NCOA6

Summary

NCOA6 (nuclear receptor coactivator 6, HGNC:15936) is a protein-coding gene on chromosome 20q11.22, encoding Nuclear receptor coactivator 6 (Q14686). Nuclear receptor coactivator that directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion.

The protein encoded by this gene is a transcriptional coactivator that can interact with nuclear hormone receptors to enhance their transcriptional activator functions. This protein has been shown to be involved in the hormone-dependent coactivation of several receptors, including prostanoid, retinoid, vitamin D3, thyroid hormone, and steroid receptors. Alternatively spliced transcript variants encoding different isoforms have been described for this gene.

Source: NCBI Gene 23054 — RefSeq curated summary.

At a glance

• GWAS associations: 21
• Clinical variants (ClinVar): 307 total
• MANE Select transcript: NM_014071

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15936
Approved symbol	NCOA6
Name	nuclear receptor coactivator 6
Location	20q11.22
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0181, RAP250, ASC2, AIB3, PRIP, TRBP, NRC
Ensembl gene	ENSG00000198646
Ensembl biotype	protein_coding
OMIM	605299
Entrez	23054

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 14 protein_coding, 3 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000359003, ENST00000374796, ENST00000434040, ENST00000471897, ENST00000593786, ENST00000612493, ENST00000616167, ENST00000626057, ENST00000628752, ENST00000887755, ENST00000887756, ENST00000887757, ENST00000931651, ENST00000931652, ENST00000931653, ENST00000931654, ENST00000931655, ENST00000931656

RefSeq mRNA: 3 — MANE Select: NM_014071 NM_001242539, NM_001318240, NM_014071

CCDS: CCDS13241, CCDS74720

Canonical transcript exons

ENST00000359003 — 15 exons

Exon	Start	End
ENSE00000860137	34758805	34758933
ENSE00001048960	34768464	34768586
ENSE00001048962	34776293	34776448
ENSE00001110012	34792450	34792563
ENSE00001311630	34782121	34782404
ENSE00001610915	34746807	34746928
ENSE00001633473	34740363	34743341
ENSE00001670104	34732559	34732595
ENSE00001698987	34714774	34715365
ENSE00001756539	34736690	34736758
ENSE00001771746	34749403	34750519
ENSE00001793538	34754722	34754868
ENSE00001923143	34825472	34825651
ENSE00002711149	34757220	34758104
ENSE00003525215	34727259	34727407

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 97.19.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.7775 / max 163.6229, expressed in 1787 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
187001	10.1545	1773
187000	1.1677	667
187002	0.4380	244
186995	0.3082	123
209088	0.2742	106
186994	0.2741	93
209089	0.1608	46

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	97.19	gold quality
cortical plate	UBERON:0005343	96.40	gold quality
oocyte	CL:0000023	96.13	gold quality
ganglionic eminence	UBERON:0004023	95.23	gold quality
tibia	UBERON:0000979	94.16	gold quality
epithelium of nasopharynx	UBERON:0001951	93.95	gold quality
gingival epithelium	UBERON:0001949	93.92	gold quality
parietal pleura	UBERON:0002400	93.86	gold quality
pancreatic ductal cell	CL:0002079	93.81	gold quality
visceral pleura	UBERON:0002401	93.67	gold quality
ventricular zone	UBERON:0003053	93.66	gold quality
urethra	UBERON:0000057	93.64	gold quality
pleura	UBERON:0000977	93.63	gold quality
saphenous vein	UBERON:0007318	93.33	gold quality
jejunal mucosa	UBERON:0000399	92.96	gold quality
hair follicle	UBERON:0002073	92.64	gold quality
gingiva	UBERON:0001828	92.57	gold quality
lower esophagus mucosa	UBERON:0035834	92.15	gold quality
upper leg skin	UBERON:0004262	92.11	gold quality
thymus	UBERON:0002370	92.04	gold quality
palpebral conjunctiva	UBERON:0001812	91.99	gold quality
embryo	UBERON:0000922	91.96	gold quality
pigmented layer of retina	UBERON:0001782	91.81	gold quality
seminal vesicle	UBERON:0000998	91.75	gold quality
penis	UBERON:0000989	91.73	gold quality
CA1 field of hippocampus	UBERON:0003881	91.73	gold quality
cerebellar vermis	UBERON:0004720	91.54	gold quality
tongue squamous epithelium	UBERON:0006919	91.33	gold quality
squamous epithelium	UBERON:0006914	91.22	gold quality
mucosa of transverse colon	UBERON:0004991	91.16	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.82

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

5 targets.

