 699, 736, 771, 780, 785, 864, 874, 1173, 1177 …

Mutagenesis-validated functional residues (5):

Position	Phenotype
644–645	by itself, does not affect nuclear receptor binding or transcriptional coactivation. abrogates ligand-induced nuclear re
693–694	by itself, does not affect nuclear receptor binding or transcriptional coactivation. abrogates ligand-induced nuclear re
748–749	by itself, does not affect nuclear receptor binding or transcriptional coactivation. abrogates ligand-induced nuclear re
1079–1083	reduces transcriptional coactivation and disrupts interaction with crebbp/cbp.
1081–1082	has little effect on transcriptional coactivation.

Function

Pathways and Gene Ontology

Reactome pathways

55 pathways

ID	Pathway
R-HSA-1368108	BMAL1:CLOCK,NPAS2 activates circadian expression
R-HSA-159418	Recycling of bile acids and salts
R-HSA-192105	Synthesis of bile acids and bile salts
R-HSA-193368	Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol
R-HSA-193807	Synthesis of bile acids and bile salts via 27-hydroxycholesterol
R-HSA-1989781	PPARA activates gene expression
R-HSA-211976	Endogenous sterols
R-HSA-2151201	Transcriptional activation of mitochondrial biogenesis
R-HSA-2426168	Activation of gene expression by SREBF (SREBP)
R-HSA-3214847	HATs acetylate histones
R-HSA-381340	Transcriptional regulation of white adipocyte differentiation
R-HSA-3899300	SUMOylation of transcription cofactors
R-HSA-400206	Regulation of lipid metabolism by PPARalpha
R-HSA-5625886	Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3
R-HSA-9018519	Estrogen-dependent gene expression
R-HSA-9707564	Cytoprotection by HMOX1
R-HSA-9707616	Heme signaling
R-HSA-9841922	MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis
R-HSA-9931509	Expression of BMAL (ARNTL), CLOCK, and NPAS2
R-HSA-9933387	RORA,B,C and NR1D1 (REV-ERBA) regulate gene expression
R-HSA-1266738	Developmental Biology
R-HSA-1368082
R-HSA-1430728	Metabolism
R-HSA-1592230	Mitochondrial biogenesis
R-HSA-162582	Signal Transduction
R-HSA-1655829	Regulation of cholesterol biosynthesis by SREBP (SREBF)
R-HSA-1852241	Organelle biogenesis and maintenance
R-HSA-194068	Bile acid and bile salt metabolism
R-HSA-194315	Signaling by Rho GTPases
R-HSA-195258	RHO GTPase Effectors

MSigDB gene sets: 746 (showing top): GOBP_CIRCADIAN_RHYTHM, REACTOME_TRANSCRIPTIONAL_REGULATION_OF_WHITE_ADIPOCYTE_DIFFERENTIATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, REACTOME_BIOLOGICAL_OXIDATIONS, GOBP_BEHAVIOR, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, REACTOME_ENDOGENOUS_STEROLS, DARWICHE_SKIN_TUMOR_PROMOTER_DN, DARWICHE_PAPILLOMA_RISK_LOW_DN, GOBP_NEUROGENESIS, DARWICHE_PAPILLOMA_RISK_HIGH_DN, TGACCTY_ERR1_Q2, DARWICHE_SQUAMOUS_CELL_CARCINOMA_DN, GOBP_VESICLE_MEDIATED_TRANSPORT

GO Biological Process (19): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of DNA-templated transcription (GO:0006355), regulation of glucose metabolic process (GO:0010906), regulation of lipid metabolic process (GO:0019216), response to progesterone (GO:0032570), cellular response to hormone stimulus (GO:0032870), circadian regulation of gene expression (GO:0032922), peroxisome proliferator activated receptor signaling pathway (GO:0035357), mRNA transcription by RNA polymerase II (GO:0042789), locomotor rhythm (GO:0045475), negative regulation of smoothened signaling pathway (GO:0045879), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of cellular response to insulin stimulus (GO:1900076), cellular response to Thyroglobulin triiodothyronine (GO:1904017), positive regulation of adipose tissue development (GO:1904179), circadian rhythm (GO:0007623), regulation of gene expression (GO:0010468), negative regulation of DNA-templated transcription (GO:0045892), rhythmic process (GO:0048511)

GO Molecular Function (13): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding (GO:0001162), chromatin binding (GO:0003682), transcription coactivator activity (GO:0003713), nuclear receptor binding (GO:0016922), aryl hydrocarbon receptor binding (GO:0017162), protein domain specific binding (GO:0019904), protein dimerization activity (GO:0046983), transcription regulator inhibitor activity (GO:0140416), transcription coregulator activity (GO:0003712), signaling receptor binding (GO:0005102), protein binding (GO:0005515), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629)

GO Cellular Component (8): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), cytoplasm (GO:0005737), nuclear body (GO:0016604), protein-containing complex (GO:0032991), RNA polymerase II transcription regulator complex (GO:0090575)

Reactome top-level categories

Rollup of top-16 pathways:

Category	Pathways
Circadian clock	3
Bile acid and bile salt metabolism	2
Synthesis of bile acids and bile salts	2
Regulation of lipid metabolism by PPARalpha	1
Cytochrome P450 - arranged by substrate type	1
Mitochondrial biogenesis	1
Regulation of cholesterol biosynthesis by SREBP (SREBF)	1
Chromatin modifying enzymes	1
Adipogenesis	1
SUMO E3 ligases SUMOylate target proteins	1
Metabolism of lipids	1
RHO GTPases activate PKNs	1
ESR-mediated signaling	1
Cellular response to chemical stress	1
Cellular responses to stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transcription by RNA polymerase II	3
regulation of gene expression	3
protein binding	3
cellular anatomical structure	3
regulation of transcription by RNA polymerase II	2
DNA-templated transcription	2
cellular response to chemical stimulus	2
positive regulation of DNA-templated transcription	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
binding	2
RNA polymerase II-specific DNA-binding transcription factor binding	2
transcription regulator activity	2
negative regulation of DNA-templated transcription	1
regulation of RNA biosynthetic process	1
glucose metabolic process	1
regulation of carbohydrate metabolic process	1
regulation of small molecule metabolic process	1
lipid metabolic process	1
regulation of primary metabolic process	1
response to steroid hormone	1
response to ketone	1
response to hormone	1
cellular response to endogenous stimulus	1
circadian rhythm	1
nuclear receptor-mediated signaling pathway	1
mRNA transcription	1
locomotory behavior	1
circadian behavior	1
smoothened signaling pathway	1
regulation of smoothened signaling pathway	1
negative regulation of signal transduction	1
cellular response to insulin stimulus	1
regulation of response to stimulus	1
regulation of cellular process	1
response to Thyroglobulin triiodothyronine	1
positive regulation of developmental process	1
positive regulation of multicellular organismal process	1
adipose tissue development	1
regulation of adipose tissue development	1
rhythmic process	1

Protein interactions and networks

STRING

2111 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NCOA2	CARM1	Q86X55	980
NCOA2	ESR1	P03372	979
NCOA2	EP300	Q09472	977
NCOA2	NCOA3	Q9Y6Q9	955
NCOA2	CREBBP	Q92793	945
NCOA2	ASXL2	Q76L83	911
NCOA2	AR	P10275	906
NCOA2	PPARG	P37231	903
NCOA2	NCOA1	Q15788	902
NCOA2	NR3C1	P04150	893
NCOA2	ESR2	Q92731	872
NCOA2	PRMT1	Q99873	820
NCOA2	KAT2B	Q92831	805
NCOA2	PGR	P06401	796
NCOA2	NCOR1	O75376	790

IntAct

100 interactions, top by confidence:

A	B	Type	Score
ESR1	ESR1	psi-mi:“MI:0914”(association)	0.870
RXRA	NCOA2	psi-mi:“MI:0407”(direct interaction)	0.780
NCOA2	RXRA	psi-mi:“MI:0915”(physical association)	0.780
MED23	MED19	psi-mi:“MI:2364”(proximity)	0.770
AR	NCOA2	psi-mi:“MI:0407”(direct interaction)	0.690
AR	NCOA2	psi-mi:“MI:0915”(physical association)	0.690
SLA	NCOA2	psi-mi:“MI:0915”(physical association)	0.590
NCOA2	ESR1	psi-mi:“MI:0915”(physical association)	0.580
ESR1	NCOA2	psi-mi:“MI:0915”(physical association)	0.580
NR5A2	NCOA2	psi-mi:“MI:0407”(direct interaction)	0.560
TXNRD1	ESR1	psi-mi:“MI:0915”(physical association)	0.560
MAGEA10	POTEF	psi-mi:“MI:0914”(association)	0.530
BAG2	HGS	psi-mi:“MI:0914”(association)	0.530
NCOA2	VDR	psi-mi:“MI:0915”(physical association)	0.520
CREBBP	IKBKB	psi-mi:“MI:0914”(association)	0.480
NCOA2	PPARA	psi-mi:“MI:0407”(direct interaction)	0.440
NCOA2	PPARD	psi-mi:“MI:0407”(direct interaction)	0.440
RARA	NCOA2	psi-mi:“MI:0407”(direct interaction)	0.410
NCOA2	Trim28	psi-mi:“MI:0915”(physical association)	0.400
NR4A1	NCOA2	psi-mi:“MI:0915”(physical association)	0.400
CTNNB1	NCOA2	psi-mi:“MI:0915”(physical association)	0.400
TXNRD1	NCOA2	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (253): NCOA2 (Reconstituted Complex), NCOA2 (Two-hybrid), NCOA2 (Affinity Capture-Western), NCOA2 (Protein-peptide), HIST4H4 (Biochemical Activity), HIST3H3 (Biochemical Activity), ETV1 (Biochemical Activity), NCOA2 (Reconstituted Complex), NCOA2 (Biochemical Activity), NCOA2 (Reconstituted Complex), NCOA2 (Two-hybrid), NCOA2 (Protein-peptide), NCOA2 (Reconstituted Complex), NCOA2 (Affinity Capture-MS), NCOA2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0R4IBL7, A2A891, A3RK74, A4L7N3, B5DE09, E1BPQ1, G3V7R4, O15014, O43524, P11420, P15806, P15881, P15884, P15923, P21677, P30985, P51514, P70365, P98180, Q01978, Q12778, Q14135, Q15596, Q15788, Q4PJW2, Q53TQ3, Q60420, Q60722, Q61026, Q61286, Q62655, Q66IY8, Q66JJ0, Q6DIH5, Q6EUW2, Q6NZT6, Q6PCG7, Q7T2G1, Q7ZXS3, Q80V24

