SET

Summary

SET (SET nuclear proto-oncogene, HGNC:10760) is a protein-coding gene on chromosome 9q34.11, encoding Protein SET (Q01105). Multitasking protein, involved in apoptosis, transcription, nucleosome assembly and histone chaperoning. It is a selective cancer dependency (DepMap: 11.1% of cell lines) and haploinsufficient (ClinGen: sufficient evidence).

The protein encoded by this gene inhibits acetylation of nucleosomes, especially histone H4, by histone acetylases (HAT). This inhibition is most likely accomplished by masking histone lysines from being acetylated, and the consequence is to silence HAT-dependent transcription. The encoded protein is part of a complex localized to the endoplasmic reticulum but is found in the nucleus and inhibits apoptosis following attack by cytotoxic T lymphocytes. This protein can also enhance DNA replication of the adenovirus genome. Several transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 6418 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual disability (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 140 total — 22 pathogenic, 16 likely-pathogenic
• Regional missense constraint (gnomAD): 1 of 3 regions constrained (≈72% of expected missense variation)
• GTEx eGene: eQTL in 9 tissues, sQTL in 1 (q < 0.05)
• Phenotypes (HPO): 41
• ChEMBL bioactivity: 1 clinical-phase molecule tested; no curated mechanism-of-action drug
• Cancer dependency (DepMap): dependent in 11.1% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.17 (highly constrained)
• MANE Select transcript: NM_003011
• Interaction hub: 1,923 STRING partners (top 8% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10760
Approved symbol	SET
Name	SET nuclear proto-oncogene
Location	9q34.11
Locus type	gene with protein product
Status	Approved
Aliases	PHAPII, 2PP2A, IPP2A2, TAF-IBETA, IGAAD, TAF-I
Ensembl gene	ENSG00000119335
Ensembl biotype	protein_coding
OMIM	600960
Entrez	6418

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 15 protein_coding, 3 protein_coding_CDS_not_defined, 3 retained_intron, 3 nonsense_mediated_decay

MANE Select: ENST00000322030

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 2: 4, TSL 3: 1, TSL 5: 2

ENST00000322030, ENST00000372686, ENST00000372688, ENST00000372692, ENST00000409104, ENST00000466009, ENST00000477806, ENST00000480217, ENST00000480536, ENST00000485056, ENST00000685073, ENST00000686568, ENST00000686840, ENST00000691158, ENST00000878517, ENST00000878518, ENST00000921998, ENST00000921999, ENST00000968516, ENST00001085967, ENST00001085968, ENST00001103326, ENST00001114476, ENST00001121157

RefSeq mRNA: 5 — MANE Select: NM_003011 NM_001122821, NM_001248000, NM_001248001, NM_001374326, NM_003011

CCDS: CCDS48037, CCDS59149, CCDS59150, CCDS6907

Canonical transcript exons

ENST00000322030 — 8 exons

Exon	Start	End
ENSE00001052379	128693896	128694042
ENSE00001243124	128689222	128689655
ENSE00001921819	128694641	128696396
ENSE00003488572	128693638	128693808
ENSE00003513201	128692662	128692765
ENSE00003548688	128691170	128691227
ENSE00003555536	128691858	128692000
ENSE00003597730	128692868	128692981

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.60.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 313.1474 / max 2545.0260, expressed in 1828 samples.

Highest expression (Bgee): ganglionic eminence, endometrium epithelium, calcaneal tendon, cortical plate, embryo.

Genetic regulation across tissues (GTEx eQTL / sQTL)

SET is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 9 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

10 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Brain Cerebellar Hemisphere	eqtl	2.2e-04	+1.02	9:128353903:C:T
Cells Cultured fibroblasts	eqtl	1.1e-03	+0.24	9:129018162:A:G
Colon Transverse	sqtl	1.7e-02	+0.55	9:128036060:G:A
Nerve Tibial	eqtl	1.7e-02	-0.26	9:129203754:G:C
Thyroid	eqtl	1.9e-02	+0.22	9:128583406:A:C
Colon Transverse	eqtl	3.5e-02	+0.30	9:128756141:T:C
Brain Nucleus accumbens basal ganglia	eqtl	3.6e-02	+0.68	9:128124627:A:G
Testis	eqtl	4.1e-02	-0.21	9:128588767:G:A
Adipose Visceral Omentum	eqtl	4.4e-02	-0.15	9:128007464:G:A
Brain Hypothalamus	eqtl	4.5e-02	+0.53	9:129019000:C:T

FANTOM5 promoters

showing 10 of 14 alternative TSS:

Promoter ID	TPM avg	Samples expressed
98826	280.9729	1828
98828	7.6702	1728
98827	7.2756	1711
98820	4.5293	1108
98829	3.2502	1260
98823	3.1807	1251
98822	3.1077	832
98819	1.8259	861
98817	0.5173	247
98824	0.2088	96