Target	Regulation
CYP2C9	Unknown
CYP3A4	Unknown
FOS	Activation
GREB1	Activation
HSF1	Activation

Upstream regulators (CollecTRI, top): ATF2, FOXC1, NR1H3, NR1I2

miRNA regulators (miRDB)

28 targeting NCOA6, 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-4803	99.98	71.99	3117
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-6762-3P	99.66	66.94	1188
HSA-MIR-5197-5P	99.64	69.08	1494
HSA-MIR-802	99.61	67.70	1254
HSA-MIR-3923	99.52	69.21	446
HSA-MIR-4437	99.52	65.29	1266
HSA-MIR-4325	99.49	72.20	1342
HSA-MIR-377-3P	99.37	70.18	1905
HSA-MIR-1253	99.12	67.08	1688
HSA-MIR-8066	99.05	68.66	1532
HSA-MIR-302F	98.44	69.02	1776
HSA-MIR-653-3P	98.31	67.71	1542
HSA-MIR-211-3P	98.14	66.77	1052
HSA-MIR-3620-3P	97.78	64.88	772
HSA-MIR-376A-5P	97.70	65.61	863
HSA-MIR-4637	97.69	68.14	632
HSA-MIR-6888-5P	95.89	63.78	831
HSA-MIR-4683	95.29	65.98	631

Literature-anchored findings (GeneRIF, showing 22)

• we show that ASC-2 belongs to a steady-state complex of approximately 2 MDa (ASC-2 complex [ASCOM]) in HeLa nuclei. ASCOM contains retinoblastoma-binding protein RBQ-3, alpha/beta-tubulins, and trithorax group proteins ALR-1, ALR-2, HALR, and ASH2. (PMID:12482968)
• The activation of DNA-PK in the absence of DNA ends by the coactivator TRBP suggests a novel mechanism of coactivator-stimulated DNA-PK phosphorylation in transcriptional regulation. (PMID:12519782)
• interacts with and stimulates its associated DNA-dependent protein kinase (PMID:12519782)
• ASC-2 is a physiologically important transcriptional coactivator of LXRs and demonstrate its pivotal role in the liver lipid metabolism (PMID:12724417)
• ASC-2 appears to contain at least three distinct nuclear receptor interaction domains; also, Rb and ASC-2 have roles in androgen receptor transactivation (PMID:14645241)
• ASC-2 has a role in inducing target gene transcription during granulocytic differentiation through binding to ATF2 (PMID:14734562)
• results suggest that ASC-2 is a novel coactivator for HSF1 and heat shock stress may contribute to the strong active transcription complex through sequential recruitment of HSF1 and ASC-2. (PMID:14960326)
• ASC-2 is a bona fide coactivator of the xenobiotic nuclear receptor CAR and mediate the specific xenobiotic response by CAR in vivo. (PMID:15764585)
• The retinoid x receptor does not interact with the NR box-1 of ASC-2, but functions as an allosteric activator of LXR binding to NR box-2 of ASC-2. (PMID:18031289)
• interaction between RAP250, Smad2, and Smad3 constitutes an important bridging mechanism linking LXR and TGF-beta signaling pathways. (PMID:18263591)
• AIB3 contributes to the maintenance of beta-cell function in nondiabetic children and regulates gene expression in INS-1 cells. (PMID:18462265)
• The coactivator NCOA6 mediates the mechanism of the synergistic activation of the CYP2C9 gene by CAR and HNF4alpha. (PMID:18552123)
• Promoter analysis showed that PRIP acted through serum-responsive factor to regulate FOS gene expression. (PMID:19329434)
• ASCOM-MLL3 and ASCOM-MLL4 play redundant but essential roles in FXR transactivation via their histone 3 lysine 4 trimethylation activity. (PMID:19556342)
• NCOA6 is responsible for the synergistic activation of CYP2C9 by HNF4alpha and pregnane X receptor and NCOA6 differentially regulates CYP2C9 and CYP3A4 gene expression though both the genes are regulated by the same nuclear receptors. (PMID:21292004)
• diverse physiological function of NCOA6 may be mediated by multiple isoforms expressed in different tissues and localized in different subcellular compartments (PMID:21552418)
• NCOA6 associates with the GREB1 promoter and enhancer in an E2-independent manner and that NCOA6 knockout reduces chromatin looping, enhancer-promoter interactions, and basal GREB1 expression in the absence of estradiol. (PMID:31744881)
• Nuclear receptor coactivator 6 promotes HTR-8/SVneo cell invasion and migration by activating NF-kappaB-mediated MMP9 transcription. (PMID:32790097)
• Application of WES Towards Molecular Investigation of Congenital Cataracts: Identification of Novel Alleles and Genes in a Hospital-Based Cohort of South India. (PMID:33339270)
• Nuclear receptor coactivator-6 is essential for the morphological change of human uterine stromal cell decidualization via regulating actin fiber reorganization. (PMID:35384116)
• Multiomics analyses and machine learning of nuclear receptor coactivator 6 reveal its essential role in hepatocellular carcinoma. (PMID:36086920)
• Nuclear receptor coactivator 6 is a critical regulator of NLRP3 inflammasome activation and gouty arthritis. (PMID:38195836)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ncoa6	ENSDARG00000071272
mus_musculus	Ncoa6	ENSMUSG00000038369
rattus_norvegicus	Ncoa6	ENSRNOG00000018288