Diamond homologs: A9YTQ3, B5DE09, O02747, O09000, O15945, O57539, P30561, P35869, P41738, P70365, P97459, Q15596, Q15788, Q3U1U7, Q4PJW2, Q61026, Q8IXF0, Q8R4S2, Q8R4S4, Q8R4S5, Q8R4S6, Q8R4S7, Q95LD9, Q98TW1, Q99742, Q9EPU2, Q9QZQ0, Q9W705, Q9WUI9, Q9Y6Q9, O02219, O08785, O15516, P05709, Q5RAK8, Q6YGZ4, Q75NT5, Q8QGQ6, Q91YA8, Q91YB0

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
ESR1	“up-regulates quantity by expression”	NCOA2	“transcriptional regulation”
NCOA2	up-regulates	RXRA	binding
NCOA2	up-regulates	PPARG	binding
NCOA2	“up-regulates activity”	AR	binding
CDK9	“up-regulates activity”	NCOA2	phosphorylation
NCOA2	up-regulates	RARA	binding
NCOA2	“up-regulates activity”	NR3C1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 107 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
SUMOylation of intracellular receptors	7	33.6×	3e-07
Nuclear Receptor transcription pathway	11	31.5×	2e-11
Deactivation of the beta-catenin transactivating complex	7	23.3×	3e-06
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	6	18.5×	5e-05
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	6	16.9×	8e-05
Adipogenesis	7	15.6×	3e-05
Transcriptional regulation of white adipocyte differentiation	8	14.8×	7e-06
Regulation of lipid metabolism by PPARalpha	7	14.1×	5e-05

GO biological processes:

GO term	Partners	Fold	FDR
intracellular receptor signaling pathway	5	54.5×	5e-06
negative regulation of miRNA transcription	5	34.3×	4e-05
RNA polymerase II preinitiation complex assembly	7	20.9×	6e-06
positive regulation of transcription initiation by RNA polymerase II	7	20.9×	6e-06
positive regulation of transcription elongation by RNA polymerase II	6	19.8×	7e-05
mRNA transcription by RNA polymerase II	5	18.2×	5e-04
somatic stem cell population maintenance	5	13.6×	2e-03
mRNA splicing, via spliceosome	7	7.0×	3e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 4 cancer types — ESCA, LUAD, LUSC, STAD.

Clinical variants and AI predictions

ClinVar

1073 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	18
Likely pathogenic	17
Uncertain significance	440
Likely benign	488
Benign	24

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
2047350	NM_001366722.1(GRIP1):c.2155C>T (p.Arg719Ter)	Pathogenic
2696242	NM_001366722.1(GRIP1):c.1559_1566dup (p.Arg523fs)	Pathogenic
2713892	NM_001366722.1(GRIP1):c.436_437del (p.Val146fs)	Pathogenic
2744863	NM_001366722.1(GRIP1):c.2768_2772delinsCTTGGTAGAACTTTGAGAAACTTTGAGAAAACTTTGAGAAAACTTTGAGAAA (p.Met923_Thr924delinsThrTrpTer)	Pathogenic
2768789	NM_001366722.1(GRIP1):c.505G>T (p.Gly169Ter)	Pathogenic
2788488	NM_001366722.1(GRIP1):c.2775_2776del (p.Leu926fs)	Pathogenic
2792993	NM_001366722.1(GRIP1):c.1633C>T (p.Arg545Ter)	Pathogenic
2835353	NM_001366722.1(GRIP1):c.2885del (p.Pro962fs)	Pathogenic
3063238	GRCh37/hg19 12q14.3(chr12:65462762-66830065)x1	Pathogenic
3244433	NC_000012.11:g.(?67072610)(67072684_?)del	Pathogenic
3244434	NC_000012.11:g.(?66859035)(66859222_?)del	Pathogenic
3244435	NC_000012.11:g.(?66838344)(67072684_?)del	Pathogenic
36970	NM_001366722.1(GRIP1):c.2269+1G>C	Pathogenic
36971	NM_001366722.1(GRIP1):c.1337_1340del (p.Lys446fs)	Pathogenic
3717575	NM_001366722.1(GRIP1):c.672_675del (p.Lys224fs)	Pathogenic
3726914	NM_001366722.1(GRIP1):c.2749del (p.Arg917fs)	Pathogenic
4682806	GRCh37/hg19 12q14.3(chr12:65953394-66867963)x1	Pathogenic
974698	NM_001366722.1(GRIP1):c.1930C>T (p.Gln644Ter)	Pathogenic
1878400	NM_001366722.1(GRIP1):c.10_13del (p.Val4fs)	Likely pathogenic
2768364	NM_001366722.1(GRIP1):c.503-2del	Likely pathogenic
2802784	NM_001366722.1(GRIP1):c.1199-2del	Likely pathogenic
2805894	NM_001366722.1(GRIP1):c.1199-1G>A	Likely pathogenic
2838526	NM_001366722.1(GRIP1):c.1769-1G>A	Likely pathogenic
2987018	NM_001366722.1(GRIP1):c.137-1G>A	Likely pathogenic
3575200	NM_021150.4(GRIP1):c.1618_1619insTATATCTCCATTATTACAGCACCAT	Likely pathogenic
3575202	NM_001366722.1(GRIP1):c.1688-1G>C	Likely pathogenic
3575209	NM_001366722.1(GRIP1):c.1285del (p.Leu429fs)	Likely pathogenic
3575210	NM_001366722.1(GRIP1):c.1279C>T (p.Arg427Ter)	Likely pathogenic
3575215	NM_001366722.1(GRIP1):c.1199-2A>G	Likely pathogenic
3575234	NM_001366722.1(GRIP1):c.206C>A (p.Ser69Ter)	Likely pathogenic