Top tissues by expression

showing 100 of 295 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
ganglionic eminence	UBERON:0004023	99.60	gold quality
endometrium epithelium	UBERON:0004811	99.59	gold quality
calcaneal tendon	UBERON:0003701	99.58	gold quality
cortical plate	UBERON:0005343	99.58	gold quality
embryo	UBERON:0000922	99.54	gold quality
ventricular zone	UBERON:0003053	99.51	gold quality
epithelium of nasopharynx	UBERON:0001951	99.21	gold quality
colonic epithelium	UBERON:0000397	99.17	gold quality
endometrium	UBERON:0001295	99.17	gold quality
germinal epithelium of ovary	UBERON:0001304	99.16	gold quality
palpebral conjunctiva	UBERON:0001812	99.15	gold quality
lymph node	UBERON:0000029	99.13	gold quality
cranial nerve II	UBERON:0000941	99.10	gold quality
parietal pleura	UBERON:0002400	99.08	gold quality
medial globus pallidus	UBERON:0002477	99.07	gold quality
corpus callosum	UBERON:0002336	99.06	gold quality
tonsil	UBERON:0002372	99.03	gold quality
islet of Langerhans	UBERON:0000006	99.02	gold quality
pleura	UBERON:0000977	98.96	gold quality
vermiform appendix	UBERON:0001154	98.93	gold quality
upper arm skin	UBERON:0004263	98.93	gold quality
monocyte	CL:0000576	98.91	gold quality
smooth muscle tissue	UBERON:0001135	98.90	gold quality
globus pallidus	UBERON:0001875	98.90	gold quality
mononuclear cell	CL:0000842	98.87	gold quality
leukocyte	CL:0000738	98.86	gold quality
caecum	UBERON:0001153	98.86	gold quality
visceral pleura	UBERON:0002401	98.86	gold quality
rectum	UBERON:0001052	98.84	gold quality
gall bladder	UBERON:0002110	98.84	gold quality
nipple	UBERON:0002030	98.80	gold quality
thymus	UBERON:0002370	98.78	gold quality
pancreas	UBERON:0001264	98.76	gold quality
tibia	UBERON:0000979	98.75	gold quality
secondary oocyte	CL:0000655	98.74	gold quality
nasal cavity epithelium	UBERON:0005384	98.74	gold quality
hair follicle	UBERON:0002073	98.72	gold quality
adrenal tissue	UBERON:0018303	98.71	gold quality
uterus	UBERON:0000995	98.70	gold quality
cartilage tissue	UBERON:0002418	98.68	gold quality
pylorus	UBERON:0001166	98.66	gold quality
urinary bladder	UBERON:0001255	98.66	gold quality
nasal cavity mucosa	UBERON:0001826	98.65	gold quality
ovary	UBERON:0000992	98.63	gold quality
body of pancreas	UBERON:0001150	98.62	gold quality
stromal cell of endometrium	CL:0002255	98.59	gold quality
epithelium of mammary gland	UBERON:0003244	98.57	gold quality
penis	UBERON:0000989	98.56	gold quality
mammary gland	UBERON:0001911	98.56	gold quality
thoracic mammary gland	UBERON:0005200	98.56	gold quality
esophagus squamous epithelium	UBERON:0006920	98.56	gold quality
bone marrow cell	CL:0002092	98.54	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.54	gold quality
female reproductive system	UBERON:0000474	98.53	gold quality
trabecular bone tissue	UBERON:0002483	98.53	gold quality
left ovary	UBERON:0002119	98.51	gold quality
mammary duct	UBERON:0001765	98.49	gold quality
spinal cord	UBERON:0002240	98.48	gold quality
type B pancreatic cell	CL:0000169	98.46	gold quality
placenta	UBERON:0001987	98.46	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.45	gold quality
mammalian vulva	UBERON:0000997	98.43	gold quality
ectocervix	UBERON:0012249	98.43	gold quality
cardia of stomach	UBERON:0001162	98.42	gold quality
endocervix	UBERON:0000458	98.37	gold quality
bone marrow	UBERON:0002371	98.37	gold quality
granulocyte	CL:0000094	98.35	gold quality
tendon	UBERON:0000043	98.35	gold quality
right ovary	UBERON:0002118	98.35	gold quality
orbitofrontal cortex	UBERON:0004167	98.35	gold quality
body of uterus	UBERON:0009853	98.35	gold quality
uterine cervix	UBERON:0000002	98.34	gold quality
renal medulla	UBERON:0000362	98.34	gold quality
squamous epithelium	UBERON:0006914	98.34	gold quality
esophagus mucosa	UBERON:0002469	98.33	gold quality
epithelium of esophagus	UBERON:0001976	98.32	gold quality
ileal mucosa	UBERON:0000331	98.31	gold quality
middle temporal gyrus	UBERON:0002771	98.31	gold quality
inferior vagus X ganglion	UBERON:0005363	98.30	gold quality
skin of hip	UBERON:0001554	98.29	gold quality
cerebellar vermis	UBERON:0004720	98.29	gold quality
myometrium	UBERON:0001296	98.28	gold quality
zone of skin	UBERON:0000014	98.27	gold quality
entorhinal cortex	UBERON:0002728	98.24	gold quality
skin of abdomen	UBERON:0001416	98.23	gold quality
right lung	UBERON:0002167	98.23	gold quality
seminal vesicle	UBERON:0000998	98.21	gold quality
olfactory bulb	UBERON:0002264	98.21	gold quality
left uterine tube	UBERON:0001303	98.19	gold quality
skin of leg	UBERON:0001511	98.19	gold quality
epithelium of bronchus	UBERON:0002031	98.19	gold quality
bronchus	UBERON:0002185	98.19	gold quality
subthalamic nucleus	UBERON:0001906	98.18	gold quality
pigmented layer of retina	UBERON:0001782	98.17	gold quality
lateral globus pallidus	UBERON:0002476	98.17	gold quality
pharyngeal mucosa	UBERON:0000355	98.15	gold quality
esophagus	UBERON:0001043	98.15	gold quality
substantia nigra	UBERON:0002038	98.15	gold quality
metanephros	UBERON:0000081	98.14	gold quality
saliva-secreting gland	UBERON:0001044	98.14	gold quality

Single-cell (SCXA)

Detected in 19 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-GEOD-89232	yes	6280.66
E-GEOD-111727	yes	1449.83
E-MTAB-10042	yes	11.22
E-CURD-122	yes	10.53
E-MTAB-10553	yes	7.20
E-MTAB-9801	yes	6.39
E-MTAB-6379	no	4913.79
E-MTAB-10018	no	2639.83
E-MTAB-9689	no	2231.31
E-MTAB-8271	no	2035.38
E-HCAD-13	no	1456.09
E-MTAB-8205	no	1379.21
E-MTAB-9154	no	1246.55
E-MTAB-5061	no	1193.80
E-MTAB-6108	no	1034.54

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 78 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Tonsil	tissue	270.7	high
Lymph node	tissue	249.4	high
Thymus	tissue	235.6
Bone marrow	tissue	204.2	high
Urinary bladder	tissue	185.3	high
Placenta	tissue	172.4	high
Thyroid gland	tissue	169.5	high
Appendix	tissue	165.8	high
Skeletal muscle	tissue	160.0	medium
Esophagus	tissue	156.3	high
Ovary	tissue	151.0	medium
Spleen	tissue	146.8	high
Rectum	tissue	145.9	high
Pancreas	tissue	144.0	high
Endometrium 1	tissue	141.4	high
Breast	tissue	138.9	high
Smooth muscle	tissue	136.0	medium
Colon	tissue	135.4	high
Fallopian tube	tissue	134.7	high
Liver	tissue	128.1	medium
Parathyroid gland	tissue	124.3	high
Cervix	tissue	124.2	high
Heart muscle	tissue	124.1	low
Stomach 1	tissue	122.6	high
Skin 1	tissue	120.5	high
Kidney	tissue	120.2	high
Gallbladder	tissue	118.2	high
Postcentral gyrus	tissue	118.2
Hippocampus	tissue	116.0	high
Locus coeruleus	tissue	114.3
Seminal vesicle	tissue	114.0	high
Small intestine	tissue	113.2	high
Prostate	tissue	112.4	medium
Salivary gland	tissue	112.2	high
Nucleus accumbens	tissue	111.3
Choroid plexus	tissue	110.4
Lung	tissue	110.2	medium
Adipose tissue	tissue	108.1	medium
Duodenum	tissue	106.0	high
Tongue	tissue	104.7
Adrenal gland	tissue	103.2	high
Testis	tissue	86.1	high
Retina	tissue	85.3
Vagina	tissue	82.4	high
Pituitary gland	tissue	43.1
Epididymis	tissue	41.4	high
Olfactory bulb	tissue	0.5
Cerebral cortex	tissue	0.4	medium
Putamen	tissue	0.4
Amygdala	tissue	0.4
Corpus callosum	tissue	0.4
Septum	tissue	0.4
Retrosplenial cortex	tissue	0.4
Prefrontal cortex	tissue	0.3
Midbrain	tissue	0.3
Medulla oblongata	tissue	0.3
Hypothalamus	tissue	0.3
Substantia nigra	tissue	0.3
Spinal cord	tissue	0.3
Hippocampal formation	tissue	0.3