Protein

Protein identifiers

Nuclear receptor coactivator 6 — Q14686 (reviewed: Q14686)

Alternative names: Activating signal cointegrator 2, Amplified in breast cancer protein 3, Cancer-amplified transcriptional coactivator ASC-2, Nuclear receptor coactivator RAP250, Nuclear receptor-activating protein, 250 kDa, Peroxisome proliferator-activated receptor-interacting protein, Thyroid hormone receptor-binding protein

All UniProt accessions (4): A0A0D9SFT8, Q14686, F6M2K2, F6M2K4

UniProt curated annotations — full annotation on UniProt →

Function. Nuclear receptor coactivator that directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion. Coactivates expression in an agonist- and AF2-dependent manner. Involved in the coactivation of different nuclear receptors, such as for steroids (GR and ERs), retinoids (RARs and RXRs), thyroid hormone (TRs), vitamin D3 (VDR) and prostanoids (PPARs). Probably functions as a general coactivator, rather than just a nuclear receptor coactivator. May also be involved in the coactivation of the NF-kappa-B pathway. May coactivate expression via a remodeling of chromatin and its interaction with histone acetyltransferase proteins.

Subunit / interactions. Monomer and homodimer. Interacts with RBM39. Interacts in vitro with the basal transcription factors GTF2A and TBP, suggesting an autonomous transactivation function. Interacts with NCOA1, CRSP3, RBM14, the histone acetyltransferases EP300 and CREBBP, and with the methyltransferases NCOA6IP and PRMT2/HRMT1L1. Component of the MLL2/3 complex (also named ASCOM complex), at least composed of KMT2D/MLL2 or KMT2C/MLL3, ASH2L, RBBP5, WDR5, NCOA6, DPY30, KDM6A, PAXIP1/PTIP, PAGR1 and alpha- and beta-tubulin. Interacts with ZNF335; may enhance ligand-dependent transcriptional activation by nuclear hormone receptors.

Subcellular location. Nucleus.

Tissue specificity. Ubiquitous. Highly expressed in brain, prostate, testis and ovary; weakly expressed in lung, thymus and small intestine.

Post-translational modifications. Phosphorylated by PRKDC. Phosphorylation on Ser-884 leads to a strong decrease in binding to ESR1 and ESR2.

Domain organisation. Contains two Leu-Xaa-Xaa-Leu-Leu (LXXLL) motifs. Only motif 1 is essential for the association with nuclear receptors, while adjacent Ser-884 displays selectivity for nuclear receptors.

Miscellaneous. Frequently amplified or overexpressed in colon, breast and lung cancers.