SpliceAI

6330 predictions. Top by Δscore:

Variant	Effect	Δscore
8:70123879:CTCA:C	donor_loss	1.0000
8:70123880:TCA:T	donor_loss	1.0000
8:70123881:CAC:C	donor_loss	1.0000
8:70123882:A:AC	donor_gain	1.0000
8:70123883:C:CC	donor_gain	1.0000
8:70123883:C:G	donor_loss	1.0000
8:70123883:CCTG:C	donor_gain	1.0000
8:70124078:ACATG:A	acceptor_gain	1.0000
8:70124079:CATG:C	acceptor_gain	1.0000
8:70124079:CATGC:C	acceptor_gain	1.0000
8:70124080:ATG:A	acceptor_gain	1.0000
8:70124081:TG:T	acceptor_gain	1.0000
8:70124083:C:CC	acceptor_gain	1.0000
8:70127067:A:C	acceptor_gain	1.0000
8:70128427:CCTTA:C	donor_loss	1.0000
8:70128428:CTTA:C	donor_loss	1.0000
8:70128429:TTA:T	donor_loss	1.0000
8:70128430:TA:T	donor_loss	1.0000
8:70128432:C:CT	donor_loss	1.0000
8:70128506:CGATT:C	acceptor_gain	1.0000
8:70128509:TT:T	acceptor_gain	1.0000
8:70128511:C:CC	acceptor_gain	1.0000
8:70128511:CTAA:C	acceptor_loss	1.0000
8:70128519:A:C	acceptor_gain	1.0000
8:70131834:TACC:T	donor_loss	1.0000
8:70131835:A:AT	donor_loss	1.0000
8:70131836:C:CG	donor_loss	1.0000
8:70131836:CCTGG:C	donor_gain	1.0000
8:70132000:TGC:T	acceptor_gain	1.0000
8:70132002:CCT:C	acceptor_loss	1.0000

AlphaMissense

9787 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:70128727:A:G	L1193P	1.000
8:70156119:A:G	L749P	1.000
8:70156122:A:G	L748S	1.000
8:70156287:A:G	L693P	1.000
8:70156296:A:G	L690S	1.000
8:70159518:G:C	H371D	1.000
8:70159524:A:G	S369P	1.000
8:70159570:G:C	S353R	1.000
8:70159570:G:T	S353R	1.000
8:70159572:T:G	S353R	1.000
8:70159577:G:C	T351R	1.000
8:70159583:G:T	A349E	1.000
8:70159589:A:T	V347D	1.000
8:70159613:A:G	F339S	1.000
8:70159627:A:C	S334R	1.000
8:70159627:A:T	S334R	1.000
8:70159629:T:G	S334R	1.000
8:70162767:A:G	F307S	1.000
8:70162778:A:C	C303W	1.000
8:70162780:A:G	C303R	1.000
8:70162839:A:G	L283P	1.000
8:70162843:A:G	S282P	1.000
8:70162848:A:C	I280S	1.000
8:70162848:A:G	I280T	1.000
8:70162854:C:A	G278V	1.000
8:70163465:C:G	G278R	1.000
8:70163476:T:G	Q274P	1.000
8:70163479:C:G	R273P	1.000
8:70163487:A:C	F270L	1.000
8:70163487:A:T	F270L	1.000

dbSNP variants (sampled 300 via entrez): RS1000014334 (8:70136002 C>G,T), RS1000014644 (8:70456395 T>C), RS1000021309 (8:70265849 TAA>T,TAAA), RS1000021761 (8:70158594 A>C), RS1000024047 (8:70225395 A>C), RS1000031129 (8:70113960 C>T), RS1000035557 (8:70326427 TCTCA>T), RS1000046016 (8:70182827 A>G,T), RS1000058740 (8:70225144 C>G,T), RS1000069842 (8:70246419 C>T), RS1000071515 (8:70342508 G>A), RS1000072137 (8:70202629 G>T), RS1000077307 (8:70406387 A>C,T), RS1000104408 (8:70408364 A>T), RS1000115222 (8:70391367 G>A,T)