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Temporal white matter (194.2), Cervical spinal cord, ventral horn (192.4), Occipital cortex (white matter) (177.7), Globus pallidus, internus (172.1), Cerebellar white matter (165.2).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): KMT2A, SERTAD1, SPI1, ZNF331

miRNA regulators (miRDB)

Targeting SET by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 155 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
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-188-3P	100.00	68.76	1240
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4282	99.99	75.36	6408
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163

Functional genomics

gnomAD constraint: pLI 1, LOEUF 0.167, missense Z 3.21 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000322030 splits into 3 regions with different missense tolerance; 1 is missense-constrained (≈72% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
9:128,689,583–128,689,643	34 / 29.5	1.15	no
9:128,689,644–128,693,904	59 / 237.2	0.25	yes (p 5.8e-31)
9:128,693,905–128,694,661	44 / 63.0	0.70	no
ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map
DepMap (CRISPR cell-line fitness): dependent in 11.1% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): Farage (-1.097), SNU-C1 (-1.003), KMS-34 (-0.882), DBTRG-05MG (-0.851), C8166 (-0.848), UM-UC-6 (-0.801), TMK-1 (-0.801), LN-340 (-0.799), NCI-H2126 (-0.785), YCUB-2 (-0.777), NCI-H1993 (-0.758), SW 626 (-0.753), SK-MEL-19 (-0.753), Panc 05.04 (-0.716), NH-12 (-0.716).

Literature-anchored findings (GeneRIF, showing 40)

• Our detailed characterization showed that the SET protein formed a complex with Cdk5/p35(nck5a) through its binding to p35(nck5a). (PMID:11741927)
• HMG2 interacts with the nucleosome assembly protein SET and is a target of the cytotoxic T-lymphocyte protease granzyme A. (PMID:11909973)
• role in inhibiting active demethylation of DNA, integrating DNA methylation and transcriptional silencing (PMID:11978794)
• SET protein regulates G(2)/M transition by modulating cyclin B-CDK1 activity. (PMID:12407107)
• this protein and Protein phosphatase 2A regulate androgen production by P450c17. (PMID:12444089)
• SET accomplishes inhibition of proliferation of U937 cells through the induction of the differentiation program, an effect that depends on the presence of its acidic domain. (PMID:14671643)
• Set/TAF-Ibeta and pp32 proteins have roles as transducers of chromatin signaling by integrating chromatin hypoacetylation and transcriptional repression (PMID:15136563)
• protein phosphatase inhibitor-2 is a bifunctional signaling protein with separate domains to inhibit PP1 and directly stimulate Aurora-A kinase (PMID:15173575)
• PTMA associates with SET and is involved in chromatin decondensation. (PMID:15556635)
• PCOTH is involved in growth and survival of prostate cancer cells thorough, in parts, the TAF-Ibeta pathway. (PMID:15930275)
• results suggest that SET is part of both IFN-gamma-mediated and stress-mediated cellular responses and that SET induces cell differentiation via calcium and MAPK/ERK pathways (PMID:15931263)
• the histone chaperone SET regulates CBP-mediated transcription (PMID:16061203)
• in BCR/ABL-transformed cells and CML blast crisis (CML-BC) progenitors, the phosphatase activity of the tumor suppressor PP2A is inhibited by the BCR/ABL-induced expression of the PP2A inhibitor SET (PMID:16286244)
• 4 out of 5 members of the SET complex aare highly expressed in invasive grade 3 epithelial ovarian tumors. (PMID:16823850)
• SET-mediated promoter hypoacetylation is a prerequisite for coactivation of the estrogen-responsive pS2 gene by PRMT1 (PMID:16861234)
• GzmK hydrolyzes the nucleosome assembly protein SET in its recombinant and native forms or in intact cells. Cleavage of SET by GzmK abrogates its nucleosome assembly activity. After GzmK loading, SET rapidly translocate into the nucleus and SET is cleaved (PMID:17008916)
• assembly of early viral chromatin requires both the association of SET/TAF-1beta and the release of protein VII. (PMID:17034827)
• Membrane targeting of SET stimulates cell migration in a Rac1-dependent manner. (PMID:17245428)
• TAF-Ialpha/CAN and TAF-Ibeta/CAN fusion transcripts are generated by chromosome 9q34 deletion in acute myeloid leukemia (PMID:17296573)
• the specific association among SET/TAF-Ibeta/INHAT, core histones, and double-stranded DNA is requisite for histone chaperone activity (PMID:17360516)
• SET and PARP1 remove DEK from chromatin to permit access by the transcription machinery. (PMID:17529993)
• Our results indicate that SET is imported into the nucleus through its association with impalpha3/impbeta, and that localization of SET is important in regulation of neuronal death. (PMID:17608644)
• Impairment of erythroid and megakaryocytic differentiation by a leukemia-associated and t(9;9)-derived fusion gene product, SET/TAF-IBeta-CAN/Nup214. (PMID:17620317)
• Data indicate that interactions between I(2)(PP2A) and WNV capsid result in increased PP2A activity. (PMID:17868381)
• SET expression is essential for suppressing protein phosphatase type 2A phosphatase activity that would otherwise limit NK cell antitumoral and/or antiinflammatory functions by impairing NK cell production of IFN-gamma (PMID:17875674)
• Set/TAF-Ibeta acts as a ligand-activated GR-responsive transcriptional repressor, while Set-Can does not retain physiologic responsiveness to ligand-bound glucocorticoid receptor. (PMID:18096310)
• SET-NUP214 binds in the promoter regions of specific HOXA genes, where it interacts with CRM1 and DOT1L, which may transcriptionally activate specific members of the HOXA cluster. (PMID:18299449)
• SET, a substrate of caspases, was cleaved by acidic cytosolic extract independent of caspase activation (PMID:18374643)
• TSPY and its X-encoded homologue interact with cyclin B but exert contrasting functions on cyclin-dependent kinase 1 activities. (PMID:18591933)
• These studies indicated that the TAF-Ialpha promoter is under the control of Sp1.(TAF-Ialpha ) (PMID:18809386)
• This procedure improved the resolution of the SET/TAF-Ibetacrystals from around 5.5 to 2.3 A without changing the crystallization conditions. (PMID:18931446)
• I2PP2A was identified in vitro and in situ as a ceramide-binding protein, which exhibits stereoisomer specificity and fatty acid chain length preference. (PMID:19028839)
• Cell lines LOUCY and MEGAL express the recently described SET-NUP214 fusion gene. (PMID:19166587)
• Lyn is downstream of Jak2, and Jak2 maintains activated Lyn kinase in CML through the SET-PP2A-Shp1 pathway. (PMID:19234487)
• Decreased expression of microRNA-199b increases protein levels of SET (protein phosphatase 2A inhibitor) in human choriocarcinoma. (PMID:19900756)
• crystals of template-activating factor Ibeta diffracted to 2.7 A resolution and belonged to space group P4(3)2(1)2. (PMID:20693670)
• The results of this study show that the knockdown of SET/TAF-Ibeta by si-RNA induces neuronal cell differentiation, thus implicating SET/TAF-Ibeta as a negative regulator of neuronal development. (PMID:20800572)
• granzyme B gene expression and therefore human NK-cell cytotoxicity can be regulated by the PP2A-SET interplay (PMID:21156847)
• Peptide mimetics of apoE derived from its receptor binding domain residues 130-150 bind to the SET protein, which is a potent physiological inhibitor of protein phosphatase 2A (PP2A). (PMID:21289314)
• SET is an important regulator of chromosome condensation/decondensation and disruption of the MCPH1-SET interaction might be important for the pathogenesis of primary microcephaly (PMID:21515671)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	setb	ENSDARG00000003920
mus_musculus	Set	ENSMUSG00000054766
rattus_norvegicus	Setl2	ENSRNOG00000069776