RefSeq proteins (3): NP_001229468, NP_001305169, NP_054790* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026638	NCOA6	Family
IPR032715	NCOA6_TRADD-N	Domain

Pfam: PF13820

UniProt features (57 total): compositionally biased region 22, region of interest 14, modified residue 8, sequence variant 5, mutagenesis site 5, short sequence motif 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14686-F1	37.29	0.02

Functional residue map

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

Post-translational modifications (8): 95, 884, 1047, 1058, 1096, 1819, 1822, 2018

Mutagenesis-validated functional residues (5):

Position	Phenotype
883–894	reduced binding to thrb, rxra, esr2 and esr1.
883–884	strong increase in binding to thrb, rxra and esr2, but dramatic decrease in binding to esr1.
884–894	reduced binding to thrb, rxra, esr2 and esr1.

Function

Pathways and Gene Ontology

Reactome pathways

32 pathways

ID	Pathway
R-HSA-1368108	BMAL1:CLOCK,NPAS2 activates circadian expression
R-HSA-1989781	PPARA activates gene expression
R-HSA-2151201	Transcriptional activation of mitochondrial biogenesis
R-HSA-2426168	Activation of gene expression by SREBF (SREBP)
R-HSA-381340	Transcriptional regulation of white adipocyte differentiation
R-HSA-400206	Regulation of lipid metabolism by PPARalpha
R-HSA-5617472	Activation of anterior HOX genes in hindbrain development during early embryogenesis
R-HSA-9707564	Cytoprotection by HMOX1
R-HSA-9707616	Heme signaling
R-HSA-9772755	Formation of WDR5-containing histone-modifying complexes
R-HSA-9818564	Epigenetic regulation of gene expression by MLL3 and MLL4 complexes
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-1655829	Regulation of cholesterol biosynthesis by SREBP (SREBF)
R-HSA-1852241	Organelle biogenesis and maintenance
R-HSA-212165	Epigenetic regulation of gene expression
R-HSA-2262752	Cellular responses to stress
R-HSA-400253
R-HSA-556833	Metabolism of lipids
R-HSA-5619507	Activation of HOX genes during differentiation
R-HSA-74160	Gene expression (Transcription)
R-HSA-8953897	Cellular responses to stimuli
R-HSA-8957322	Metabolism of steroids
R-HSA-9711123	Cellular response to chemical stress
R-HSA-9843745	Adipogenesis

MSigDB gene sets: 213 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, REACTOME_TRANSCRIPTIONAL_REGULATION_OF_WHITE_ADIPOCYTE_DIFFERENTIATION, E2F_Q4_01, NIKOLSKY_BREAST_CANCER_20Q11_AMPLICON, TATTATA_MIR374, TGACCTY_ERR1_Q2, AP2_Q3, GTACAGG_MIR486, SP1_Q2_01, INGRAM_SHH_TARGETS_UP, TGTGTGA_MIR377, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_DN, SCHAEFFER_PROSTATE_DEVELOPMENT_AND_CANCER_BOX4_UP, GOBP_DNA_DAMAGE_RESPONSE, GOBP_DNA_TEMPLATED_TRANSCRIPTION_INITIATION

GO Biological Process (8): DNA-templated transcription initiation (GO:0006352), DNA damage response (GO:0006974), brain development (GO:0007420), heart development (GO:0007507), response to hormone (GO:0009725), myeloid cell differentiation (GO:0030099), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944)

GO Molecular Function (7): chromatin binding (GO:0003682), transcription coactivator activity (GO:0003713), enzyme binding (GO:0019899), nuclear estrogen receptor binding (GO:0030331), nuclear retinoid X receptor binding (GO:0046965), nuclear thyroid hormone receptor binding (GO:0046966), protein binding (GO:0005515)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), cytosol (GO:0005829), histone methyltransferase complex (GO:0035097), MLL3/4 complex (GO:0044666)

Reactome top-level categories

Rollup of top-13 pathways:

Category	Pathways
Circadian clock	3
Epigenetic regulation by WDR5-containing histone modifying complexes	2
Regulation of lipid metabolism by PPARalpha	1
Mitochondrial biogenesis	1
Regulation of cholesterol biosynthesis by SREBP (SREBF)	1
Adipogenesis	1
Metabolism of lipids	1
Activation of HOX genes during differentiation	1
Cellular response to chemical stress	1
Cellular responses to stress	1
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1
Organelle biogenesis and maintenance	1
Metabolism of steroids	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA-templated transcription	2
animal organ development	2
positive regulation of DNA-templated transcription	2
binding	2
nuclear receptor binding	2
cellular anatomical structure	2
RNA biosynthetic process	1
cellular response to stress	1
central nervous system development	1
head development	1
circulatory system development	1
response to endogenous stimulus	1
response to chemical	1
hemopoiesis	1
cell differentiation	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
transcription coregulator activity	1
protein binding	1
nuclear retinoic acid receptor binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
protein-containing complex	1
cytoplasm	1
nucleoplasm	1
methyltransferase complex	1
nuclear protein-containing complex	1
histone methyltransferase complex	1