Disease associations

OMIM: gene MIM:601993 | disease phenotypes: MIM:617667, MIM:219000

GenCC curated gene-disease

Disease	Classification	Inheritance
Fraser syndrome 3	Strong	Autosomal recessive
Fraser syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Fraser syndrome 3	Definitive	AR

Mondo (5): Fraser syndrome 3 (MONDO:0054739), Fraser syndrome 1 (MONDO:0054737), intellectual disability (MONDO:0001071), microcephaly (MONDO:0001149), Fraser syndrome (MONDO:0009046)

Orphanet (2): Fraser syndrome (Orphanet:2052), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

84 total (30 of 84 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000046	Small scrotum
HP:0000047	Hypospadias
HP:0000062	Ambiguous genitalia
HP:0000068	Urethral atresia
HP:0000079	Abnormality of the urinary system
HP:0000142	Abnormal vagina morphology
HP:0000148	Vaginal atresia
HP:0000202	Orofacial cleft
HP:0000204	Cleft upper lip
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000316	Hypertelorism
HP:0000347	Micrognathia
HP:0000356	Abnormality of the outer ear
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000370	Abnormality of the middle ear
HP:0000377	Abnormal pinna morphology
HP:0000405	Conductive hearing impairment
HP:0000413	Atresia of the external auditory canal
HP:0000430	Underdeveloped nasal alae
HP:0000431	Wide nasal bridge
HP:0000444	Convex nasal ridge
HP:0000445	Wide nose
HP:0000528	Anophthalmia
HP:0000568	Microphthalmia
HP:0000618	Blindness

GWAS associations

52 associations (top):

Study	Trait	p-value
GCST001734_10	Non-small cell lung cancer	7.000000e-06
GCST001776_2	Cardiac Troponin-T levels	9.000000e-09
GCST001817_9	Metabolite levels (HVA-5-HIAA Factor score)	6.000000e-06
GCST002500_63	QT interval	1.000000e-09
GCST003264_1589	Post bronchodilator FEV1/FVC ratio	4.000000e-09
GCST003264_1616	Post bronchodilator FEV1/FVC ratio	1.000000e-06
GCST004232_89	HDL cholesterol levels	6.000000e-08
GCST004525_8	Subclinical trait of interstitial lung disease (basilar peel-core ratio of high attentuation areas on CT scan)	8.000000e-10
GCST004631_55	Basophil percentage of white cells	1.000000e-17
GCST004634_39	Basophil percentage of granulocytes	3.000000e-17
GCST005316_85	Intelligence (MTAG)	5.000000e-08
GCST005531_97	Multiple sclerosis	7.000000e-07
GCST006016_16	Serum alkaline phosphatase levels	3.000000e-09
GCST006291_69	Spherical equivalent or myopia (age of diagnosis)	4.000000e-10
GCST006611_94	HDL cholesterol	2.000000e-14
GCST009391_2129	Metabolite levels	3.000000e-06
GCST010002_303	Refractive error	1.000000e-26
GCST010241_211	Apolipoprotein A1 levels	1.000000e-09
GCST010242_43	HDL cholesterol levels	6.000000e-15
GCST010796_2823	Electrocardiogram morphology (amplitude at temporal datapoints)	7.000000e-15
GCST010796_3293	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-16
GCST010796_3294	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-11
GCST010796_3295	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-11
GCST010796_3296	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-12
GCST010796_3297	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-15
GCST010796_3298	Electrocardiogram morphology (amplitude at temporal datapoints)	9.000000e-15
GCST010796_3299	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-14
GCST010796_3300	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-14
GCST010796_3301	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-14
GCST010796_3302	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-14

EFO canonical traits (17, from GWAS)

EFO ID	Trait name
EFO:0005043	cardiac troponin T measurement
EFO:0005131	HVA measurement
EFO:0005132	5-HIAA measurement
EFO:0004682	QT interval
EFO:0004713	FEV/FVC ratio
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0007627	airway imaging measurement
EFO:0007992	basophil percentage of leukocytes
EFO:0007995	basophil percentage of granulocytes
EFO:0004337	intelligence
EFO:0004533	alkaline phosphatase measurement
EFO:0004847	age at onset
EFO:0010383	phosphatidylcholine 36:5 measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004327	electrocardiography
EFO:0008039	BMI-adjusted hip circumference
EFO:0007985	platelet crit

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D058497	Fraser Syndrome	C05.116.099.370.894.819.428; C05.660.585.800.428; C05.660.906.819.428; C11.250.390; C12.050.351.875.397; C12.200.706.410; C12.800.410; C16.131.077.371; C16.131.384.442; C16.131.621.585.800.428; C16.131.621.906.819.428; C16.131.939.410
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
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): CHEMBL2095163 (PROTEIN-PROTEIN INTERACTION), CHEMBL6195557 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 113,934 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL405110	METHYLENE BLUE ANHYDROUS	4	113,934