Paralogs (19): TSPY2 (ENSG00000168757), NAP1L5 (ENSG00000177432), TSPYL6 (ENSG00000178021), TSPYL5 (ENSG00000180543), TSPYL2 (ENSG00000184205), NAP1L3 (ENSG00000186310), NAP1L2 (ENSG00000186462), NAP1L1 (ENSG00000187109), TSPYL4 (ENSG00000187189), TSPYL1 (ENSG00000189241), NAP1L4 (ENSG00000205531), TSPY3 (ENSG00000228927), TSPY8 (ENSG00000229549), SETSIP (ENSG00000230667), TSPY4 (ENSG00000233803), TSPY10 (ENSG00000236424), TSPY9 (ENSG00000238074), TSPY1 (ENSG00000258992), (ENSG00000293164)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1860267) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 4 distinct phenotype terms.

Mouse phenotype (MP)	Records
open neural tube	1
decreased embryo size	1
embryonic lethality during organogenesis, complete penetrance	1
cardiac edema	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Oryza sativa Indica Group	A2XU85	100.0%	Diamond
Oryza sativa Japonica Group	Q7X7C9	100.0%	Diamond
Pongo abelii	Q5R5G8	95.9%	Diamond
Macaca fascicularis	Q9BE64	93.1%	Diamond
Arabidopsis thaliana	Q8LC68	87.2%	Diamond
Bos taurus	Q0P5N2	76.9%	Diamond
Drosophila melanogaster	P53997	64.4%	Diamond
Caenorhabditis elegans	Q18240	45.2%	Diamond
Dictyostelium discoideum	Q55ED1	37.3%	Diamond
Plasmodium falciparum FCM17/Senegal	P13825	34.3%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
SPTAN1	protein-coding	6709
DYNC2I2	protein-coding	89891
PKN3	protein-coding	29941
ZDHHC12-DT	ncRNA	100506100
ZER1	protein-coding	10444
ZDHHC12	protein-coding	84885
GLE1	protein-coding	2733

Protein

Protein identifiers

Protein SET — Q01105 (reviewed: Q01105)

Alternative names: HLA-DR-associated protein II, Inhibitor of granzyme A-activated DNase, PHAPII, Phosphatase 2A inhibitor I2PP2A, Template-activating factor I

All UniProt accessions (6): A0A0C4DFV9, A0A8I5KS71, A0A8I5KTZ2, A0A8J8YYJ1, Q01105, Q5VXV3

UniProt curated annotations — full annotation on UniProt →

Function. Multitasking protein, involved in apoptosis, transcription, nucleosome assembly and histone chaperoning. Isoform 2 anti-apoptotic activity is mediated by inhibition of the GZMA-activated DNase, NME1. In the course of cytotoxic T-lymphocyte (CTL)-induced apoptosis, GZMA cleaves SET, disrupting its binding to NME1 and releasing NME1 inhibition. Isoform 1 and isoform 2 are potent inhibitors of protein phosphatase 2A. Isoform 1 and isoform 2 inhibit EP300/CREBBP and PCAF-mediated acetylation of histones (HAT) and nucleosomes, most probably by masking the accessibility of lysines of histones to the acetylases. The predominant target for inhibition is histone H4. HAT inhibition leads to silencing of HAT-dependent transcription and prevents active demethylation of DNA. Both isoforms stimulate DNA replication of the adenovirus genome complexed with viral core proteins; however, isoform 2 specific activity is higher.

Subunit / interactions. Headphone-shaped homodimer. Isoforms 1 and 2 interact directly with each other and with ANP32A within the tripartite INHAT (inhibitor of acetyltransferases) complex. Isoform 1 and isoform 2 interact also with histones. Isoform 2 is a component of the SET complex, composed of at least ANP32A, APEX1, HMGB2, NME1, SET and TREX1, but not NME2 or TREX2. Within this complex, directly interacts with ANP32A, NME1, HMGB2 and TREX1; the interaction with ANP32A is enhanced after cleavage. Interacts with APBB1, CHTOP, SETBP1, SGO1. (Microbial infection) Interacts with herpes simplex virus 1 VP22.

Subcellular location. Cytoplasm. Cytosol. Endoplasmic reticulum. Nucleus. Nucleoplasm.

Tissue specificity. Widely expressed. Low levels in quiescent cells during serum starvation, contact inhibition or differentiation. Highly expressed in Wilms’ tumor.

Post-translational modifications. Isoform 2 is phosphorylated on Ser-15 and Ser-24. Isoform 2 is acetylated on Lys-11. Some glutamate residues are glycylated by TTLL8. This modification occurs exclusively on glutamate residues and results in a glycine chain on the gamma-carboxyl group. N-terminus of isoform 1 is methylated by METTL11A/NTM1. Mainly trimethylated. Cleaved after Lys-176 by GZMA. The cleavage inhibits its nucleosome assembly activity and disrupts the inhibition on NME1.

Disease relevance. A chromosomal aberration involving SET is found in some cases of acute undifferentiated leukemia (AUL). Translocation t(6;9)(q21;q34.1) with NUP214/CAN. Intellectual developmental disorder, autosomal dominant 58 (MRD58) [MIM:618106] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRD58 patients show delayed development, intellectual disability, language delay and speech impairment. Some patients have motor delay or incoordination, and minor dysmorphic features. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. A long alpha helix in the N-terminus mediates dimerization, while the earmuff domain is responsible for core histone and dsDNA binding. The C-terminal acidic domain mediates the inhibition of histone acetyltransferases and is required for the DNA replication stimulatory activity.