Protein interactions and networks

STRING

2731 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NCOA6	PAXIP1	Q6ZW49	997
NCOA6	KMT2C	Q8NEZ4	995
NCOA6	KDM6A	O15550	991
NCOA6	TGS1	Q96RS0	946
NCOA6	RBBP5	Q15291	946
NCOA6	ASH2L	Q9UBL3	940
NCOA6	WDR5	P61964	930
NCOA6	DPY30	Q9C005	921
NCOA6	PAGR1	Q9BTK6	862
NCOA6	PPARG	P37231	852
NCOA6	RBM14	Q96PK6	765
NCOA6	SETD1A	O15047	738
NCOA6	MED1	Q15648	733
NCOA6	KMT2D	O14686	722
NCOA6	CREBBP	Q92793	710

IntAct

117 interactions, top by confidence:

A	B	Type	Score
RBBP5	WDR5	psi-mi:“MI:0914”(association)	0.960
ASH2L	WDR5	psi-mi:“MI:0914”(association)	0.950
ASH2L	NCOA6	psi-mi:“MI:0914”(association)	0.930
NCOA6	ASH2L	psi-mi:“MI:0915”(physical association)	0.930
NCOA6	WDR5	psi-mi:“MI:0914”(association)	0.920
WDR5	NCOA6	psi-mi:“MI:0915”(physical association)	0.920
WDR5	KMT2D	psi-mi:“MI:0914”(association)	0.910
PAXIP1	WDR5	psi-mi:“MI:0914”(association)	0.900
RBBP5	NCOA6	psi-mi:“MI:0914”(association)	0.890
NCOA6	RBBP5	psi-mi:“MI:0914”(association)	0.890
ASH2L	KMT2D	psi-mi:“MI:0403”(colocalization)	0.890
ASH2L	KMT2D	psi-mi:“MI:0914”(association)	0.890
RBBP5	KMT2D	psi-mi:“MI:0914”(association)	0.840
KMT2C	NCOA6	psi-mi:“MI:0915”(physical association)	0.830
KMT2C	NCOA6	psi-mi:“MI:0914”(association)	0.830
PAXIP1	NCOA6	psi-mi:“MI:0914”(association)	0.790
KMT2B	NCOA6	psi-mi:“MI:0915”(physical association)	0.760
WDR5	MEN1	psi-mi:“MI:0914”(association)	0.710
TP53	WDR5	psi-mi:“MI:0914”(association)	0.690
PAGR1	KMT2D	psi-mi:“MI:0914”(association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640

BioGRID (311): NCOA6 (Affinity Capture-MS), THRA (Reconstituted Complex), ESR1 (Reconstituted Complex), RXRA (Reconstituted Complex), NCOA6 (Protein-peptide), NCOA6 (Reconstituted Complex), NCOA6 (Affinity Capture-Western), ASH2L (Affinity Capture-Western), RBBP5 (Affinity Capture-Western), WDR5 (Affinity Capture-Western), HCFC1 (Affinity Capture-Western), NCOA6 (Protein-peptide), NCOA6 (Affinity Capture-MS), NCOA1 (Reconstituted Complex), NCOA1 (Two-hybrid)

ESM2 similar proteins: A0A0R4IBL7, A3RK74, A4L7N3, A5D7F6, B2RWS6, B5DE09, E1BPQ1, G3V7R4, O00512, O43524, P11420, P45481, P78364, Q09472, Q12778, Q13227, Q14686, Q15596, Q17BA4, Q61026, Q64028, Q66JJ0, Q67FY2, Q6AI39, Q6JHU9, Q6T264, Q7ZUK7, Q810W5, Q86UU0, Q8CHH5, Q8CHP6, Q8IXK0, Q8IZL2, Q921N8, Q924H2, Q92585, Q92793, Q961D9, Q96JK9, Q96RN5