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — 2.3.1.48 Histone acetyltransferases (HATs)

Binding affinities (BindingDB)

97 measured of 339 human assays (398 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
2-(benzylsulfanyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile	IC50	25.4 nM
2,5-bis(chloranyl)-3-[2-(dimethylamino)-1,3-thiazol-5-yl]-6-pyrrolidin-1-yl-cyclohexa-2,5-diene-1,4-dione	EC50	210 nM
4-amino-3-(4-methylphenyl)-5-[(4-methyl-1-piperazinyl)carbonyl]-1,3-thiazole-2(3H)-thione	IC50	250 nM
3,4-dimethyl-N-(5-thiophen-2-yl-1,3,4-thiadiazol-2-yl)benzamide	EC50	786 nM
5-bromanyl-N-(4-piperidin-1-ylphenyl)pyridine-3-carboxamide	EC50	1020 nM
1-[[1-(4-methoxyphenyl)-3-pyrrolidinyl]methyl]-3-phenylurea	IC50	2580 nM
2-(2-Adamantan-1-yl-2-oxo-ethylsulfanyl)-6-amino-4-(4-chloro-phenyl)-pyridine-3,5-dicarbonitrile	EC50	2940 nM
4-[(2-benzoxybenzyl)amino]phenol	EC50	2980 nM
MLS000107751	EC50	3570 nM
2-(4-chloranyl-3-methyl-phenoxy)-N-[2-methyl-5-(3-methyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)phenyl]ethanamide	IC50	4880 nM
MLS000560834	EC50	6080 nM
(7-Cyano-[1,3]dioxolo[4,5-g]quinolin-6-ylsulfanyl)-acetic acid methyl ester	EC50	7890 nM
2-[(3,4-dimethoxyphenyl)-oxomethyl]imino-3,4-dimethyl-5-thiazolecarboxylic acid ethyl ester	EC50	8100 nM
MLS000040305	EC50	8460 nM
2-[[1-(3,5-dimethoxyphenyl)-1,2,3,4-tetrazol-5-yl]sulfanyl]-N-(4-ethanoylphenyl)ethanamide	EC50	8560 nM
3-[(5-bromothiophene-2-carbonyl)amino]thiophene-2-carboxylic acid methyl ester	EC50	8670 nM
4-bromanyl-N-(1-propylbenzimidazol-2-yl)benzamide	EC50	8960 nM
2-[2-(2-chlorophenyl)-4-phenyl-1,3-thiazol-5-yl]-N-phenyl-ethanamide	EC50	10000 nM
2-[3-Cyano-6-(4-methoxy-phenyl)-4-thiophen-2-yl-pyridin-2-ylsulfanyl]-N-(2-methoxy-benzyl)-acetamide	EC50	10300 nM
10-methoxy-5H-[1]benzothiolo[2,3-c]quinolin-6-one	EC50	11000 nM
2-[(6-amino-3,5-dicyano-4-p-phenetyl-2-pyridyl)thio]acetic acid butyl ester	IC50	11000 nM
2-[(3-methoxyphenyl)-oxomethyl]imino-3,4-dimethyl-5-thiazolecarboxylic acid ethyl ester	EC50	11000 nM
2-[2-(3-chlorobenzothiophene-2-carbonyl)imino-6-sulfamoyl-1,3-benzothiazol-3-yl]acetic acid ethyl ester	EC50	11200 nM
3-(4-Chloro-phenyl)-1-cyclopropyl-1-(7-ethyl-1,2,3,9b-tetraaza-cyclopenta[a]naphthalen-4-ylmethyl)-thiourea	EC50	11500 nM
(7-Cyano-[1,3]dioxolo[4,5-g]quinolin-6-ylsulfanyl)-acetic acid isopropyl ester	EC50	11900 nM
5-[[4-(4-methylpiperidino)sulfonylbenzoyl]oxymethyl]furan-2-carboxylic acid methyl ester	EC50	12600 nM
2-[[5-(1-benzofuran-2-yl)-4-methyl-1,2,4-triazol-3-yl]sulfanyl]-N-(3-bromophenyl)acetamide	EC50	13300 nM
2,5-bis(chloranyl)-N-[3-(2-ethoxyethyl)-6-sulfamoyl-1,3-benzothiazol-2-ylidene]thiophene-3-carboxamide	EC50	13400 nM
2-[4-(1,3-benzothiazol-2-yl)-1-piperazinyl]-4-methoxy-1,3-benzothiazole	EC50	13400 nM
2-({5-[2-(4-bromophenyl)-2-oxoethyl]-3-cyano-4,6-dimethyl-2-pyridinyl}sulfanyl)-N-(4-fluorophenyl)acetamide	EC50	13800 nM
MLS000543203	EC50	14400 nM
2-[2-oxidanylidene-2-(2-oxidanylidenechromen-3-yl)ethyl]sulfanyl-6-phenyl-pyridine-3-carbonitrile	EC50	15500 nM
4-[[4-(4-chlorophenyl)-3-cyano-6-phenyl-2-pyridinyl]thio]-3-oxobutanoic acid ethyl ester	EC50	16400 nM
N-(4-(4-(azepan-1-ylsulfonyl)phenyl)thiazol-2-yl)thiophene-2-carboxamide	EC50	16500 nM
6-(4-fluorophenyl)-3-methyl-N-(6-methyl-2-pyridinyl)-2-imidazo[2,1-b]thiazolecarboxamide	EC50	16800 nM
2-(1,3-benzoxazol-2-ylsulfanyl)-1-(3,4,5-trimethoxyphenyl)ethanone	EC50	16900 nM
4-[4-(2,4-dichlorophenyl)-1,3-thiazol-2-yl]-N-prop-2-enyl-benzamide	EC50	17100 nM
4-fluoranyl-N-(2-phenylquinazolin-4-yl)benzamide	EC50	17200 nM
5-bromanyl-N-(phenylcarbamothioyl)furan-2-carboxamide	EC50	17600 nM
4-methyl-N-(4-pyrrolidin-1-ylphenyl)benzamide	IC50	17900 nM
2-(4-isopropoxybenzoyl)imino-3,4-dimethyl-4-thiazoline-5-carboxylic acid ethyl ester	EC50	18300 nM
6-amino-5-[1-(4-chlorophenyl)-3-methyl-thieno[2,3-c]pyrazole-5-carbonyl]-1,3-dimethyl-pyrimidine-2,4-quinone	EC50	18400 nM
5-chloranyl-N-(4-methoxy-3-prop-2-ynyl-1,3-benzothiazol-2-ylidene)thiophene-2-carboxamide	EC50	18400 nM
2-[3-cyano-6-(4-methoxyphenyl)-4-thiophen-2-yl-pyridin-2-yl]sulfanyl-N-(phenylmethyl)ethanamide	EC50	18800 nM
2-(3-Cyano-6-methyl-quinolin-2-ylsulfanyl)-N-thiophen-2-ylmethyl-acetamide	EC50	19000 nM
2-(3-bromophenyl)-4-quinolinecarboxylic acid [2-[3-(dimethylsulfamoyl)anilino]-2-oxoethyl] ester	EC50	19100 nM
3,6-bis(chloranyl)-1-[2-[[3-chloranyl-5-(trifluoromethyl)pyridin-2-yl]amino]ethyl]quinoxalin-2-one	EC50	19800 nM
1-(1,3-benzodioxol-5-ylmethyl)-3-(2,1,3-benzothiadiazol-5-yl)urea	EC50	20400 nM
4-(4-{[4-cyclohexyl-3-(2-hydroxyethyl)piperazin-1-yl]methyl}phenyl)-2-methylbut-3-yn-2-ol	IC50	21200 nM
3-chloro-1-benzothiophene-2-carboxylic acid [2-[(3,5-dichloro-2-pyridinyl)amino]-2-oxoethyl] ester	EC50	21600 nM