Similarity. Belongs to the nucleosome assembly protein (NAP) family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q01105-1	1, TAF-I alpha	yes
Q01105-2	2, TAF-I beta
Q01105-3	3
Q01105-4	4

RefSeq proteins (5): NP_001116293, NP_001234929, NP_001234930, NP_001361255, NP_003002* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002164	NAP	Family
IPR037231	NAP-like_sf	Homologous_superfamily

Pfam: PF00956

UniProt features (47 total): modified residue 11, helix 10, region of interest 5, strand 5, sequence variant 4, splice variant 3, compositionally biased region 3, turn 2, initiator methionine 1, chain 1, site 1, cross-link 1

Structure

Experimental structures (PDB)

3 structures by resolution:

PDB	Title	Method	Resolution (Å)
7MTO	Crystal Structure of SET/I2PP2A/TAF-1Beta core	X-RAY DIFFRACTION	1.79
2E50	Crystal structure of SET/TAF-1beta/INHAT	X-RAY DIFFRACTION	2.3
9I15	Crystal structure of SET cleaved after Asn175 by legumain	X-RAY DIFFRACTION	2.47

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q01105-F1	78.62	0.58

Human Protein Atlas

Protein class: Predicted intracellular proteins, Plasma proteins, Cancer-related genes, Disease related genes, Human disease related genes, Mental and behavioural disorders

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm; lipid droplets

Antibody reliability (HPA): IH supported · IF enhanced

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)

Position	Role
283–284	breakpoint for translocation to form set-can oncogene

Post-translational modifications (12)

Type	Positions
N,n,n-trimethylalanine	2
Phosphoserine	7, 28, 63, 15, 24
N6-acetyllysine	68, 150, 172, 11
Phosphotyrosine	146
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in ubiquitin)	154

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 8; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

8 pathways:

ID	Pathway	Evidence
R-HSA-2299718	Condensation of Prophase Chromosomes	curated
R-HSA-450520	HuR (ELAVL1) binds and stabilizes mRNA	curated
R-HSA-1640170	Cell Cycle	—
R-HSA-69278	Cell Cycle, Mitotic	—
R-HSA-68886	M Phase	—
R-HSA-8953854	Metabolism of RNA	—
R-HSA-68875	Mitotic Prophase	—
R-HSA-450531	Regulation of mRNA stability by proteins that bind AU-rich elements	—

MSigDB gene sets: 448 (showing top): MORF_MTA1, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, MORF_SMC1L1, GCM_MSN, PAL_PRMT5_TARGETS_UP, GCM_NPM1, MORF_UBE2I, MORF_HDAC1, MORF_UBE2N, MORF_RAD21, HSIAO_HOUSEKEEPING_GENES, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, LANG_MYB_FAMILY_TARGETS, MORF_HDAC2, USF_C

GO Biological Process (8): DNA replication (GO:0006260), nucleosome assembly (GO:0006334), nucleosome disassembly (GO:0006337), negative regulation of neuron apoptotic process (GO:0043524), negative regulation of DNA-templated transcription (GO:0045892), base-excision repair (GO:0006284), granzyme-mediated apoptotic signaling pathway (GO:0008626), regulation of transferase activity (GO:0051338)

GO Molecular Function (6): DNA binding (GO:0003677), chromatin binding (GO:0003682), protein phosphatase inhibitor activity (GO:0004864), protein phosphatase regulator activity (GO:0019888), histone binding (GO:0042393), protein binding (GO:0005515)

GO Cellular Component (9): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), lipid droplet (GO:0005811), cytosol (GO:0005829), protein-containing complex (GO:0032991), perinuclear region of cytoplasm (GO:0048471)

Reactome top-level categories

6 top-level categories:

Category	Pathways
Mitotic Prophase	1
Regulation of mRNA stability by proteins that bind AU-rich elements	1
Metabolism of RNA	1
M Phase	1
Cell Cycle, Mitotic	1
Cell Cycle	1

GO top-level categories

34 GO namespaces:

Category	Terms
cellular anatomical structure	5
cytoplasm	3
nucleosome organization	2
binding	2
phosphoprotein phosphatase activity	2
intracellular membrane-bounded organelle	2
DNA metabolic process	1
DNA biosynthetic process	1
chromatin organization	1
protein-DNA complex assembly	1
protein-DNA complex disassembly	1
negative regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
DNA repair	1
apoptotic signaling pathway	1
granzyme-mediated programmed cell death signaling pathway	1
transferase activity	1
regulation of catalytic activity	1
nucleic acid binding	1
phosphatase inhibitor activity	1
protein phosphatase regulator activity	1
phosphatase regulator activity	1
protein phosphatase binding	1
protein binding	1
chromosome	1
nuclear lumen	1
intracellular anatomical structure	1
endomembrane system	1
intracellular membraneless organelle	1
cellular_component	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 9 of 23 annotations. The rest are phylogenetic / computational / electronic (IEA).

9 experimentally-supported GO terms:

GO term	NS	Evidence
negative regulation of DNA-templated transcription	BP	direct assay
negative regulation of neuron apoptotic process	BP	genetic interaction
cytoplasm	CC	direct assay
endoplasmic reticulum	CC	direct assay
lipid droplet	CC	direct assay
nucleoplasm	CC	direct assay
nucleus	CC	direct assay
perinuclear region of cytoplasm	CC	direct assay
protein-containing complex	CC	direct assay

Protein interactions and networks

STRING

showing 15 of 1,923 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SET	ANP32A	P39687	950
SET	NME1	P15531	856
SET	GZMA	P12544	805
SET	APEX1	P27695	762
SET	LGMN	Q99538	674
SET	SETBP1	Q9Y6X0	648
SET	AGAP2	Q99490	636
SET	HMGB2	P26583	605
SET	CIP2A	Q8TCG1	599
SET	DEK	P35659	584
SET	PPP2CA	P05323	570
SET	NDUFS3	O75489	487
SET	PTMA	P06454	470
SET	Q32Q12	Q32Q12	428
SET	CR2	P20023	427

IntAct

Human interaction partners of SET in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 54 partners by confidence:

Partner	Interaction type	MIscore	Records
THAP7	physical association	0.810	7
RAC1	physical association	0.680	8
FAM111B	physical association	0.670	3
UBTF	physical association	0.640	4
TAF1C	physical association	0.630	4
TBP	physical association	0.630	4
FOXO1	physical association	0.590	5
CSNK2A1	phosphorylation reaction	0.590	1
MEOX2	physical association	0.560	3
SDCBP	physical association	0.560	3
REPIN1	association	0.530	2
TAF1B	physical association	0.520	3
PRKAR1A	physical association	0.520	2
TAF1A	physical association	0.520	2
PTMA	physical association	0.510	3
ARHGDIA	physical association	0.400	1
PPP2R5A	physical association	0.400	1
PYGM	physical association	0.400	1
RRN3	physical association	0.400	1
YWHAZ	physical association	0.400	1
ELF4	physical association	0.370	1
JUNB	physical association	0.370	1
NUCB1	physical association	0.370	1
NUPR1	physical association	0.370	1
PCNA	physical association	0.370	1
TERF1	physical association	0.370	1
TERF2	physical association	0.370	1
TERF2IP	physical association	0.370	1
CBX6	association	0.350	1
E	association	0.350	1