Diamond homologs: Q14686, Q9JL19, Q9JLI4

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
NCOA6	“up-regulates quantity by expression”	GREB1	“transcriptional regulation”
MAPK1	“up-regulates activity”	NCOA6	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 66 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
Formation of WDR5-containing histone-modifying complexes	13	65.1×	1e-18
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	5	63.4×	3e-07
Activation of HOX genes during differentiation	6	49.7×	5e-08
Deactivation of the beta-catenin transactivating complex	11	48.4×	3e-14
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	12	44.6×	4e-15
SUMOylation of intracellular receptors	7	44.4×	6e-09
FOXO-mediated transcription	6	38.0×	2e-07
Nuclear Receptor transcription pathway	8	30.2×	6e-09

GO biological processes:

GO term	Partners	Fold	FDR
retinoic acid receptor signaling pathway	5	53.1×	4e-06
transcription initiation-coupled chromatin remodeling	6	37.7×	2e-06
mRNA transcription by RNA polymerase II	6	32.5×	4e-06
positive regulation of miRNA transcription	6	28.6×	7e-06
negative regulation of osteoblast differentiation	5	24.2×	1e-04
somatic stem cell population maintenance	5	20.3×	2e-04
negative regulation of cell growth	5	11.8×	2e-03
chromatin remodeling	9	10.8×	1e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	240
Likely benign	17
Benign	13

Top pathogenic / likely-pathogenic (0)

SpliceAI

4236 predictions. Top by Δscore:

Variant	Effect	Δscore
20:34704509:CCAGG:C	donor_loss	1.0000
20:34704511:AGGTG:A	donor_loss	1.0000
20:34704513:G:C	donor_loss	1.0000
20:34708859:GCCGG:G	donor_gain	1.0000
20:34709523:GG:G	donor_gain	1.0000
20:34709524:GG:G	donor_gain	1.0000
20:34710056:A:AG	acceptor_gain	1.0000
20:34710056:AG:A	acceptor_gain	1.0000
20:34710056:AGG:A	acceptor_gain	1.0000
20:34710057:G:GG	acceptor_gain	1.0000
20:34710057:GG:G	acceptor_gain	1.0000
20:34710057:GGG:G	acceptor_gain	1.0000
20:34715361:TATGT:T	acceptor_gain	1.0000
20:34715363:TGT:T	acceptor_gain	1.0000
20:34715364:GT:G	acceptor_gain	1.0000
20:34715366:C:CC	acceptor_gain	1.0000
20:34736684:CCTTA:C	donor_loss	1.0000
20:34736685:CTTA:C	donor_loss	1.0000
20:34736686:TTACC:T	donor_loss	1.0000
20:34736687:TA:T	donor_loss	1.0000
20:34736688:A:AG	donor_loss	1.0000
20:34736754:CGGGG:C	acceptor_gain	1.0000
20:34736757:GG:G	acceptor_gain	1.0000
20:34736759:C:CC	acceptor_gain	1.0000
20:34736765:C:CT	acceptor_gain	1.0000
20:34736766:A:T	acceptor_gain	1.0000
20:34746805:ACCTG:A	donor_loss	1.0000
20:34746806:CCTG:C	donor_loss	1.0000
20:34746838:AGGG:A	donor_gain	1.0000
20:34746862:T:TA	donor_gain	1.0000

AlphaMissense

13554 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:34742417:A:G	L1280S	1.000
20:34742504:A:G	L1251P	1.000
20:34742513:A:C	I1248R	1.000
20:34742513:A:T	I1248K	1.000
20:34742525:A:G	L1244P	1.000
20:34742525:A:T	L1244H	1.000
20:34742540:A:G	L1239P	1.000
20:34742540:A:T	L1239Q	1.000
20:34742546:A:C	I1237S	1.000
20:34742546:A:G	I1237T	1.000
20:34742603:C:G	R1218T	1.000
20:34742608:G:C	S1216R	1.000
20:34742608:G:T	S1216R	1.000
20:34742610:T:G	S1216R	1.000
20:34742614:T:A	R1214S	1.000
20:34742614:T:G	R1214S	1.000
20:34742615:C:G	R1214T	1.000
20:34742617:G:C	N1213K	1.000
20:34742617:G:T	N1213K	1.000
20:34749523:A:C	L891W	1.000
20:34749523:A:G	L891S	1.000
20:34749526:A:G	L890S	1.000
20:34749535:A:G	L887S	1.000
20:34749543:G:C	S884R	1.000
20:34749543:G:T	S884R	1.000
20:34749545:T:G	S884R	1.000
20:34749550:A:G	L882P	1.000
20:34749556:A:T	V880D	1.000
20:34776304:A:T	V127D	1.000
20:34776308:A:G	S126P	1.000