ChEMBL bioactivities

93 potent at pChembl≥5 of 338 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.13	EC50	742	nM	METHYLENE BLUE ANHYDROUS
5.86	EC50	1386	nM	CHEMBL1613238
5.76	EC50	1745	nM	CHEMBL1388589
5.71	EC50	1935	nM	CHEMBL1427926
5.67	EC50	2150	nM	CHEMBL1331930
5.63	EC50	2353	nM	CHEMBL1587518
5.61	EC50	2465	nM	CHEMBL1349621
5.61	EC50	2473	nM	CHEMBL1539280
5.55	EC50	2833	nM	CHEMBL3198000
5.53	EC50	2921	nM	CHEMBL1386916
5.50	EC50	3184	nM	CHEMBL1589567
5.49	EC50	3263	nM	CHEMBL1538790
5.49	EC50	3251	nM	CHEMBL1321356
5.47	EC50	3418	nM	CHEMBL1556161
5.47	EC50	3373	nM	CHEMBL1380232
5.47	EC50	3398	nM	CHEMBL1374054
5.42	EC50	3813	nM	CHEMBL1330383
5.41	EC50	3889	nM	CHEMBL1450791
5.41	EC50	3912	nM	CHEMBL1426003
5.40	EC50	3979	nM	CHEMBL1417231
5.38	EC50	4139	nM	CHEMBL1331978
5.38	EC50	4135	nM	CHEMBL1303333
5.37	EC50	4258	nM	CHEMBL1503060
5.37	EC50	4226	nM	CHEMBL1510408
5.34	EC50	4577	nM	CHEMBL1556190
5.33	EC50	4727	nM	CHEMBL1359775
5.32	EC50	4786	nM	CHEMBL1416815
5.32	EC50	4773	nM	CHEMBL1326901
5.30	EC50	5015	nM	CHEMBL1462764
5.30	EC50	4969	nM	CHEMBL1452524
5.29	EC50	5163	nM	CHEMBL1547257
5.29	EC50	5171	nM	CHEMBL1587976
5.29	EC50	5170	nM	CHEMBL1462713
5.29	EC50	5128	nM	CHEMBL1414657
5.29	EC50	5170	nM	CHEMBL1351131
5.28	EC50	5269	nM	CHEMBL1604975
5.26	EC50	5522	nM	CHEMBL1484562
5.25	EC50	5643	nM	CHEMBL1388862
5.25	EC50	5604	nM	CHEMBL1350581
5.24	EC50	5816	nM	CHEMBL1363571
5.20	EC50	6256	nM	CHEMBL1510509
5.20	EC50	6294	nM	CHEMBL1511437
5.18	EC50	6529	nM	CHEMBL1580375
5.17	EC50	6712	nM	CHEMBL1324024
5.17	EC50	6708	nM	CHEMBL1427022
5.17	EC50	6834	nM	CHEMBL1390336
5.17	EC50	6824	nM	CHEMBL1425135
5.15	EC50	7113	nM	CHEMBL1529744
5.14	EC50	7178	nM	CHEMBL1503047
5.14	EC50	7231	nM	CHEMBL1426930