BioGRID (457 interactions; top human partners by supporting records): REPIN1 (Affinity Capture-MS; 6 records), ANP32A (Reconstituted Complex; 5 records), SETSIP (Cross-Linking-MS (XL-MS); 5 records), TP53 (Reconstituted Complex; 5 records), GZMK (Affinity Capture-MS; 4 records), HIST1H3A (Proximity Label-MS; 4 records), THAP7 (Two-hybrid; 4 records), XRCC6 (Reconstituted Complex; 4 records), APBB1 (Affinity Capture-MS; 3 records), ASPM (Cross-Linking-MS (XL-MS); 3 records), CDKN1A (Co-localization; 3 records), CHAF1A (Affinity Capture-MS; 3 records), FAM111B (Two-hybrid; 3 records), HIST1H1A (Reconstituted Complex; 3 records), KLF5 (Affinity Capture-MS; 3 records)

SIGNOR signaling

8 signaling interactions:

A	Effect	B	Mechanism
GZMA	down-regulates	SET	cleavage
SET	down-regulates	PPP2CA	binding
SET	down-regulates	PPP2CB	binding
SETBP1	up-regulates	SET	binding
CLN8	“down-regulates activity”	SET	binding
PIK3CG	“up-regulates activity”	SET	phosphorylation
PRKD2	“down-regulates activity”	SET	phosphorylation
SET	down-regulates	NME1	binding

Protein complexes (CORUM) (6)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

6 complexes by size:

Complex	Subunits	Members
ANP32A-APEX1-HMG2-NME1-SET complex	5	ANP32A, APEX1, HMGB2, NME1, SET
ProTalpha C2 complex	4	ACTB, MARCKSL1, PTMA, SET
★ CHRM2-SET complex	2	CHRM2, SET
★ FLT3-SET complex	2	FLT3, SET
CTCF-SET complex	2	CTCF, SET
ProTalpha C9 complex	2	SET, PTMA

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 54 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
RNA Polymerase I Transcription Termination	5	37.1×	2e-05
RNA Polymerase I Promoter Clearance	5	33.3×	2e-05
RNA Polymerase I Transcription	5	32.4×	2e-05
RNA Polymerase I Transcription Initiation	6	30.5×	9e-06
RNA Polymerase I Promoter Escape	6	16.6×	7e-05
Cellular Senescence	5	15.6×	5e-04
NoRC negatively regulates rRNA expression	5	11.9×	1e-03
PIP3 activates AKT signaling	5	7.6×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
transcription by RNA polymerase II	6	8.0×	5e-03
negative regulation of apoptotic process	9	5.9×	1e-03

Disease & clinical

Genetic variants

Variant evidence for SET: 140 ClinVar records (38 pathogenic / likely pathogenic); 3 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	22
Likely pathogenic	16
Uncertain significance	51
Likely benign	24
Benign	4

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 38 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
860686	NM_003011.4(SET):c.663+5G>C	Pathogenic	criteria provided, multiple submitters, no conflicts	2
560207	NM_003011.4(SET):c.313C>T (p.His105Tyr)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3
560209	NM_003011.4(SET):c.660_662del (p.Tyr220_Leu221delinsTer)	Pathogenic	criteria provided, single submitter	2
807681	NM_003011.4(SET):c.418_419del (p.Ser140fs)	Pathogenic	criteria provided, single submitter	1
817064	NM_003011.4(SET):c.185_186del (p.Lys62fs)	Pathogenic	criteria provided, single submitter	1
986988	NM_003011.4(SET):c.615_619del (p.Glu206fs)	Pathogenic	criteria provided, single submitter	1
992875	NM_003011.4(SET):c.663+1G>C	Pathogenic	criteria provided, single submitter	1
1344907	NM_003011.4(SET):c.458C>A (p.Ser153Ter)	Pathogenic	criteria provided, single submitter	1
2499108	NM_003011.4(SET):c.488_489del (p.Gly163fs)	Pathogenic	criteria provided, single submitter	1
3160560	NM_003011.4(SET):c.452del (p.Pro151fs)	Pathogenic	criteria provided, single submitter	1
3317680	NM_003011.4(SET):c.599del (p.Gly200fs)	Pathogenic	criteria provided, single submitter	1
3392539	NM_003011.4(SET):c.442_443del (p.Ser148fs)	Pathogenic	criteria provided, single submitter	1
4540565	NM_003011.4(SET):c.106_109del (p.Asp36fs)	Pathogenic	criteria provided, single submitter	1
4540568	NM_003011.4(SET):c.77_78del (p.Lys26fs)	Pathogenic	criteria provided, single submitter	1
4540569	NM_003011.4(SET):c.328_332del (p.Val110fs)	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore SET’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 33 predictions of 579):

Position(s)	Effect	Δscore	Sites
9:128689656–128689657	donor_loss	1.0000	4
9:128691169	acceptor_loss	1.0000
9:128691228–128691229	donor_loss	1.0000	5
9:128691848	acceptor_gain	1.0000
9:128691856	acceptor_loss	1.0000	2
9:128692654–128692655	acceptor_gain	1.0000	2
9:128692660–128692661	acceptor_loss	1.0000	5
9:128692766–128692767	donor_loss	1.0000	5
9:128692866–128692867	acceptor_loss	1.0000	3
9:128693636–128693637	acceptor_loss	1.0000	5

AlphaMissense

1,206 missense substitutions predicted likely pathogenic (of 1,884 scored), across 224 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
H102	8	0.999	1.000
D223	8	0.999	1.000
D56	8	0.998	1.000
D215	8	0.998	1.000
D224	8	0.998	1.000
N144	8	0.997	1.000
F147	8	0.997	1.000
F94	8	0.996	1.000
D113	8	0.996	1.000
F203	8	0.996	1.000
D49	8	0.995	0.998
F141	8	0.995	1.000
D130	8	0.994	0.999
F202	8	0.993	0.999
F99	8	0.990	0.999
N59	8	0.989	1.000
F139	8	0.988	1.000
N228	8	0.985	1.000
S63	8	0.984	0.999
F206	8	0.976	1.000

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

3 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	2.55e-06
Liver Hepatocellular Carcinoma (validation)	unfavorable	3.85e-06
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	0.000166

Disease associations

OMIM: gene MIM:600960 | disease phenotypes: MIM:618106

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
intellectual disability, autosomal dominant 58	Definitive	Autosomal dominant	4
autosomal dominant non-syndromic intellectual disability	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity

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

1 validity classifications:

Disease	Classification	Inheritance
intellectual disability	Definitive	AD

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (6 panels, 5 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

6 panels:

Panel	Rating
DDG2P	green
Hypotonic infant	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Paediatric disorders	green
Fetal anomalies	amber

Mondo (3): intellectual disability, autosomal dominant 58 (MONDO:0020847), intellectual disability (MONDO:0001071), autosomal dominant non-syndromic intellectual disability (MONDO:0015802)

Orphanet (1): NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

41 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000154	Wide mouth
HP:0000176	Submucous cleft hard palate
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000297	Facial hypotonia
HP:0000307	Pointed chin
HP:0000316	Hypertelorism
HP:0000324	Facial asymmetry
HP:0000331	Short chin
HP:0000358	Posteriorly rotated ears
HP:0000400	Macrotia
HP:0000431	Wide nasal bridge
HP:0000455	Broad nasal tip
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000678	Dental crowding
HP:0000750	Delayed speech and language development
HP:0000954	Single transverse palmar crease
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001348	Brisk reflexes
HP:0001357	Plagiocephaly
HP:0001382	Joint hypermobility
HP:0001611	Hypernasal speech
HP:0002311	Incoordination
HP:0002465	Poor speech
HP:0002527	Falls
HP:0003186	Inverted nipples
HP:0003593	Infantile onset
HP:0004322	Short stature
HP:0007429	Few cafe-au-lait spots
HP:0008936	Axial hypotonia
HP:0010808	Protruding tongue
HP:0011937	Hypoplastic fifth toenail
HP:0011968	Feeding difficulties
HP:0012471	Thick vermilion border
HP:0031936	Delayed ability to walk

GWAS associations

3 associations:

Study	Trait	p-value
GCST005951_75	Body mass index	5e-9
GCST001959_5	Eating disorders (purging via substances)	5e-6
GCST002115_14	Axial length	6e-6

EFO canonical traits (from GWAS)

2 canonical traits:

EFO ID	Trait name
EFO:0005318	axial length measurement
EFO:0004340	body mass index

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295798 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,601 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

1 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,601

PharmGKB: 1 entry (CPIC guideline: no)

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
7.52	IC50	30	nM	MOLIBRESIB

PubChem BioAssay actives

1 with measured affinity, of 8 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178941: Inhibition of SET (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	0.0300	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression, affects cotreatment	4
Cadmium Chloride	increases expression, decreases expression	3
bisphenol F	decreases expression, increases expression, affects cotreatment	2
bisphenol S	increases expression, affects cotreatment, decreases expression	2
Cisplatin	increases response to substance, increases expression	2
Estradiol	affects localization, affects cotreatment, decreases expression	2
Lipopolysaccharides	decreases expression, decreases reaction, increases expression, affects expression, affects response to substance	2
Tretinoin	affects reaction, decreases expression, increases expression, affects expression, affects cotreatment (+1 more)	2
Valproic Acid	decreases expression, affects expression	2
aristolochic acid I	decreases expression	1
berzosertib	affects localization, affects reaction	1
FR900359	affects phosphorylation	1
9-hydroxyoctadecadienoic acid	decreases expression	1
bufotalin	decreases expression	1
alpha phellandrene	decreases expression	1
titanium dioxide	decreases phosphorylation	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression	1
trichostatin A	affects cotreatment, increases expression	1
arsenite	increases phosphorylation, affects localization, affects reaction	1
mono-(2-ethylhexyl)phthalate	increases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
tetrabromobisphenol A	increases expression	1
perfluorooctanoic acid	decreases expression	1
coumarin	increases phosphorylation	1
leptomycin B	affects localization, affects reaction, decreases reaction	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	decreases expression	1
CD 437	decreases expression	1
chloropicrin	affects expression	1
U 0126	affects cotreatment, increases cleavage	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118953	Binding	Binding affinity to SET in human NCI-H358 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — *Bioorg Med Chem*

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1380	Loucy	Cancer cell line	Female
CVCL_1833	MEGAL	Cancer cell line	Female
CVCL_E0WR	Ubigene K-562 SET KO	Cancer cell line	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 300 trials:

NCT	Phase	Status	Title
NCT00168987	Phase 4	COMPLETED	Influence of an Oral Nutritional Supplement Rich in Omega-3 Fatty Acids on Functional State and Quality of Life in Malnourished Patients With Gastroenterological Tumors
NCT00554905	Phase 4	UNKNOWN	Radiofrequency Ablation With or With Transcatheter Arterial Embolization for Hepatocellular Carcinoma
NCT00555334	Phase 4	UNKNOWN	Nucleoid as an Adjuvant Therapy After Radiofrequency Ablation for Hepatocellular Carcinoma
NCT00556803	Phase 4	UNKNOWN	TACE as an Adjuvant Therapy After Radiofrequency Ablation (RFA) for Hepatocellular Carcinoma
NCT00557024	Phase 4	UNKNOWN	Radiotherapy as an Adjuvant Therapy After Radiofrequency Ablation for Hepatocellular Carcinoma
NCT00646100	Phase 4	COMPLETED	Transarterial Chemoembolization for Unresectable Hepatocellular Carcinoma With Portal Vein Tumor Thrombosis
NCT00768157	Phase 4	UNKNOWN	Efficacy of Antiviral Therapy After Radical Resection for Hepatitis B Virus-Related Hepatocellular Carcinoma
NCT00834860	Phase 4	UNKNOWN	Peginterferon Plus Ribavirin for Hepatitis C Patients Concomitant With Hepatocellular Carcinoma
NCT01098760	Phase 4	COMPLETED	Hepatocellular Carcinoma - Advanced Stage - Sorafenib Trial in Taiwanese Patients
NCT01102335	Phase 4	UNKNOWN	Synergistic Treatment for Hepatocellular Carcinoma (HCC) Using Transcatheter Arterial Chemoembolization (TACE) With Anti-hepatitis B Virus (Anti-HBV) Therapy
NCT01203787	Phase 4	COMPLETED	Sorafenib Dose Ramp-Up in Hepatocellular Carcinoma (HCC)
NCT01298284	Phase 4	UNKNOWN	A Trial of EVL\GVS Alone vs. EVL\GVS Combined Propranolol
NCT01332669	Phase 4	COMPLETED	Drug-eluting Bead in Hepatocellular Carcinoma
NCT01351194	Phase 4	UNKNOWN	Radiofrequency Ablation Versus Hepatic Resection for the Treatment of Hepatocellular Carcinomas Smaller Than 2 cm
NCT01409499	Phase 4	COMPLETED	Palliative Treatments for Patients With Advanced Hepatocellular Carcinoma (HCC)
NCT01415063	Phase 4	UNKNOWN	Radiofrequency Ablation Combined With Transcatheter Arterial Chemoembolization Versus Radiofrequency Ablation Alone for Recurrent Hepatocellular Carcinoma
NCT01438437	Phase 4	UNKNOWN	Trial of Ablation of Small Hepatocellular Carcinomas in Patients of Cirrhosis
NCT01451658	Phase 4	UNKNOWN	A Trial of EVL\GVS Alone vs. EVL\GVS Combined Propranolol (S-HCC)
NCT01570075	Phase 4	UNKNOWN	Radiofrequency Ablation Versus Liver Resection for Elderly Patients With Hepatocellular Carcinoma (HCC) Within the Milan Criteria
NCT01575574	Phase 4	COMPLETED	Magnetic Resonance With Gadoxetic Acid for the Diagnosis of Hepatocellular Carcinoma in Patients With Liver Cirrhosis. Evaluation of Its Impact for the Non-invasive Diagnosis
NCT01639703	Phase 4	COMPLETED	Hepatic Xenetix-CT Perfusion
NCT01798160	Phase 4	COMPLETED	Selective Internal Radiation Therapy (SIRT) Versus Transarterial Chemoembolisation (TACE) for the Treatment of Hepatocellular Carcinoma (HCC).
NCT01806740	Phase 4	TERMINATED	DCE-MRI Using Dotarem® in Evaluation of Therapeutic Response to Sorafenib in Patients With Advanced Stage HCC
NCT01849588	Phase 4	TERMINATED	HCV-RNA Kinetics During Sorafenib for Hepatocellular Carcinoma (HCC)
NCT01894269	Phase 4	UNKNOWN	Chemoembolization With or Without Antiviral Therapy for Unresectable HBV-related HCC With Low HBV DNA Replication
NCT01970748	Phase 4	UNKNOWN	Primary Prevention of Patients With Hepatocellular Carcinoma and Concomitant Esophageal Varices
NCT01997957	Phase 4	UNKNOWN	A RCT of Oral S-1 in Combination With Sequential HAIC of Oxaliplatin After TACE in Patients With Advanced HCC
NCT02174575	Phase 4	WITHDRAWN	Anesthetic Agents and Acute Kidney Injury After Liver Resection Surgery
NCT02253511	Phase 4	UNKNOWN	A Prospective Control Study of Cidan Capsule Combined With TACE in Hepatocellular Carcinoma
NCT02399033	Phase 4	UNKNOWN	Xihuang Capsules Prevention of Recurrence in Patients With Hepatocellular Carcinoma After Hepatectomy
NCT02472249	Phase 4	COMPLETED	Pharmacological Manipulation of Intrahepatic Arterial Blood Flow in HCC
NCT02504983	Phase 4	UNKNOWN	Clinical Trial for GALNT14 Genotype - Guided, Sorafenib in Combination With TACE in Hepatocellular Carcinoma
NCT02525380	Phase 4	UNKNOWN	Safety and Efficacy of Doxorubicin-eluting-bead Embolization in Patients With Advanced Hepatocellular Carcinoma
NCT02534961	Phase 4	UNKNOWN	Prophylactic Antibiotics Before RFA for HCC
NCT02535117	Phase 4	UNKNOWN	Laparoscopic Surgery Versus Radiofrequency Ablation for Recurrent HCC
NCT02729506	Phase 4	UNKNOWN	Transarterial Radioembolization Versus Chemoembolization for the Treatment of Hepatocellular Carcinoma
NCT02733809	Phase 4	UNKNOWN	Mechanism of Sorafenib Resistance in Patients With Advanced Hepatocellular Carcinoma
NCT02785380	Phase 4	NOT_YET_RECRUITING	Laparoscopic Surgery VS RFA for Recurrent HCC
NCT02959359	Phase 4	WITHDRAWN	DAA in the Risk of Recurrence After Curative Treatment of HCC
NCT02961998	Phase 4	COMPLETED	Preventive Effect of Celecoxib on Sorafenib-related Hand Foot Syndrome, a Single Center, Randomized Controlled Clinical Trail
NCT03007212	Phase 4	COMPLETED	Outcome of Transarterial Chemo-embolization (TACE) in Hepatocellular Carcinoma Patients With Partial Portal Vein Thrombosis
NCT03007225	Phase 4	COMPLETED	Efficacy and Safety of Drug Eluting Beads TACE in Treatment of HCC in Egyptian Patients
NCT03024684	Phase 4	ACTIVE_NOT_RECRUITING	Statin for Preventing Hepatocellular Carcinoma Recurrence After Curative Treatment
NCT03151213	Phase 4	COMPLETED	Effect of Pregabalin on the Postoperative Analgesia in RFA of Focal Lesions in the Liver
NCT03212625	Phase 4	COMPLETED	The Effect of Urea Cream on Sorafenib-associated Hand-Foot Skin Reaction
NCT03515369	Phase 4	UNKNOWN	Effect of Babaodan on Tumor Recurrence After Curative Resection of Hepatocellular Carcinoma
NCT03518502	Phase 4	UNKNOWN	Sorafenib Monotherapy vs. TACE-sorafenib Sequential Therapy for HCC With Metastasis
NCT03963206	Phase 4	COMPLETED	Cabozantinib toLERANCE Study in HepatoCellular Carcinoma (CLERANCE)
NCT03996681	Phase 4	UNKNOWN	TACE Combined With Methylcantharidimide Tablets in the Treatment of Large and Unresectable Hepatocellular Carcinoma
NCT04015245	Phase 4	COMPLETED	SNMC (Stronger Neo-Minophagen C ) for Acute Hepatitis Post Transarterial Chemoembolization Therapy
NCT04032860	Phase 4	UNKNOWN	RCT of Different Effects of Nucleot(s)Ide Analogues on the Prognosis of HBV-HCC Patients After Curative Resection
NCT04288323	Phase 4	COMPLETED	Gadolinium Contrast-enhanced Abbreviated MRI (AMRI) vs. Standard Ultrasound for Hepatocellular Carcinoma (HCC) Surveillance in Patients With Cirrhosis
NCT04562428	Phase 4	COMPLETED	The Safety and Efficacy Evaluation of XSLJZ in Advanced Hepatocellular Carcinoma Patients With Multiple Protein Kinase Inhibitor Therapy: A Randomized, Double-Blind, Controlled Trial
NCT04569799	Phase 4	COMPLETED	Accuracy of Contrast-Enhanced Ultrasound for Hepatocellular Carcinoma Post TACE
NCT04653818	Phase 4	COMPLETED	HCV Related Hepatocellular Carcinoma Recurrence After Directly Acting Antivirals: A Randomized Controlled Trial
NCT05022628	Phase 4	UNKNOWN	Clinical Study of Radiotherapy Combined With Donafenib for Neoadjuvant Treatment of Patients With HCC With Portal Vein Carcinoma Thrombosis
NCT05113290	Phase 4	UNKNOWN	Effect and Safety of Recombinant Human Adenovirus Type 5 in Advanced HCC With Stable Disease After Sorafenib Treatment
NCT05185505	Phase 4	RECRUITING	Atezolizumab and Bevacizumab Pre-Liver Transplantation for Patients With Hepatocellular Carcinoma Beyond Milan Criteria
NCT05331911	Phase 4	RECRUITING	Impact of Propofol-Based Total Intravenous Anesthesia Versus Anesthesia With Sevoflurane on Long-term Outcomes With Patients Undergoing Elective Excision of Primary Liver Tumors
NCT05416073	Phase 4	UNKNOWN	Effect of Esketamine on Abdominal Pain During TACE-HAIC in Patients With Hepatocellular Carcinoma

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for SET across ~30M SureChEMBL compounds — explore on Sugi Predict.