dbSNP variants (sampled 300 via entrez): RS1000011722 (20:34807858 G>C), RS1000017610 (20:34823028 G>A), RS1000048148 (20:34807664 TA>T), RS1000054498 (20:34763116 G>A,C), RS1000074152 (20:34754274 A>G), RS1000089382 (20:34762451 G>A), RS1000124453 (20:34781239 C>T), RS1000137159 (20:34744131 T>A,C), RS1000149823 (20:34800010 C>G,T), RS1000156815 (20:34785128 C>T), RS1000332881 (20:34787947 A>C,G), RS1000348135 (20:34769904 T>C), RS1000350587 (20:34739843 CTTTGT>C), RS1000377981 (20:34788163 T>C), RS1000395377 (20:34794559 A>T)

Disease associations

OMIM: gene MIM:605299 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

21 associations (top):

Study	Trait	p-value
GCST004067_137	Hip circumference adjusted for BMI	2.000000e-07
GCST004067_2	Hip circumference adjusted for BMI	8.000000e-08
GCST004067_94	Hip circumference adjusted for BMI	9.000000e-13
GCST005196_243	Coronary artery disease	2.000000e-09
GCST005956_31	Waist-to-hip ratio adjusted for BMI	8.000000e-08
GCST005958_16	Waist-to-hip ratio adjusted for BMI (age >50)	6.000000e-06
GCST005962_40	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	3.000000e-08
GCST006948_26	Feeling nervous	2.000000e-08
GCST008103_149	Bipolar disorder	3.000000e-06
GCST008163_266	Height	1.000000e-06
GCST008163_447	Height	4.000000e-06
GCST008163_533	Height	1.000000e-10
GCST008745_28	Estimated glomerular filtration rate in non-diabetics	2.000000e-24
GCST008972_241	Urate levels	4.000000e-09
GCST010135_33	Oily fish consumption	7.000000e-09
GCST010140_23	Pork consumption	7.000000e-09
GCST010142_10	Fish- and plant-related diet	8.000000e-12
GCST012227_1080	Hip circumference adjusted for BMI	4.000000e-09
GCST90000025_642	Appendicular lean mass	3.000000e-20
GCST90020028_1515	Hip circumference adjusted for BMI	1.000000e-08
GCST90020028_1625	Hip circumference adjusted for BMI	5.000000e-10

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0008039	BMI-adjusted hip circumference
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0009597	feeling nervous measurement
EFO:0004531	urate measurement
EFO:0008111	diet measurement
EFO:0004980	appendicular lean mass

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects cotreatment, increases expression, affects binding, increases reaction	4
bisphenol A	increases reaction, affects cotreatment, decreases expression, affects binding, affects folding (+1 more)	3
Cadmium Chloride	increases expression, decreases expression, increases abundance	3
Tretinoin	decreases expression	2
Metribolone	increases reaction, increases expression, affects binding, affects folding	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
androstan-3-ol	affects binding, decreases reaction, increases reaction, increases activity	1
dicrotophos	increases expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
arsenite	affects binding, decreases reaction	1
1,4-bis(2-(3,5-dichloropyridyloxy))benzene	affects binding, increases activity, increases reaction, decreases reaction, increases expression	1
aflatoxin B2	decreases methylation	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	affects expression	1
tamibarotene	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
GW 1929	affects binding, increases reaction	1
bisphenol AF	affects binding, affects folding, decreases reaction	1
Temozolomide	decreases expression	1
Norethindrone Acetate	affects cotreatment, increases expression	1
Acetaminophen	increases response to substance, increases reaction	1
Atrazine	decreases expression	1
Cadmium	decreases expression, increases abundance	1
Carbamazepine	affects expression	1
Cisplatin	decreases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Diethylstilbestrol	affects binding, increases reaction	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Formaldehyde	decreases expression	1

Clinical trials (associated diseases)

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