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects reaction, increases reaction, increases expression, affects cotreatment, decreases reaction (+2 more)	18
Benzo(a)pyrene	decreases reaction, decreases expression, decreases methylation, affects methylation, affects localization	6
bisphenol A	affects binding, decreases reaction, increases reaction, increases activity	5
Tetrachlorodibenzodioxin	affects binding, increases activity, increases reaction, affects reaction, increases expression	5
Calcitriol	decreases reaction, increases reaction, increases activity, increases response to substance, affects binding	4
Diethylstilbestrol	affects binding, increases reaction	4
Tamoxifen	increases reaction, increases expression, affects binding, decreases reaction	4
Doxorubicin	affects binding, decreases reaction, increases reaction, affects localization, decreases expression	3
Dihydrotestosterone	affects binding, increases reaction, decreases reaction, increases activity, increases expression	3
Valproic Acid	decreases expression, increases methylation	3
Aflatoxin B1	affects expression, decreases methylation	3
Genistein	affects binding, increases reaction	3
oxybenzone	affects binding, increases reaction, increases expression	2
arsenite	affects binding, decreases reaction, increases expression	2
afimoxifene	decreases reaction, affects cotreatment, increases activity, affects binding	2
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	2
lithocholic acid acetate	affects binding, decreases reaction	2
bisphenol S	increases reaction, affects binding	2
Resveratrol	decreases reaction, increases reaction, increases expression, affects binding, affects cotreatment	2
Fulvestrant	affects binding, affects cotreatment, decreases reaction, increases reaction, increases expression	2
Air Pollutants	decreases expression, affects cotreatment, increases abundance	2
Chenodeoxycholic Acid	affects binding, affects localization, decreases reaction, increases reaction	2
Tretinoin	affects binding, increases reaction, increases expression	2
Triiodothyronine	affects binding, increases reaction	2
Zearalenone	affects binding, increases activity, increases reaction	2
Metribolone	affects binding, decreases reaction, increases reaction, affects folding	2
Cyproterone Acetate	affects binding, affects folding, increases reaction	2
Cadmium Chloride	affects binding, increases reaction, decreases expression	2
Raloxifene Hydrochloride	affects binding, increases reaction, increases expression	2
aristolochic acid I	decreases expression	1

ChEMBL screening assays

3 unique, capped per target: 2 functional, 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1613807	Functional	PUBCHEM_BIOASSAY: Dose response biochemical High Throughput Screening assay for agonists of the steroid receptor coactivator 2 (SRC-2) recruitment by the peroxisome proliferator-activated receptor gamma (PPARgamma). (Class of assay: confirm	PubChem BioAssay data set
CHEMBL6182478	Binding	PROTAC activity at CRBN/SRC-2 in human MCF7 cells assessed as induction of SRC-2 degradation at 0.01 to 10 uM measured after 36 hrs by immunoblot analysis	Intercepting the Downstream of the Estrogen Receptor Signaling Pathway: Discovery of a Potent and Efficient SRC-3 PROTAC Degrader for Overcoming Endocrine Resistance Breast Cancer. — J Med Chem

Cellosaurus cell lines

7 cell lines: 4 spontaneously immortalized cell line, 1 transformed cell line, 1 embryonic stem cell, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3BX	Abcam HEK293T NCOA2 KO	Transformed cell line	Female
CVCL_BW96	ES-R1 CAG-S-hSRC-2	Embryonic stem cell	Male
CVCL_KX08	PathHunter CHO-K1 FXR Protein Interaction	Spontaneously immortalized cell line	Female
CVCL_KX92	PathHunter CHO-K1 LXRalpha Protein Interaction	Spontaneously immortalized cell line	Female
CVCL_KY93	PathHunter CHO-K1 RARbeta Protein Interaction	Spontaneously immortalized cell line	Female
CVCL_KZ20	PathHunter CHO-K1 THRalpha Protein Interaction	Spontaneously immortalized cell line	Female
CVCL_LB30	PathHunter U2OS RXRalpha Protein Interaction	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT00032877	Not specified	COMPLETED	Genetic Analysis of Fraser Syndrome and Fryns Syndrome
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability