STAT6

Summary

STAT6 (signal transducer and activator of transcription 6, HGNC:11368) is a protein-coding gene on chromosome 12q13.3, encoding Signal transducer and activator of transcription 6 (P42226). Carries out a dual function: signal transduction and activation of transcription.

The protein encoded by this gene is a member of the STAT family of transcription factors. In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. This protein plays a central role in exerting IL4 mediated biological responses. It is found to induce the expression of BCL2L1/BCL-X(L), which is responsible for the anti-apoptotic activity of IL4. Knockout studies in mice suggested the roles of this gene in differentiation of T helper 2 (Th2) cells, expression of cell surface markers, and class switch of immunoglobulins. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 6778 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hyper-IgE syndrome 6, autosomal dominant, with recurrent infections (Strong, ClinGen)
• GWAS associations: 59 (top 1% of genes corpus-wide)
• Clinical variants (ClinVar): 148 total — 5 pathogenic, 1 likely-pathogenic
• Regional missense constraint (gnomAD): 1 of 4 regions constrained (≈4% of expected missense variation)
• GTEx eGene: eQTL in 25 tissues, sQTL in 26 (q < 0.05)
• Phenotypes (HPO): 46
• ChEMBL bioactivity: 11 clinical-phase molecules tested; no curated mechanism-of-action drug
• Cancer driver (intOGen): activating (oncogene-like) across 3 cancer types (inferred from mutation patterns)
• Constraint (gnomAD): pLI 0.56 (intermediate), LOEUF 0.52 (moderately constrained)
• Transcription factor: yes — 138 downstream targets (CollecTRI)
• MANE Select transcript: NM_003153
• Interaction hub: 3,006 STRING partners (top 2% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11368
Approved symbol	STAT6
Name	signal transducer and activator of transcription 6
Location	12q13.3
Locus type	gene with protein product
Status	Approved
Aliases	D12S1644, IL-4-STAT
Ensembl gene	ENSG00000166888
Ensembl biotype	protein_coding
OMIM	601512
Entrez	6778

Gene structure

Transcript identifiers

Ensembl transcripts: 57 — 38 protein_coding, 13 nonsense_mediated_decay, 6 retained_intron

MANE Select: ENST00000300134

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 9, TSL 3: 5, TSL 4: 5, TSL 5: 2

ENST00000300134, ENST00000454075, ENST00000537215, ENST00000538913, ENST00000543873, ENST00000553275, ENST00000553397, ENST00000553499, ENST00000553533, ENST00000554202, ENST00000554764, ENST00000555104, ENST00000555222, ENST00000555318, ENST00000555375, ENST00000555641, ENST00000555849, ENST00000556155, ENST00000556259, ENST00000557563, ENST00000557635, ENST00000557781, ENST00000640254, ENST00000651176, ENST00000714370, ENST00000714371, ENST00000714372, ENST00000714373, ENST00000714374, ENST00000861685, ENST00000861686, ENST00000861687, ENST00000861688, ENST00000861689, ENST00000861690, ENST00000861691, ENST00000920257, ENST00000920258, ENST00000920259, ENST00000953180, ENST00000953181, ENST00000953182, ENST00000953183, ENST00000953184, ENST00000953185, ENST00000953186, ENST00000953187, ENST00000982373, ENST00000982379, ENST00000982381, ENST00001028955, ENST00001028956, ENST00001028957, ENST00001028958, ENST00001089992, ENST00001089993, ENST00001143493

RefSeq mRNA: 5 — MANE Select: NM_003153 NM_001178078, NM_001178079, NM_001178080, NM_001178081, NM_003153

CCDS: CCDS53804, CCDS8931

Canonical transcript exons

ENST00000300134 — 22 exons

Exon	Start	End
ENSE00001107465	57095408	57096761
ENSE00001353600	57111129	57111362
ENSE00003275456	57108163	57108299
ENSE00003458544	57096850	57096978
ENSE00003484230	57107231	57107314
ENSE00003491794	57099767	57099903
ENSE00003500520	57107605	57107743
ENSE00003520637	57098505	57098597
ENSE00003547481	57098792	57098902
ENSE00003553085	57099294	57099440
ENSE00003557323	57099015	57099078
ENSE00003576863	57106191	57106339
ENSE00003598889	57099996	57100090
ENSE00003603066	57104726	57104813
ENSE00003606856	57104464	57104586
ENSE00003622644	57097068	57097133
ENSE00003635281	57106528	57106580
ENSE00003659238	57102829	57102921
ENSE00003661799	57102290	57102496
ENSE00003663096	57105468	57105599
ENSE00003686557	57105151	57105339
ENSE00003790783	57106693	57106831

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 99.21.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 34.8048 / max 517.7107, expressed in 1788 samples.

Highest expression (Bgee): granulocyte, ovary, small intestine Peyer’s patch, endocervix, spleen.

Genetic regulation across tissues (GTEx eQTL / sQTL)

STAT6 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 25 tissues and its splicing (sQTL) in 26 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 51 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Skin Not Sun Exposed Suprapubic	sqtl	1.4e-26	+0.43	12:57109992:C:T
Skin Sun Exposed Lower leg	sqtl	6.8e-23	+0.35	12:57115272:T:C
Cells Cultured fibroblasts	sqtl	4.0e-21	+0.45	12:57109992:C:T
Adipose Subcutaneous	sqtl	1.6e-16	+0.31	12:57118687:C:G
Esophagus Mucosa	sqtl	4.4e-16	+0.38	12:57108399:C:T
Adipose Visceral Omentum	sqtl	2.5e-15	+0.40	12:57109992:C:T
Artery Tibial	sqtl	6.0e-15	+0.34	12:57109992:C:T
Esophagus Muscularis	sqtl	9.9e-15	+0.42	12:57109992:C:T
Whole Blood	sqtl	1.8e-13	-0.29	12:57109992:C:T
Brain Cerebellar Hemisphere	eqtl	1.3e-12	+0.68	12:57110414:G:T
Nerve Tibial	sqtl	2.0e-12	+0.33	12:57109992:C:T
Colon Sigmoid	sqtl	2.7e-12	+0.48	12:57109992:C:T
Lung	sqtl	7.6e-12	+0.32	12:57115786:C:T
Artery Aorta	sqtl	2.1e-11	+0.45	12:57109992:C:T
Cells Cultured fibroblasts	eqtl	4.1e-11	-0.21	12:57095926:T:C
Colon Transverse	sqtl	2.8e-09	+0.38	12:57109992:C:T
Thyroid	sqtl	3.3e-09	+0.35	12:57109992:C:T
Brain Cerebellum	eqtl	4.5e-09	+0.51	12:57104187:G:A
Stomach	sqtl	8.8e-09	+0.45	12:57109992:C:T
Esophagus Gastroesophageal Junction	sqtl	9.3e-09	+0.42	12:57109992:C:T

FANTOM5 promoters

7 alternative TSS:

Promoter ID	TPM avg	Samples expressed
131635	30.0051	1776
131634	3.3396	1256
131637	0.5251	295
131632	0.3365	186
131636	0.2783	106
131639	0.2045	102
131633	0.1158	28

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.21	gold quality
right ovary	UBERON:0002118	98.79	gold quality
left ovary	UBERON:0002119	98.77	gold quality
small intestine Peyer’s patch	UBERON:0003454	98.77	gold quality
endocervix	UBERON:0000458	98.68	gold quality
spleen	UBERON:0002106	98.62	gold quality
mucosa of stomach	UBERON:0001199	98.61	gold quality
lower esophagus mucosa	UBERON:0035834	98.58	gold quality
right adrenal gland cortex	UBERON:0035827	98.57	gold quality
right uterine tube	UBERON:0001302	98.50	gold quality
left uterine tube	UBERON:0001303	98.49	gold quality
body of uterus	UBERON:0009853	98.49	gold quality
transverse colon	UBERON:0001157	98.48	gold quality
right adrenal gland	UBERON:0001233	98.48	gold quality
monocyte	CL:0000576	98.47	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.47	gold quality
descending thoracic aorta	UBERON:0002345	98.46	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.46	gold quality
leukocyte	CL:0000738	98.45	gold quality
mononuclear cell	CL:0000842	98.44	gold quality
metanephros cortex	UBERON:0010533	98.44	gold quality
ileal mucosa	UBERON:0000331	98.41	gold quality
right coronary artery	UBERON:0001625	98.41	gold quality
lower esophagus	UBERON:0013473	98.41	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.41	gold quality
skin of abdomen	UBERON:0001416	98.40	gold quality
ectocervix	UBERON:0012249	98.40	gold quality
upper lobe of left lung	UBERON:0008952	98.37	gold quality
right lung	UBERON:0002167	98.36	gold quality
body of stomach	UBERON:0001161	98.34	gold quality
small intestine	UBERON:0002108	98.34	gold quality
lymph node	UBERON:0000029	98.32	gold quality
blood	UBERON:0000178	98.32	gold quality
minor salivary gland	UBERON:0001830	98.31	gold quality
upper lobe of lung	UBERON:0008948	98.30	gold quality
gall bladder	UBERON:0002110	98.28	gold quality
vagina	UBERON:0000996	98.25	gold quality
skin of leg	UBERON:0001511	98.25	gold quality
adrenal cortex	UBERON:0001235	98.20	gold quality
fundus of stomach	UBERON:0001160	98.19	gold quality
left adrenal gland cortex	UBERON:0035825	98.19	gold quality
left adrenal gland	UBERON:0001234	98.18	gold quality
esophagus	UBERON:0001043	98.15	gold quality
right lobe of thyroid gland	UBERON:0001119	98.14	gold quality
thoracic aorta	UBERON:0001515	98.13	gold quality
peripheral nervous system	UBERON:0000010	98.12	gold quality
nerve	UBERON:0001021	98.12	gold quality
tibial nerve	UBERON:0001323	98.12	gold quality
vermiform appendix	UBERON:0001154	98.11	gold quality
ascending aorta	UBERON:0001496	98.10	gold quality
aorta	UBERON:0000947	98.07	gold quality
popliteal artery	UBERON:0002250	98.05	gold quality
tibial artery	UBERON:0007610	98.05	gold quality
left coronary artery	UBERON:0001626	98.03	gold quality
omental fat pad	UBERON:0010414	98.01	gold quality
peritoneum	UBERON:0002358	98.00	gold quality
pancreatic ductal cell	CL:0002079	97.99	gold quality
coronary artery	UBERON:0001621	97.99	gold quality
esophagus mucosa	UBERON:0002469	97.99	gold quality
caecum	UBERON:0001153	97.98	gold quality
prostate gland	UBERON:0002367	97.95	gold quality
adipose tissue of abdominal region	UBERON:0007808	97.92	gold quality
mouth mucosa	UBERON:0003729	97.90	gold quality
rectum	UBERON:0001052	97.85	gold quality
adrenal gland	UBERON:0002369	97.84	gold quality
left lobe of thyroid gland	UBERON:0001120	97.82	gold quality
stomach	UBERON:0000945	97.76	gold quality
zone of skin	UBERON:0000014	97.63	gold quality
thyroid gland	UBERON:0002046	97.54	gold quality
colon	UBERON:0001155	97.51	gold quality
uterine cervix	UBERON:0000002	97.50	gold quality
intestine	UBERON:0000160	97.45	gold quality
saliva-secreting gland	UBERON:0001044	97.45	gold quality
mucosa of transverse colon	UBERON:0004991	97.44	gold quality
smooth muscle tissue	UBERON:0001135	97.43	gold quality
pylorus	UBERON:0001166	97.42	gold quality
large intestine	UBERON:0000059	97.31	gold quality
right lobe of liver	UBERON:0001114	97.31	gold quality
body of pancreas	UBERON:0001150	97.27	gold quality
duodenum	UBERON:0002114	97.26	gold quality
calcaneal tendon	UBERON:0003701	97.23	gold quality
subcutaneous adipose tissue	UBERON:0002190	97.20	gold quality
sigmoid colon	UBERON:0001159	97.17	gold quality
lower lobe of lung	UBERON:0008949	97.06	gold quality
cervix squamous epithelium	UBERON:0006922	97.03	gold quality
myometrium	UBERON:0001296	96.98	gold quality
nipple	UBERON:0002030	96.98	gold quality
stromal cell of endometrium	CL:0002255	96.94	gold quality
colonic epithelium	UBERON:0000397	96.94	gold quality
apex of heart	UBERON:0002098	96.89	gold quality
lung	UBERON:0002048	96.88	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.88	gold quality
thymus	UBERON:0002370	96.77	gold quality
right atrium auricular region	UBERON:0006631	96.77	gold quality
tendon of biceps brachii	UBERON:0008188	96.76	gold quality
urinary bladder	UBERON:0001255	96.75	gold quality
tonsil	UBERON:0002372	96.70	gold quality
urethra	UBERON:0000057	96.69	gold quality
adipose tissue	UBERON:0001013	96.65	gold quality
saphenous vein	UBERON:0007318	96.62	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.65
E-MTAB-7606	no	518.39
E-MTAB-6379	no	204.47

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Skin 1	tissue	102.2	medium
Tonsil	tissue	86.2	high
Urinary bladder	tissue	81.6	high
Small intestine	tissue	81.5	low
Vagina	tissue	79.1	low
Ovary	tissue	78.8	medium
Thymus	tissue	76.2
Spleen	tissue	75.3	high
Smooth muscle	tissue	75.2	low
Duodenum	tissue	74.4	low
Lymph node	tissue	73.2	high
Lung	tissue	68.4	medium
Esophagus	tissue	67.3	medium
Rectum	tissue	66.8	medium
Seminal vesicle	tissue	64.7	medium
Appendix	tissue	64.3	high
Colon	tissue	63.3	medium
Gallbladder	tissue	62.1	medium
Fallopian tube	tissue	60.5	high
Adipose tissue	tissue	60.1	not detected
Stomach 1	tissue	60.0	medium
Cervix	tissue	57.1	medium
Prostate	tissue	54.4	medium
Endometrium 1	tissue	52.0	medium
Liver	tissue	49.8	not detected
Parathyroid gland	tissue	49.7	low
Adrenal gland	tissue	48.1	medium
Epididymis	tissue	46.3	medium
Placenta	tissue	42.3	low
Choroid plexus	tissue	40.7
Kidney	tissue	40.3	medium
Breast	tissue	39.4
Salivary gland	tissue	38.5	low
Bone marrow	tissue	37.8	medium
Thyroid gland	tissue	34.6	medium
Heart muscle	tissue	28.5	not detected
Pancreas	tissue	26.4	not detected
Nucleus accumbens	tissue	25.2
Postcentral gyrus	tissue	23.4
Hippocampus	tissue	22.1	not detected
Tongue	tissue	19.1
Pituitary gland	tissue	18.6
Locus coeruleus	tissue	18.5
Spinal cord	tissue	14.6
Testis	tissue	12.1	medium
Skeletal muscle	tissue	11.2	not detected
Substantia nigra	tissue	10.8
Superior colliculi	tissue	10.1
Medulla oblongata	tissue	8.9
Hypothalamus	tissue	8.1
Midbrain	tissue	8.0
Corpus callosum	tissue	7.9
Periaqueductal gray	tissue	7.9
Pons	tissue	7.5
Septum	tissue	7.5
Thalamus	tissue	7.4
Olfactory bulb	tissue	6.8
Basal ganglia	tissue	6.3	not detected
Putamen	tissue	6.3
Hippocampal formation	tissue	6.3

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Blood vessel (98.2), Area parastriata, superior (31.8), Anterior thalamic nucleus, ventral (31.6), Orbitofrontal gyrus, anterior (31.3), Claustrum (28.9).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

showing 30 of 138 targets:

Target	Regulation
ADRA2B	Unknown
ALOX12	Unknown
ALOX15	Activation
ANXA2
ARG1
ATP11C
BATF	Activation
BCL2L1	Unknown
BCL6
CCL1	Activation
CCL11	Activation
CCL13	Activation
CCL17	Activation
CCL2	Repression
CCL23
CCL26	Activation
CCL7	Repression
CCL8	Repression
CCR4	Unknown
CCR8	Unknown
CD4	Unknown
CD40	Unknown
CD86	Unknown
CDKN1A	Unknown
CDKN1B
CDKN2A
CEL
CHI3L1	Activation
CISH	Unknown
CNR1	Activation

Upstream regulators (CollecTRI, top): BCL6, CEBPB, CUX1, HAND2, HDAC9, MYC, NFKB, PRDM1, SFPQ, SPI1, STAT1, STAT6, TBX21, TP63

miRNA regulators (miRDB)

Targeting STAT6 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 52 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6505-5P	99.73	69.25	1595
HSA-MIR-3177-5P	99.65	70.38	1174
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-6716-5P	99.56	68.62	1244
HSA-MIR-6751-5P	99.56	64.99	1145
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-3182	99.40	68.15	2454
HSA-MIR-135A-5P	99.36	71.85	1601
HSA-MIR-135B-5P	99.36	71.63	1613
HSA-MIR-6744-3P	99.22	64.41	972
HSA-MIR-6803-5P	99.19	63.90	1026
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-491-5P	99.13	65.98	1468
HSA-MIR-4757-5P	99.12	64.51	981
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-1909-3P	99.03	66.56	1662

Functional genomics

gnomAD constraint: pLI 0.561, LOEUF 0.515, missense Z 3.35 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000300134 splits into 4 regions with different missense tolerance; 1 is missense-constrained (≈4% 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
12:57,096,575–57,098,885	226 / 236.7	0.95	no
12:57,098,886–57,104,521	222 / 354.6	0.63	no
12:57,104,522–57,104,760	13 / 41.1	0.32	yes (p 1.2e-05)
12:57,104,761–57,108,278	336 / 429.8	0.78	no

Literature-anchored findings (GeneRIF, showing 40)

• IL-4-dependent Stat6 activation is inhibited by an intracellularly delivered peptide derived from the Stat6-binding region of IL-4Ralpha. (PMID:11532018)
• role in mediating responses of bronchial epithelium to cytokines in asthmatics (PMID:11692112)
• Oligonucleotide fishing for STAT6: cross-talk between IL-4 and chemokines. (PMID:11872954)
• STAT6 polymorphism is associated with increase in eosinophil cell count contributing to the pathogenesis of Asthma (PMID:11912176)
• 3’UTR polymorphism is associated with susceptibility and severity in nut allergic patients (PMID:12058257)
• STAT6 is required for IL-4-mediated growth inhibition and induction of apoptosis in human breast cancer cells. (PMID:12082548)
• STAT6 has a protein binding motif that controls the interaction with NcoA-1 in transcriptional activation (PMID:12138096)
• These results show that p38 MAPK provides a costimulatory signal for IL-4-induced gene responses by directly stimulating the transcriptional activation of STAT6. (PMID:12161424)
• These findings identify p100 as a novel coactivator for STAT6 and suggest that p100 functions as a bridging factor between STAT6 and the basal transcription machinery. (PMID:12234934)
• Protein phosphatase 2A (PP2A) regulates interleukin-4-mediated signaling by this protein. (PMID:12426308)
• regulation of dephosphorylation by of mitogen-activated protein kinase and myosin light chain kinase (PMID:12459556)
• IL-4-induced Stat6 signaling is a polygenic quantitative trait regulated by a collection of several contributing genetic loci. (PMID:12651067)
• when osteoclastogenesis was induced independently of RANKL by using TNF-alpha, IL-4 inhibited osteoclast differentiation through a STAT6-dependent mechanism (PMID:12689929)
• Characterization of the IL-4-responsive enhanceosome of the human polymeric Ig receptor gene demonstrates cooperation of STAT6, HNF1 and additional DNA-binding factors in mediating IL-4 responsiveness in HT-29 cells. (PMID:12794133)
• These results suggest that MIP-T3 is a novel inhibitor of IL-13 signaling and may be a useful molecule in ameliorating various conditions in which IL-13 plays a central role. (PMID:12935900)
• the Stat6 TAD contributes to promoter specificity by the differential recruitment of and requirement for a p160-class coactivator (PMID:14519766)
• STAT6 is required for IL-4-IL-13-dependent SOCS-1 expression in A549 human lung adenocarcinoma cells; three identified STAT6-binding motifs in the SOCS-1 promoter cooperate to induce maximal transcription. (PMID:14634100)
• the Stat6 signaling pathway may play a role in maintaining the Th1/Th2 cytokine balance by directly and indirectly down-regulating the production of proinflammatory cytokines (PMID:14719123)
• Results demonstrate that induction of adenine nucleotide translocase 3 by interleukin-4 and interferon-gamma proceeds via pathways involving STAT6 and STAT1, respectively. (PMID:14746803)
• STAT6 activation mediates a transcriptional enhancement of trefoil factor-3 (TFF3) by induction of de novo synthesized protein in mucus-producing HT-29 CL.16E intestinal goblet cells. (PMID:15004182)
• Constitutive STAT6 phosphorylation and DNA-binding activity were detected in primary mediastinal large B-cell lymphoma cell lines but not diffuse large B-cell lymphoma cell lines (PMID:15044251)
• IL-4 and IL-13 promote Stat6 serine phosphorylation in PHA-activated human T-cells. (PMID:15069079)
• As no exonic variants of STAT6 are known as yet, repeat polymorphisms in the regulatory regions and their haplotypes could be important in deciphering the genetic role of STAT6 in asthma and atopy. (PMID:15105161)
• FN-gamma regulates IL-4- and STAT6-dependent signaling and gene expression in airway epithelial cells by multiple mechanisms (PMID:15297269)
• genetic variants within STAT6 contribute significantly to IgE regulation and manifestation of atopic diseases (PMID:15342695)
• Role for Stat6 in apoptosis regulation. Stat6(null phenotype) cell lines exhibit variably increased levels of Th1 cytokines. May be source for investigations into Inflammatory bowel disease pathophysiology. (PMID:15522309)
• IL-4 and IL-13 mediate the hypercontractility of intestinal muscle via a STAT6 pathway at the level of the smooth muscle cell. The STAT6 pathway may contribute to the hypercontractility of intestinal muscle in Crohn’s disease. (PMID:15528258)
• p100 has an important role in the assembly of STAT6 transcriptosome, and that p100 stimulates IL-4-dependent transcription by mediating interaction between STAT6 and CBP and recruiting chromatin modifying activities to STAT6-responsive promoters (PMID:15695802)
• PI3-K promotes the expression of TFF3 and MUC2 and that the PI3-K pathway may play a pivotal role in intestinal goblet cell differentiation. (PMID:15733066)
• Alterations in the STAT6 pathway may play a crucial role in the pathogenesis of distinct subgroups of patients with Crohn’s disease. (PMID:15888279)
• IL-4 regulates TNFalpha-induced IL-8 expression at a transcriptional level and this mechanism involves STAT6 and NF-kappaB transcription factors (PMID:16004996)
• results demonstrate that epithelial eotaxin-3 is up-regulated in the context of a T helper 2 mediated inflammatory bowel disease via the signal transducer and activator of transcription 6 (PMID:16084752)
• Findings suggest that Stat6 signaling pathway plays a role in the regulation of cell proliferation and apoptosis in colon cancer cells, which promises further investigation for targeted cancer therapy. (PMID:16387423)
• STAT6 binding to STAT6 promotor gene was regulated by H4 receptor-induced signal transduction and/or cross talk particularly in atopic human lymphocytes ex vivo (PMID:16547812)
• IL-4 has differential effects in coronary artery smooth muscle cells: short-term exposure enhances OPG production through a STAT6-dependent mechanism, but long-term exposure causes Cbfa1-dependent osteogenic transformation and decreased production of OPG (PMID:16601843)
• Essential for IL-4-induced human T-cell expression of CCL17/thymus- and activation-regulated chemokine(TARC). (PMID:16810739)
• Activation of STAT6 appears to be a key factor in P-selectin expression induced by substance P and IL-4 because treatment with STAT6 decoy oligodeoxynucleotides significantly inhibited P-selectin expression. (PMID:16877367)
• Stat6 exerts a stimulatory effect on early growth response (Egr)-1 gene and platelet-derived growth factor (PDGF) ligand mRNA transcription. (PMID:16951379)
• The STAT6 G2964A polymorphism is not involved in the genetic susceptibility to ulcerative colitis in Chinese patients. (PMID:17074026)
• specific increases in T-cell protein tyrosine phosphatase expression in activated-B-cell-like diffuse large B-cell lymphomas may contribute to the different biological characteristics of these tumors (PMID:17210636)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	stat6	ENSDARG00000015902
mus_musculus	Stat6	ENSMUSG00000002147
rattus_norvegicus	Stat6	ENSRNOG00000025023

Paralogs (6): STAT1 (ENSG00000115415), STAT5A (ENSG00000126561), STAT4 (ENSG00000138378), STAT3 (ENSG00000168610), STAT2 (ENSG00000170581), STAT5B (ENSG00000173757)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:103034) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 68 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased IgE level	5
decreased IgG1 level	3
increased interferon-gamma secretion	3
decreased interleukin-4 secretion	3
abnormal airway responsiveness	2
decreased T cell proliferation	2
abnormal mammary gland growth during pregnancy	2
abnormal T-helper 1 cell differentiation	2
abnormal T-helper 2 cell differentiation	2
increased IgG2a level	2
abnormal respiratory epithelium morphology	2
abnormal mast cell morphology	1
abnormal mammary gland morphology	1
skin lesions	1
decreased metastatic potential	1
abnormal circulating alanine transaminase level	1
abnormal humoral immune response	1
decreased IgM level	1
decreased IgA level	1
acanthosis	1
increased cellular sensitivity to gamma-irradiation induced cell death	1
abnormal tumor susceptibility	1
abnormal leukocyte physiology	1
abnormal macrophage physiology	1
abnormal B cell physiology	1

+43 more (showing top 25).

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
Bos taurus	Q9TUM3	98.0%	Diamond
Sus scrofa	Q9TUZ0	98.0%	Diamond
Xenopus laevis	Q7ZXK3	96.1%	Diamond
Ovis aries	P42231	94.7%	Diamond
Caenorhabditis briggsae	Q61AP6	79.5%	Diamond
Caenorhabditis elegans	Q9NAD6	79.5%	Diamond
Dictyostelium discoideum	Q54BD4	44.5%	Diamond
Drosophila melanogaster	Q24151	43.3%	Diamond
Anopheles gambiae	Q7QDU4	39.5%	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
LRP1-AS	ncRNA	105751187
NXPH4	protein-coding	11247
LRP1	protein-coding	4035
COXFA4L2	protein-coding	56901
SHMT2	protein-coding	6472
MIR1228	ncRNA	100302201
NAB2	protein-coding	4665
NEMP1	protein-coding	23306
MYO1A	protein-coding	4640
ACKR5	protein-coding	11318
TAC3	protein-coding	6866
ZBTB39	protein-coding	9880

Protein

Protein identifiers

Signal transducer and activator of transcription 6 — P42226 (reviewed: P42226)

Alternative names: IL-4 Stat

All UniProt accessions (14): P42226, A0A1W2PNW1, A0A494C0T4, A0AAQ5BHX1, A0AAQ5BI40, G3V2L2, G3V2M3, G3V370, G3V568, G3V5I8, G3V5K5, H0YIY2, H0YJH6, Q5FBW6

UniProt curated annotations — full annotation on UniProt →

Function. Carries out a dual function: signal transduction and activation of transcription. Involved in IL4/interleukin-4- and IL3/interleukin-3-mediated signaling.

Subunit / interactions. Forms a homodimer or a heterodimer with a related family member. Interacts with NCOA1 via its C-terminal LXXLL motif.

Subcellular location. Cytoplasm. Nucleus.

Post-translational modifications. Tyrosine phosphorylated on Tyr-641 following stimulation by IL4/interleukin-4. Tyrosine phosphorylated following stimulation by IL3/interleukin-3. Dephosphorylation on tyrosine residues by PTPN2 negatively regulates the IL4/interleukin-4 mediated signaling. Mono-ADP-ribosylated by PARP14.

Disease relevance. Hyper-IgE syndrome 6, autosomal dominant, with recurrent infections (HIES6) [MIM:620532] An immunologic disorder characterized by severe allergic disease with onset in infancy. Common features are treatment-resistant atopic dermatitis, food allergies, asthma, eosinophilic gastrointestinal disease, and severe episodes of anaphylaxis. Half of the patients present with recurrent skin, respiratory, and viral infections. Clinical laboratory testing is notable for eosinophilia and markedly elevated serum IgE levels. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the transcription factor STAT family.

Isoforms (3)

UniProt ID	Names	Canonical?
P42226-1	1	yes
P42226-2	2
P42226-3	3

RefSeq proteins (5): NP_001171549, NP_001171550, NP_001171551, NP_001171552, NP_003144* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000980	SH2	Domain
IPR001217	STAT	Family
IPR008967	p53-like_TF_DNA-bd_sf	Homologous_superfamily
IPR012345	STAT_TF_DNA-bd_N	Homologous_superfamily
IPR013799	STAT_TF_prot_interaction	Domain
IPR013800	STAT_TF_alpha	Domain
IPR013801	STAT_TF_DNA-bd	Domain
IPR015988	STAT_TF_CC	Homologous_superfamily
IPR028187	STAT6_C	Domain
IPR035857	STAT6_SH2	Domain
IPR036535	STAT_N_sf	Homologous_superfamily
IPR036860	SH2_dom_sf	Homologous_superfamily
IPR048988	STAT_linker	Domain

Pfam: PF00017, PF01017, PF02864, PF02865, PF14596, PF21354

UniProt features (81 total): helix 24, strand 23, sequence variant 12, turn 6, mutagenesis site 3, sequence conflict 3, splice variant 3, modified residue 2, initiator methionine 1, chain 1, domain 1, region of interest 1, short sequence motif 1

Structure

Experimental structures (PDB)

7 structures by resolution:

PDB	Title	Method	Resolution (Å)
1OJ5	Crystal structure of the Nco-A1 PAS-B domain bound to the STAT6 transactivation domain …	X-RAY DIFFRACTION	2.21
5NWX	Insight into the molecular recognition mechanism of the coactivator NCoA1 by STAT6	X-RAY DIFFRACTION	2.51
4Y5U	Transcription factor	X-RAY DIFFRACTION	2.71
4Y5W	Transcription factor-DNA complex	X-RAY DIFFRACTION	3.1
5D39	Transcription factor-DNA complex	X-RAY DIFFRACTION	3.2
9BIG	Stat6 bound to degrader AK-1690	X-RAY DIFFRACTION	3.3
5NWM	Insight into the molecular recognition mechanism of the coactivator NCoA1 by STAT6	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P42226-F1	77.44	0.55

Human Protein Atlas

Protein class: Predicted intracellular proteins, Transcription factors, Immunoglobulin fold, Cancer-related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; nucleoplasm; connecting piece

Antibody reliability (HPA): IH approved · IF supported

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 (2)

Type	Positions
N-acetylserine	2
Phosphotyrosine	641

Mutagenesis-validated functional residues (3)

Position	Phenotype
641	abolishes phosphorylation. loss of dna-binding transcription factor activity.
802	abolishes the interaction with ncoa1; when associated with a-805.
805	abolishes the interaction with ncoa1; when associated with a-802.

Function

Pathways and Gene Ontology

Reactome pathways

3 curated (TAS) of 15; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

15 pathways:

ID	Pathway	Evidence
R-HSA-186763	Downstream signal transduction	curated
R-HSA-6785807	Interleukin-4 and Interleukin-13 signaling	curated
R-HSA-3249367	STAT6-mediated induction of chemokines	curated
R-HSA-9938027	Affinity selection of immunoglobulins	electronic
R-HSA-1280215	Cytokine Signaling in Immune system	—
R-HSA-1834949	Cytosolic sensors of pathogen-associated DNA	—
R-HSA-9976102	Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	electronic
R-HSA-168256	Immune System	—
R-HSA-168249	Innate Immune System	—
R-HSA-1834941	STING mediated induction of host immune responses	—
R-HSA-162582	Signal Transduction	—
R-HSA-449147	Signaling by Interleukins	—
R-HSA-186797	Signaling by PDGF	—
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases	—
R-HSA-9938024	Somatic hypermutation of immunoglobulin genes	electronic

MSigDB gene sets: 582 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_REGULATION_OF_CELL_ACTIVATION, RNGTGGGC_UNKNOWN, CREL_01, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_DNA_RECOMBINATION, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_MAMMARY_GLAND_MORPHOGENESIS, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GNF2_MSN, GOBP_GLAND_MORPHOGENESIS, GNF2_BNIP2, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_INTERLEUKIN_4

GO Biological Process (14): DNA-templated transcription (GO:0006351), regulation of transcription by RNA polymerase II (GO:0006357), defense response (GO:0006952), cell surface receptor signaling pathway via JAK-STAT (GO:0007259), cytokine-mediated signaling pathway (GO:0019221), interleukin-4-mediated signaling pathway (GO:0035771), regulation of cell population proliferation (GO:0042127), response to peptide hormone (GO:0043434), positive regulation of transcription by RNA polymerase II (GO:0045944), growth hormone receptor signaling pathway via JAK-STAT (GO:0060397), positive regulation of cold-induced thermogenesis (GO:0120162), regulation of DNA-templated transcription (GO:0006355), signal transduction (GO:0007165), gene expression (GO:0010467)

GO Molecular Function (11): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), transcription coactivator binding (GO:0001223), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA-binding transcription factor activity (GO:0003700), protein phosphatase binding (GO:0019903), identical protein binding (GO:0042802), DNA binding (GO:0003677), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (6): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), RNA polymerase II transcription regulator complex (GO:0090575)

Reactome top-level categories

12 top-level categories:

Category	Pathways
Immune System	2
Signaling by PDGF	1
STING mediated induction of host immune responses	1
Signaling by Interleukins	1
Affinity selection of immunoglobulins	1
Immunoglobulin maturation	1
Differentiation of T cells	1
Cytosolic sensors of pathogen-associated DNA	1
Innate Immune System	1
Signaling by Receptor Tyrosine Kinases	1
Cytokine Signaling in Immune system	1
Signal Transduction	1

GO top-level categories

52 GO namespaces:

Category	Terms
cellular anatomical structure	4
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
regulation of cellular process	2
regulation of transcription by RNA polymerase II	2
transcription cis-regulatory region binding	2
gene expression	1
RNA biosynthetic process	1
response to stress	1
cell surface receptor signaling pathway via STAT	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
cytokine-mediated signaling pathway	1
cellular response to interleukin-4	1
cell population proliferation	1
response to hormone	1
response to nitrogen compound	1
response to oxygen-containing compound	1
positive regulation of DNA-templated transcription	1
growth hormone receptor signaling pathway	1
positive regulation of multicellular organismal process	1
cold-induced thermogenesis	1
regulation of cold-induced thermogenesis	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cell communication	1
cellular process	1
signaling	1
cellular response to stimulus	1
macromolecule biosynthetic process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
transcription coregulator binding	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
transcription regulator activity	1
phosphatase binding	1
protein binding	1
nucleic acid binding	1
binding	1
DNA binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
transcription regulator complex	1
nuclear protein-containing complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 14 of 31 annotations. The rest are phylogenetic / computational / electronic (IEA).

14 experimentally-supported GO terms:

GO term	NS	Evidence
cell surface receptor signaling pathway via JAK-STAT	BP	mutant phenotype
cytokine-mediated signaling pathway	BP	mutant phenotype
interleukin-4-mediated signaling pathway	BP	direct assay
positive regulation of transcription by RNA polymerase II	BP	direct assay
cytosol	CC	direct assay
nucleoplasm	CC	direct assay
nucleus	CC	direct assay
DNA-binding transcription activator activity, RNA polymerase II-specific	MF	direct assay
DNA-binding transcription factor activity	MF	direct assay
DNA-binding transcription factor activity, RNA polymerase II-specific	MF	mutant phenotype
RNA polymerase II transcription regulatory region sequence-specific DNA binding	MF	direct assay
identical protein binding	MF	physical interaction
protein phosphatase binding	MF	physical interaction
transcription coactivator binding	MF	experiment

Protein interactions and networks

STRING

showing 15 of 3,006 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
STAT6	IL4	P05112	952
STAT6	IL13	P35225	936
STAT6	IL4R	P24394	917
STAT6	NAB2	Q15742	894
STAT6	JAK1	P23458	878
STAT6	GATA3	P23771	871
STAT6	IL13RA1	P78552	857
STAT6	IFNG	P01579	851
STAT6	CD4	P01730	849
STAT6	IL5	P05113	832
STAT6	ARG1	P05089	822
STAT6	IL13RA2	Q14627	815
STAT6	IL10	P22301	814
STAT6	JAK3	P52333	814
STAT6	TBX21	Q9UL17	805

IntAct

Human interaction partners of STAT6 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

23 partners by confidence:

Partner	Interaction type	MIscore	Records
IL4R	association	0.640	4
STING1	physical association	0.630	10
TBK1	phosphorylation reaction	0.580	1
NMI	physical association	0.570	2
MAVS	association	0.460	3
EP300	physical association	0.400	2
PARP14	physical association	0.400	1
PLEC	physical association	0.400	1
ANKZF1	physical association	0.370	1
CEBPZ	physical association	0.370	1
DAZAP2	physical association	0.370	1
EEF1A1	physical association	0.370	1
RCN3	physical association	0.370	1
RLIM	physical association	0.370	1
STAT3	physical association	0.370	1
TFAP2C	physical association	0.370	1
TRIM24	physical association	0.370	1
WWP1	physical association	0.370	1
ZBTB2	physical association	0.370	1
ZNF407	physical association	0.370	1
ZNF92	physical association	0.370	1
INPPL1	association	0.350	1
PKNOX1	physical association	0.000	1

BioGRID (131 interactions; top human partners by supporting records): NCOA1 (Reconstituted Complex; 11 records), EP300 (Affinity Capture-Western; 8 records), SND1 (Affinity Capture-MS; 6 records), ANXA2 (Two-hybrid; 5 records), CREBBP (Reconstituted Complex; 5 records), IL4R (Reconstituted Complex; 4 records), IRF4 (Reconstituted Complex; 3 records), LITAF (Affinity Capture-Western; 3 records), PPARG (Affinity Capture-Western; 3 records), PTPN2 (Biochemical Activity; 3 records), SFPQ (Reconstituted Complex; 3 records), EEF1A1 (Co-fractionation; 2 records), JUN (Affinity Capture-Western; 2 records), NFKB1 (Affinity Capture-Western; 2 records), TRAF6 (Affinity Capture-Western; 2 records)

SIGNOR signaling

showing 28 of 33 signaling interactions:

A	Effect	B	Mechanism
MAPK8	down-regulates	STAT6	phosphorylation
TBK1	up-regulates	STAT6	phosphorylation
PTPN2	“down-regulates activity”	STAT6	dephosphorylation
JAK1	“up-regulates activity”	STAT6	phosphorylation
JAK2	“up-regulates activity”	STAT6	phosphorylation
STAT6	“up-regulates quantity by expression”	PPARG	“transcriptional regulation”
STAT6	“up-regulates quantity by expression”	PPARA	“transcriptional regulation”
STAT6	“up-regulates quantity by expression”	MRC1	“transcriptional regulation”
STAT6	“up-regulates quantity by expression”	RETN	“transcriptional regulation”
STAT6	“up-regulates quantity by expression”	CHI3L1	“transcriptional regulation”
STAT6	“up-regulates quantity by expression”	PPARGC1A	“transcriptional regulation”
STAT6	“up-regulates quantity by expression”	KDM6B	“transcriptional regulation”
STAT6	up-regulates	M2_polarization
STAT6	“down-regulates activity”	STAT1	binding
STAT6	“down-regulates activity”	NfKb-p65/p50	binding
STAT6	“up-regulates quantity by expression”	KLF4	“transcriptional regulation”
KLF4	up-regulates	STAT6
STAT6	“up-regulates quantity by expression”	SOCS1	“transcriptional regulation”
STAT6	up-regulates	ALOX15
STAT6	up-regulates	GATA3
STAT6	“up-regulates quantity by expression”	HSD3B2	“transcriptional regulation”
STAT6	“up-regulates quantity by expression”	SLC26A4	“transcriptional regulation”
PTPN1	“down-regulates activity”	STAT6	dephosphorylation
CBLB	“down-regulates quantity”	STAT6	ubiquitination
PTPN6	down-regulates	STAT6
STAT6	“down-regulates activity”	PPARG
STAT6	up-regulates	ARG1
SND1	“up-regulates activity”	STAT6	binding

Protein complexes (CORUM) (1)

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

1 complexes by size:

Complex	Subunits	Members
DHX9-SND1-STAT6 complex	3	DHX9, SND1, STAT6

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 3 cancer types — DLBCLNOS, MLYM, NHL.

intOGen’s role is a computational inference from cohort mutation patterns and may diverge from the gene’s curated/literature role; read it alongside the evidence above.

Genetic variants

Variant evidence for STAT6: 148 ClinVar records (6 pathogenic / likely pathogenic); 1 PharmGKB clinical annotation; 59 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	1
Uncertain significance	99
Likely benign	12
Benign	4

Top pathogenic / likely-pathogenic (6)

Showing all 6 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
2582689	NM_003153.5(STAT6):c.1255G>C (p.Asp419His)	Likely pathogenic	criteria provided, single submitter	3
2582687	NM_003153.5(STAT6):c.1256A>G (p.Asp419Gly)	Pathogenic	no assertion criteria provided	1
2582688	NM_003153.5(STAT6):c.1255G>T (p.Asp419Tyr)	Pathogenic	no assertion criteria provided	1
2582690	NM_003153.5(STAT6):c.1144G>C (p.Glu382Gln)	Pathogenic	no assertion criteria provided	1
2582691	NM_003153.5(STAT6):c.1555G>C (p.Asp519His)	Pathogenic	no assertion criteria provided	1
2582692	NM_003153.5(STAT6):c.1114G>A (p.Glu372Lys)	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore STAT6’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; 23 predictions of 1,965):

Position(s)	Effect	Δscore	Sites
12:57098770	donor_gain	1.0000
12:57098779	donor_gain	1.0000
12:57098798	donor_gain	1.0000
12:57099275	donor_gain	1.0000
12:57099994–57099995	donor_loss	1.0000	5
12:57100091–57100092	acceptor_loss	1.0000	6
12:57102289	donor_loss	1.0000	3
12:57102497	acceptor_gain	1.0000
12:57102497–57102498	acceptor_loss	1.0000	3
12:57102822	donor_gain	1.0000

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

1 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	0.000115

Disease associations

OMIM: gene MIM:601512 | disease phenotypes: MIM:620532

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
hyper-IgE syndrome 6, autosomal dominant, with recurrent infections	Strong	Autosomal dominant	2

ClinGen Gene-Disease Validity

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

1 validity classifications:

Disease	Classification	Inheritance
hyper-IgE syndrome 6, autosomal dominant, with recurrent infections	Strong	AD

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (1 panels, 1 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

1 panels:

Panel	Rating
Primary immunodeficiency or monogenic inflammatory bowel disease	green

Mondo (1): hyper-IgE syndrome 6, autosomal dominant, with recurrent infections (MONDO:0957807)

HPO phenotypes

46 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000016	Urinary retention
HP:0000290	Abnormal forehead morphology
HP:0000651	Diplopia
HP:0000939	Osteoporosis
HP:0001047	Atopic dermatitis
HP:0001581	Recurrent skin infections
HP:0001824	Weight loss
HP:0001880	Increased total eosinophil count
HP:0001943	Hypoglycemia
HP:0001945	Fever
HP:0001988	Recurrent hypoglycemia
HP:0002019	Constipation
HP:0002020	Gastroesophageal reflux
HP:0002099	Asthma
HP:0002205	Recurrent respiratory infections
HP:0002585	Abnormal peritoneum morphology
HP:0002664	Neoplasm
HP:0002896	Neoplasm of the liver
HP:0003212	Increased circulating IgE concentration
HP:0003419	Low back pain
HP:0003593	Infantile onset
HP:0004322	Short stature
HP:0004375	Neoplasm of the nervous system
HP:0004429	Recurrent viral infections
HP:0004912	Hypophosphatemic rickets
HP:0007185	Loss of consciousness
HP:0008775	Abnormal prostate morphology
HP:0010784	Uterine neoplasm
HP:0010787	Genital neoplasm
HP:0012125	Prostate cancer
HP:0012191	B-cell lymphoma
HP:0012378	Fatigue
HP:0030166	Night sweats
HP:0030795	Decreased circulating C-peptide concentration
HP:0031459	Soft tissue neoplasm
HP:0031501	Pelvic mass
HP:0032064	Gastrointestinal eosinophilia
HP:0040216	Hypoinsulinemia
HP:0045026	Abnormal mediastinum morphology
HP:0100526	Neoplasm of the lung
HP:0100527	Neoplasia of the pleura
HP:0100650	Vaginal neoplasm
HP:0100845	Anaphylactic shock
HP:0410151	Eosinophilic infiltration of the esophagus
HP:0500093	Food allergy

GWAS associations

showing 30 of 59 associations:

Study	Trait	p-value
GCST010002_69	Refractive error	6e-174
GCST003720_1	Migraine	6e-49
GCST005337_1	Headache	5e-47
GCST010043_47	Asthma	3e-39
GCST007800_15	Asthma (childhood onset)	2e-34
GCST007798_56	Asthma	8e-34
GCST010042_84	Asthma	3e-32
GCST009798_35	Asthma	3e-29
GCST009720_16	Asthma	1e-28
GCST007798_55	Asthma	6e-28
GCST008916_32	Asthma	1e-27
GCST90014325_27	Asthma	5e-26
GCST005038_113	Allergic disease (asthma, hay fever or eczema)	1e-22
GCST007799_14	Asthma (adult onset)	5e-20
GCST004606_162	Eosinophil count	5e-18
GCST004600_57	Eosinophil percentage of white cells	6e-18
GCST90002381_392	Eosinophil count	8e-18
GCST90002382_497	Eosinophil percentage of white cells	2e-17
GCST004617_72	Eosinophil percentage of granulocytes	3e-17
GCST004624_28	Sum eosinophil basophil counts	5e-17
GCST007941_30	Medication use (adrenergics, inhalants)	6e-17
GCST007995_40	Asthma (childhood onset)	7e-17
GCST003721_7	Migraine without aura	4e-16
GCST007934_4	Medication use (anti-inflammatory and antirheumatic products, non-steroids)	1e-15
GCST004623_24	Neutrophil percentage of granulocytes	2e-15
GCST002084_10	Allergic sensitization	1e-14
GCST004861_90	Itch intensity from mosquito bite	3e-13
GCST006911_24	Asthma (moderate or severe)	4e-13
GCST007564_8	Asthma or allergic disease (pleiotropy)	8e-13
GCST001316_2	IgE levels	2e-12

EFO canonical traits (from GWAS)

17 canonical traits:

EFO ID	Trait name
EFO:0005298	allergic sensitization measurement
EFO:0005324	post-operative sensory disturbance
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004842	eosinophil count
EFO:0007996	eosinophil percentage of granulocytes
EFO:0007994	neutrophil percentage of granulocytes
EFO:0005090	basophil count
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0008380	perceived unattractiveness to mosquitos measurement
EFO:0006953	family history of lung cancer
EFO:0004847	age at onset
EFO:1002011	adult onset asthma
EFO:0009935	Non-steroidal anti-inflammatory and antirheumatic product use measurement
EFO:0009941	Inhalant adrenergic use measurement
EFO:0009943	Antihistamine use measurement
EFO:0010092	bitter alcoholic beverage consumption measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4523694 (PROTEIN-PROTEIN INTERACTION), CHEMBL5401 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 645,075 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

11 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL477	ADENOSINE	4	224,426
CHEMBL660	AMANTADINE	4	70,248
CHEMBL43	AMSACRINE	4	83,286
CHEMBL942	BISACODYL	4	14,793
CHEMBL359744	DOXORUBICIN HYDROCHLORIDE	4	143,174
CHEMBL1200916	THIORIDAZINE HYDROCHLORIDE	4	14,260
CHEMBL50	QUERCETIN	3	75,572
CHEMBL84158	TIAPRIDE	3	3,552
CHEMBL22077	HYCANTHONE	2	2,233
CHEMBL86754	IODOQUINOL	2	4,622
CHEMBL417799	SANGUINARIUM	2	8,909

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB clinical annotations

1 annotations by evidence level (1 strongest → 4):

Variant	Association	Level	Drugs	Phenotypes
rs1059513	Efficacy	3	esomeprazole	eosinophilic esophagitis

PharmGKB variants

1 variants:

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1059513	NAB2, STAT6	3	2.25	1	esomeprazole

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

2 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs1059513	esomeprazole	Efficacy	Genotypes CC + CT are associated with increased response to esomeprazole in children with eosinophilic esophagitis as compared to genotype TT.	PMID:31490856
rs324011	Protein kinase inhibitors	Toxicity	Genotype TT is associated with increased severity of adverse events when treated with Protein kinase inhibitors in people with Carcinoma, Non-Small-Cell Lung as compared to genotypes CC + CT.	PMID:37151185

GtoPdb / IUPHAR curated pharmacology

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

Target class: other protein — STAT transcription factors

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
AK-1690	Binding	8.0	pKi
AS-1517499	Inhibition	7.68	pIC50
compound 19a [PMID: 26506089]	Inhibition	7.55	pIC50

Binding affinities (BindingDB)

360 measured of 386 human assays (399 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
AS-1617612	IC50	0.7 nM
2-(4-morpholinophenylamino)-4-(2,3,6-trifluorobenzylamino)pyrimidine-5-carboxamide	IC50	0.7 nM
4-[(2-Fluorobenzyl)amino]-2-[(4-morpholin-4-ylphenyl)amino]pyrimidine-5-carboxamide	IC50	1.4 nM
4-[(2,5-Difluorobenzyl)amino]-2-[(4-morpholin-4-ylphenyl)amino]pyrimidine-5-carboxamide	IC50	1.6 nM
2-[(4-Morpholin-4-ylphenyl)amino]-4-[(2,3,5-trifluorobenzyl)amino]pyrimidine-5-carboxamid	IC50	1.8 nM
4-[(3-Fluorobenzyl)amino]-2-[(4-morpholin-4-ylphenyl)amino]pyrimidine-5-carboxamide	IC50	1.8 nM
2-[4-(4-{[7-(3,5-Difluorobenzyl)-7H-pyrrolo[2,3-d]-pyrimidin-2-yl]amino}phenyl)piperazin-1-yl]acetamide	IC50	1.9 nM
4-[(2,3-Difluorobenzyl)amino]-2-[(4-morpholin-4-ylphenyl)amino]pyrimidine-5-carboxamide	IC50	2.1 nM
4-[(2,6-Difluorobenzyl)amino]-2-[(4-morpholin-4-ylphenyl)amino]pyrimidine-5-carboxamide	IC50	2.2 nM
7-(3,5-Difluorobenzyl)-N-[4-(4-methylpiperazin-1-yl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-2-amine	IC50	3.2 nM
2-[4-(4-{[7-(3,5-Difluorobenzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}phenyl)piperazin-1-yl]-N-methylacetamide	IC50	4.7 nM
4-[(3,5-Difluorobenzyl)amino]-2-[(4-morpholin-4-ylphenyl)amino]pyrimidine-5-carboxamide	IC50	5.5 nM
2-[4-(4-{[7-(3,5-Difluorobenzyl)-7H-pyrrolo[2,3-d]-pyrimidin-2-yl]amino}phenyl)piperazin-1-yl]ethanol	IC50	5.6 nM
4-Benzylamino-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidine-5-carboxamide	IC50	6.2 nM
4-(benzylamino)-2-(4-morpholinophenylamino)pyrimidine-5-carboxamide	IC50	6.5 nM
4-Benzylamino-2-[(4-piperazin-1-ylphenyl)amino]-pyrimidine-5-carboxamide	IC50	7 nM
4-[(2-Chlorobenzyl)amino]-2-[(4-morpholin-4-ylphenyl)amino]pyrimidine-5-carboxamide	IC50	7.9 nM
4-[(2-Methoxybenzyl)amino]-2-[(4-morpholin-4-ylphenyl)amino]pyrimidine-5-carboxamide	IC50	8.2 nM
2-Amino-5-[2-[[4-[4- (dimethylcarbamoyl)phenyl]-1- piperidyl]methyl]-1-methyl- pyrrolo[2,3-b]pyridin-4-yl]benzoic acid	KD	9.05 nM	US-20250340551: SMALL MOLECULE MODULATORS OF STAT6
4-[(2-Methylbenzyl)amino]-2-[(4-morpholin-4-ylphenyl)amino]pyrimidine-5-carboxamide	IC50	11 nM
Ethyl 6-amino-3-[2-[[4-[4- (dimethylcarbamoyl)phenyl]-1- piperidyl]methyl]-1-methyl- pyrrolo[2,3-b]pyridin-4-yl]pyridine-2- carboxylate	KD	11 nM	US-20250340551: SMALL MOLECULE MODULATORS OF STAT6
4-[1-[[4-(6-amino-3-pyridinyl)-1-methylpyrrolo[2,3-b]pyridin-2-yl]methyl]piperidin-4-yl]-N-[4-[1-[[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxobenzimidazol-5-yl]methyl]piperidin-4-yl]phenyl]-N-methylbenzamide	KD	11.4 nM	US-20250325677: STAT6 DEGRADERS
4-[1-[[4-(6-Amino-3-pyridyl)-1- methyl-pyrrolo[2,3-b]pyridin-2- yl]methyl]-4-piperidyl]-N,N-dimethyl- benzamide	KD	11.4 nM	US-20250340551: SMALL MOLECULE MODULATORS OF STAT6
7-(3,5-Difluorobenzyl)-N-(4-piperazin-1-ylphenyl)-7Hpyrrolo[2,3-d]pyrimidin-2-amine	IC50	12 nM
2-(2-Amino-5-(2-((4-(4- (dimethylcarbamoyl)phenyl)piperidin- 1-yl)methyl)-1-methyl-1H-pyrrolo[2,3- b]pyridin-4-yl)phenyl)-2-oxoacetic acid	KD	12.8 nM	US-20250340551: SMALL MOLECULE MODULATORS OF STAT6
4-[1-[(1R)-1-[4-(6-amino-3-pyridinyl)-1-methylpyrrolo[2,3-b]pyridin-2-yl]ethyl]piperidin-4-yl]-N,N-dimethylbenzamide	KD	12.9 nM	US-20250340551: SMALL MOLECULE MODULATORS OF STAT6
4-[1-[[4-(6-Aminopyridazin-3-yl)-1- methyl-pyrrolo[2,3-b]pyridin-2- yl]methyl]-4-piperidyl]-N,N-dimethyl- benzamide	KD	13.5 nM	US-20250340551: SMALL MOLECULE MODULATORS OF STAT6
N,N-dimethyl-4-[1-[(1R)-1-[1-methyl-4-[6-(methylamino)-3-pyridinyl]pyrrolo[2,3-b]pyridin-2-yl]ethyl]piperidin-4-yl]benzamide	KD	14.6 nM	US-20250340551: SMALL MOLECULE MODULATORS OF STAT6
4-[1-[(1R)-1-[4-(5-amino-2-pyridinyl)-1-methylpyrrolo[2,3-b]pyridin-2-yl]ethyl]-3,6-dihydro-2H-pyridin-4-yl]-3-methyl-N,N-bis(trideuteriomethyl)benzamide	KD	15.4 nM	US-20250340551: SMALL MOLECULE MODULATORS OF STAT6
4-[1-[(1R)-1-[4-(5-amino-2-pyridinyl)-1-methylpyrrolo[2,3-b]pyridin-2-yl]ethyl]piperidin-4-yl]-N,N-dimethylbenzamide	KD	15.5 nM	US-20250340551: SMALL MOLECULE MODULATORS OF STAT6
4-[1-[(1R)-1-[4-(5-amino-2-pyridinyl)-1-methylpyrrolo[2,3-b]pyridin-2-yl]ethyl]piperidin-4-yl]-N,N-bis(trideuteriomethyl)benzamide	KD	15.7 nM	US-20250340551: SMALL MOLECULE MODULATORS OF STAT6
4-Benzylamino-2-{[4-(4-hydroxypiperidin-1-yl)phenyl]amino}pyrimidine-5-carboxamide	IC50	16 nM
N,N-Dimethyl-4-[1-[1-methyl-4-[6- (methylamino)-3-pyridyl]pyrrolo[2,3- b]pyridin-2-yl]methyl]-4- piperidyl]benzamide	KD	16 nM	US-20250340551: SMALL MOLECULE MODULATORS OF STAT6
N,N,3-Trimethyl-4-[1-[[1-methyl-4-[5- (methylamino)-1-oxido-pyridin-1-ium- 2-yl]pyrrolo[2,3-b]pyridin-2- yl]methyl]-3,6-dihydro-2H-pyridin-4- yl]benzamide	KD	16 nM	US-20250340551: SMALL MOLECULE MODULATORS OF STAT6
2-[[5-[2-[[4-[4- (Dimethylcarbamoyl)phenyl]-1- piperidyl]methyl]-1-methyl- pyrrolo[2,3-b]pyridin-4-yl]-2- pyridyl]amino]acetic acid	KD	16.3 nM	US-20250340551: SMALL MOLECULE MODULATORS OF STAT6
4-[1-[[4-[6-(2-Hydroxyethylamino)-3- pyridyl]-1-methyl-pyrrolo[2,3- b]pyridin-2-yl]methyl]-4-piperidyl]- N,N-dimethyl-benzamide	KD	16.5 nM	US-20250340551: SMALL MOLECULE MODULATORS OF STAT6
Methyl 2-[[5-[2-[[4-[4- (dimethylcarbamoyl)phenyl]-1- piperidyl]methyl]-1-methyl- pyrrolo[2,3-b]pyridin-4-yl]-2- pyridyl]amino]acetate	KD	16.8 nM	US-20250340551: SMALL MOLECULE MODULATORS OF STAT6
4-Benzylamino-2-{[4-(1-methylpiperidin-4-yl)phenyl]-amino}pyrimidine-5-carboxamide	IC50	17 nM
N,N-Dimethyl-4-[(2R,4R)-1-[[4-(5- amino-2-pyridyl)-1-methyl- pyrrolo[2,3-b]pyridin-2-yl]methyl]-2- methyl-4-piperidyl]benzamide and N,N-dimethyl-4-[(2S,4S)-1-[[4-(5- amino-2-pyridyl)-1-methyl- pyrrolo[2,3-b]pyridin-2-yl]methyl]-2- methyl-4-piperidyl]benzamide	KD	18.1 nM	US-20250340551: SMALL MOLECULE MODULATORS OF STAT6
N,N-Dimethyl-4-[(2R,4R)-1-[[4-(6- amino-2-cyano-3-pyridyl)-1-methyl- pyrrolo[2,3-b]pyridin-2-yl]methyl]-2- methyl-4-piperidyl]benzamide and N,N-dimethyl-4-[(2S,4S)-1-[[4-(6- amino-2-cyano-3-pyridyl)-1-methyl- pyrrolo[2,3-b]pyridin-2-yl]methyl]-2- methyl-4-piperidyl]benzamide	KD	18.4 nM	US-20250340551: SMALL MOLECULE MODULATORS OF STAT6
4-[1-[(1R)-1-[4-(6-amino-2-cyano-3-pyridinyl)-1-methylpyrrolo[2,3-b]pyridin-2-yl]ethyl]piperidin-4-yl]-N,N-dimethylbenzamide	KD	18.5 nM	US-20250340551: SMALL MOLECULE MODULATORS OF STAT6
4-[1-[(1R)-1-[4-(5-amino-2-pyridinyl)-1-methylpyrrolo[2,3-b]pyridin-2-yl]ethyl]-3,6-dihydro-2H-pyridin-4-yl]-N,N,3-trimethylbenzamide	KD	18.6 nM	US-20250340551: SMALL MOLECULE MODULATORS OF STAT6
4-(1-((4-(5-Aminopyridin-2-yl)-1- methyl-1H-pyrrolo[2,3-b]pyridin-2- yl)methyl)piperidin-4-yl)-N,N- dimethylbenzamide	KD	18.8 nM	US-20250340551: SMALL MOLECULE MODULATORS OF STAT6
4-[(3-Hydroxybenzyl)amino]-2-[(4-morpholin-4-ylphenyl)amino]pyrimidine-5-carboxamide	IC50	19 nM
N,N,3-Trimethyl-4-[4-[[1-methyl-4-[6- (methylamino)pyridazin-3- yl]pyrrolo[2,3-b]pyridin-2- yl]methyl]piperazin-1-yl]benzamide	KD	19.2 nM	US-20250340551: SMALL MOLECULE MODULATORS OF STAT6
4-[1-[(1R)-1-[4-(6-amino-2-cyano-3-pyridinyl)-1-methylpyrrolo[2,3-b]pyridin-2-yl]ethyl]-3,6-dihydro-2H-pyridin-4-yl]-3-methyl-N,N-bis(trideuteriomethyl)benzamide	KD	20 nM	US-20250340551: SMALL MOLECULE MODULATORS OF STAT6
4-[1-[[4-(6-Amino-2-methyl-3- pyridyl)-1-methyl-pyrrolo[2,3- b]pyridin-2-yl]methyl]-4-piperidyl]- N,N-dimethyl-benzamide	KD	20.1 nM	US-20250340551: SMALL MOLECULE MODULATORS OF STAT6
4-[(3R,4S)-3-fluoro-1-[[1-methyl-4-[6-(methylamino)-3-pyridinyl]pyrrolo[2,3-b]pyridin-2-yl]methyl]piperidin-4-yl]-N,N-dimethylbenzamide	KD	20.6 nM	US-20250340551: SMALL MOLECULE MODULATORS OF STAT6
AS-1517499	IC50	21 nM
4-[1-[(1R)-1-[4-(6-amino-2-cyano-3-pyridinyl)-1-methylpyrrolo[2,3-b]pyridin-2-yl]ethyl]-3,6-dihydro-2H-pyridin-4-yl]-N,N,3-trimethylbenzamide	KD	21.6 nM	US-20250340551: SMALL MOLECULE MODULATORS OF STAT6

ChEMBL bioactivities

312 potent at pChembl≥5 of 468 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.15	IC50	0.7	nM	CHEMBL487451
9.15	IC50	0.7	nM	CHEMBL593171
8.85	IC50	1.4	nM	CHEMBL470963
8.80	IC50	1.6	nM	CHEMBL488814
8.74	IC50	1.8	nM	CHEMBL519249
8.74	IC50	1.8	nM	CHEMBL512874
8.72	IC50	1.9	nM	CHEMBL595058
8.68	IC50	2.1	nM	CHEMBL529443
8.66	IC50	2.2	nM	CHEMBL519410
8.49	IC50	3.2	nM	CHEMBL596420
8.33	IC50	4.7	nM	CHEMBL606350
8.26	IC50	5.5	nM	CHEMBL487450
8.25	IC50	5.6	nM	CHEMBL596421
8.22	Ki	6	nM	CHEMBL6169609
8.22	Ki	6	nM	CHEMBL6148327
8.22	Ki	6	nM	CHEMBL6169593
8.21	IC50	6.2	nM	CHEMBL470949
8.20	Potency	6.3	nM	CHEMBL1380504
8.19	IC50	6.5	nM	CHEMBL471114
8.15	IC50	7	nM	CHEMBL471113
8.10	IC50	7.9	nM	CHEMBL471131
8.09	IC50	8.2	nM	CHEMBL469910
8.00	Ki	10	nM	CHEMBL6132917
8.00	Ki	10	nM	CHEMBL6146875
7.96	IC50	11	nM	CHEMBL512533
7.92	IC50	12	nM	CHEMBL594344
7.90	Potency	12.6	nM	CHEMBL1544947
7.80	IC50	16	nM	CHEMBL517122
7.77	IC50	17	nM	CHEMBL513401
7.72	IC50	19	nM	CHEMBL487460
7.70	IC50	20	nM	CHEMBL5280678
7.68	IC50	21	nM	CHEMBL228192
7.66	IC50	22	nM	CHEMBL471130
7.64	IC50	23	nM	CHEMBL486643
7.60	IC50	25	nM	CHEMBL471743
7.60	IC50	25	nM	CHEMBL512519
7.58	IC50	26	nM	CHEMBL595488
7.55	IC50	28	nM	CHEMBL3741938
7.52	IC50	30	nM	CHEMBL226930
7.48	Ki	33	nM	CHEMBL6142401
7.47	IC50	34	nM	CHEMBL594821
7.44	IC50	36	nM	CHEMBL471559
7.43	IC50	37	nM	CHEMBL603203
7.42	IC50	38	nM	CHEMBL520234
7.38	Ki	42	nM	CHEMBL6169635
7.36	IC50	44	nM	CHEMBL3741162
7.35	IC50	45	nM	CHEMBL228018
7.30	IC50	50	nM	CHEMBL5410106
7.25	IC50	56	nM	CHEMBL5267203
7.24	Ki	57	nM	CHEMBL6152739

PubChem BioAssay actives

198 with measured affinity, of 337 total; 50 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-(4-morpholin-4-ylanilino)-4-[(2,3,6-trifluorophenyl)methylamino]pyrimidine-5-carboxamide	452105: Inhibition of STAT6 in IL4-stimulated human FW4 reporter cells by luciferase assay	ic50	0.0007	uM
2-(4-morpholin-4-ylanilino)-4-[(2,4,6-trifluorophenyl)methylamino]pyrimidine-5-carboxamide	343057: Inhibition of STAT6 activation in FW4 reporter cells	ic50	0.0007	uM
4-[(2-fluorophenyl)methylamino]-2-(4-morpholin-4-ylanilino)pyrimidine-5-carboxamide	343057: Inhibition of STAT6 activation in FW4 reporter cells	ic50	0.0014	uM
4-[(2,5-difluorophenyl)methylamino]-2-(4-morpholin-4-ylanilino)pyrimidine-5-carboxamide	343057: Inhibition of STAT6 activation in FW4 reporter cells	ic50	0.0016	uM
2-(4-morpholin-4-ylanilino)-4-[(2,3,5-trifluorophenyl)methylamino]pyrimidine-5-carboxamide	343057: Inhibition of STAT6 activation in FW4 reporter cells	ic50	0.0018	uM
4-[(3-fluorophenyl)methylamino]-2-(4-morpholin-4-ylanilino)pyrimidine-5-carboxamide	343057: Inhibition of STAT6 activation in FW4 reporter cells	ic50	0.0018	uM
2-[4-[4-[[7-[(3,5-difluorophenyl)methyl]pyrrolo[2,3-d]pyrimidin-2-yl]amino]phenyl]piperazin-1-yl]acetamide	452105: Inhibition of STAT6 in IL4-stimulated human FW4 reporter cells by luciferase assay	ic50	0.0019	uM
4-[(2,3-difluorophenyl)methylamino]-2-(4-morpholin-4-ylanilino)pyrimidine-5-carboxamide	343057: Inhibition of STAT6 activation in FW4 reporter cells	ic50	0.0021	uM
4-[(2,6-difluorophenyl)methylamino]-2-(4-morpholin-4-ylanilino)pyrimidine-5-carboxamide	343057: Inhibition of STAT6 activation in FW4 reporter cells	ic50	0.0022	uM
7-[(3,5-difluorophenyl)methyl]-N-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,3-d]pyrimidin-2-amine	452105: Inhibition of STAT6 in IL4-stimulated human FW4 reporter cells by luciferase assay	ic50	0.0032	uM
2-[4-[4-[[7-[(3,5-difluorophenyl)methyl]pyrrolo[2,3-d]pyrimidin-2-yl]amino]phenyl]piperazin-1-yl]-N-methylacetamide	452105: Inhibition of STAT6 in IL4-stimulated human FW4 reporter cells by luciferase assay	ic50	0.0047	uM
4-[(3,5-difluorophenyl)methylamino]-2-(4-morpholin-4-ylanilino)pyrimidine-5-carboxamide	343057: Inhibition of STAT6 activation in FW4 reporter cells	ic50	0.0055	uM
2-[4-[4-[[9-[(3,5-difluorophenyl)methyl]purin-2-yl]amino]phenyl]piperazin-1-yl]ethanol	452105: Inhibition of STAT6 in IL4-stimulated human FW4 reporter cells by luciferase assay	ic50	0.0056	uM
[[2-[[(2S)-3,3-dimethyl-1-oxo-1-[(2S)-2-[(2R)-2-phenylmorpholine-4-carbonyl]pyrrolidin-1-yl]butan-2-yl]carbamoyl]-1-benzothiophen-5-yl]-difluoromethyl]phosphonic acid	2231010: Binding affinity to N-terminal his6-tgged STAT6 (unknown origin) (113 to 658 residues) assessed as inhibition constant incubated for 1 hr by fluorescence polarization assay	ki	0.0060	uM
[difluoro-[2-[[(2S)-1-[(2S,4S)-4-methoxy-2-[(2R)-2-phenylmorpholine-4-carbonyl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl]-1-benzothiophen-5-yl]methyl]phosphonic acid	2231010: Binding affinity to N-terminal his6-tgged STAT6 (unknown origin) (113 to 658 residues) assessed as inhibition constant incubated for 1 hr by fluorescence polarization assay	ki	0.0060	uM
[[2-[[(2S)-1-[(2S,4S)-4-acetamido-2-[(2R)-2-phenylmorpholine-4-carbonyl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl]-1-benzothiophen-5-yl]-difluoromethyl]phosphonic acid	2231010: Binding affinity to N-terminal his6-tgged STAT6 (unknown origin) (113 to 658 residues) assessed as inhibition constant incubated for 1 hr by fluorescence polarization assay	ki	0.0060	uM
4-(benzylamino)-2-[4-(4-methylpiperazin-1-yl)anilino]pyrimidine-5-carboxamide	343057: Inhibition of STAT6 activation in FW4 reporter cells	ic50	0.0062	uM
4-(benzylamino)-2-(4-morpholin-4-ylanilino)pyrimidine-5-carboxamide	343057: Inhibition of STAT6 activation in FW4 reporter cells	ic50	0.0065	uM
4-(benzylamino)-2-(4-piperazin-1-ylanilino)pyrimidine-5-carboxamide	343057: Inhibition of STAT6 activation in FW4 reporter cells	ic50	0.0070	uM
4-[(2-chlorophenyl)methylamino]-2-(4-morpholin-4-ylanilino)pyrimidine-5-carboxamide	343057: Inhibition of STAT6 activation in FW4 reporter cells	ic50	0.0079	uM
4-[(2-methoxyphenyl)methylamino]-2-(4-morpholin-4-ylanilino)pyrimidine-5-carboxamide	343057: Inhibition of STAT6 activation in FW4 reporter cells	ic50	0.0082	uM
[difluoro-[2-[[(2S)-1-[(2S,4S)-4-hydroxy-2-[(2R)-2-phenylmorpholine-4-carbonyl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl]-1-benzothiophen-5-yl]methyl]phosphonic acid	2231010: Binding affinity to N-terminal his6-tgged STAT6 (unknown origin) (113 to 658 residues) assessed as inhibition constant incubated for 1 hr by fluorescence polarization assay	ki	0.0100	uM
[[2-[[(2S)-1-[(2S,4S)-4-amino-2-[(2R)-2-phenylmorpholine-4-carbonyl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl]-1-benzothiophen-5-yl]-difluoromethyl]phosphonic acid	2231010: Binding affinity to N-terminal his6-tgged STAT6 (unknown origin) (113 to 658 residues) assessed as inhibition constant incubated for 1 hr by fluorescence polarization assay	ki	0.0100	uM
4-[(2-methylphenyl)methylamino]-2-(4-morpholin-4-ylanilino)pyrimidine-5-carboxamide	343057: Inhibition of STAT6 activation in FW4 reporter cells	ic50	0.0110	uM
7-[(3,5-difluorophenyl)methyl]-N-(4-piperazin-1-ylphenyl)pyrrolo[2,3-d]pyrimidin-2-amine	452105: Inhibition of STAT6 in IL4-stimulated human FW4 reporter cells by luciferase assay	ic50	0.0120	uM
4-(benzylamino)-2-[4-(4-hydroxypiperidin-1-yl)anilino]pyrimidine-5-carboxamide	343057: Inhibition of STAT6 activation in FW4 reporter cells	ic50	0.0160	uM
4-(benzylamino)-2-[4-(1-methylpiperidin-4-yl)anilino]pyrimidine-5-carboxamide	343057: Inhibition of STAT6 activation in FW4 reporter cells	ic50	0.0170	uM
4-[(3-hydroxyphenyl)methylamino]-2-(4-morpholin-4-ylanilino)pyrimidine-5-carboxamide	343057: Inhibition of STAT6 activation in FW4 reporter cells	ic50	0.0190	uM
(5R,6S,9E)-16-chloro-13,15-dihydroxy-5,6,10-trimethyl-4-oxabicyclo[10.4.0]hexadeca-1(12),9,13,15-tetraene-3,11-dione	1954728: Inhibition of IL-4 induced STAT6 signaling in human HepG2 cells harboring pRL-EF1alpha, pGL3-TK-7xN4 and TOPO-Stat6 plasmid assessed as luciferase activity incubated for 24 hrs by Promega reporter rene assay	ic50	0.0200	uM
4-(benzylamino)-2-[2-(3-chloro-4-hydroxyphenyl)ethylamino]pyrimidine-5-carboxamide	284275: Inhibition of STAT6 in human IL4-stimulated FW4 cells	ic50	0.0210	uM
4-[(2-hydroxyphenyl)methylamino]-2-(4-morpholin-4-ylanilino)pyrimidine-5-carboxamide	343057: Inhibition of STAT6 activation in FW4 reporter cells	ic50	0.0220	uM
4-[(2-methylsulfanylphenyl)methylamino]-2-(4-morpholin-4-ylanilino)pyrimidine-5-carboxamide	343057: Inhibition of STAT6 activation in FW4 reporter cells	ic50	0.0230	uM
4-[(3-methoxyphenyl)methylamino]-2-(4-morpholin-4-ylanilino)pyrimidine-5-carboxamide	343057: Inhibition of STAT6 activation in FW4 reporter cells	ic50	0.0250	uM
2-(4-morpholin-4-ylanilino)-4-[[2-(trifluoromethyl)phenyl]methylamino]pyrimidine-5-carboxamide	343057: Inhibition of STAT6 activation in FW4 reporter cells	ic50	0.0250	uM
2-[4-[4-[[7-[(3,5-difluorophenyl)methyl]pyrrolo[2,3-d]pyrimidin-2-yl]amino]phenyl]piperazin-1-yl]acetic acid	452105: Inhibition of STAT6 in IL4-stimulated human FW4 reporter cells by luciferase assay	ic50	0.0260	uM
[4-[(E)-4-[[(2S)-1-[(2S)-2-[(4-iodophenyl)-phenylcarbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]amino]-4-oxobut-2-en-2-yl]phenyl] dihydrogen phosphate	1264595: Inhibition of STAT6 (unknown origin) expressed in Escherichia coli using FAM-Ala-pTyr-Lys-ProPhe-Gln-Asp-Leu-Ile-NH2 as substrate by fluorescence polarization assay	ic50	0.0280	uM
4-(benzylamino)-2-[2-(3-chloro-4-hydroxyphenyl)ethylamino]-N-methylpyrimidine-5-carboxamide	284275: Inhibition of STAT6 in human IL4-stimulated FW4 cells	ic50	0.0300	uM
[[2-[[(2S)-3,3-dimethyl-1-oxo-1-[(1S)-1-[(2R)-2-phenylmorpholine-4-carbonyl]-1,3-dihydroisoindol-2-yl]butan-2-yl]carbamoyl]-1-benzothiophen-5-yl]-difluoromethyl]phosphonic acid	2231010: Binding affinity to N-terminal his6-tgged STAT6 (unknown origin) (113 to 658 residues) assessed as inhibition constant incubated for 1 hr by fluorescence polarization assay	ki	0.0330	uM
N-[4-[4-(2-aminoethyl)piperazin-1-yl]phenyl]-7-[(3,5-difluorophenyl)methyl]pyrrolo[2,3-d]pyrimidin-2-amine	452105: Inhibition of STAT6 in IL4-stimulated human FW4 reporter cells by luciferase assay	ic50	0.0340	uM
4-[(3-chlorophenyl)methylamino]-2-(4-morpholin-4-ylanilino)pyrimidine-5-carboxamide	343057: Inhibition of STAT6 activation in FW4 reporter cells	ic50	0.0360	uM
7-[(3-fluorophenyl)methyl]-N-(4-morpholin-4-ylphenyl)pyrrolo[2,3-d]pyrimidin-2-amine	452105: Inhibition of STAT6 in IL4-stimulated human FW4 reporter cells by luciferase assay	ic50	0.0370	uM
2-(4-morpholin-4-ylanilino)-4-[(2-nitrophenyl)methylamino]pyrimidine-5-carboxamide	343057: Inhibition of STAT6 activation in FW4 reporter cells	ic50	0.0380	uM
[[2-[[(2S)-3,3-dimethyl-1-oxo-1-[(1S)-1-[(3R)-3-phenylpiperidine-1-carbonyl]-1,3-dihydroisoindol-2-yl]butan-2-yl]carbamoyl]-1-benzothiophen-5-yl]-difluoromethyl]phosphonic acid	2231010: Binding affinity to N-terminal his6-tgged STAT6 (unknown origin) (113 to 658 residues) assessed as inhibition constant incubated for 1 hr by fluorescence polarization assay	ki	0.0420	uM
[4-[(E)-3-[[(2S)-1-[(2S)-2-[(4-iodophenyl)-phenylcarbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]amino]-3-oxoprop-1-enyl]phenyl] dihydrogen phosphate	1264595: Inhibition of STAT6 (unknown origin) expressed in Escherichia coli using FAM-Ala-pTyr-Lys-ProPhe-Gln-Asp-Leu-Ile-NH2 as substrate by fluorescence polarization assay	ic50	0.0440	uM
2-[2-(3-chloro-4-hydroxyphenyl)ethylamino]-4-(3-methylanilino)pyrimidine-5-carboxamide	284275: Inhibition of STAT6 in human IL4-stimulated FW4 cells	ic50	0.0450	uM
(5R,6S,7S,9E)-16-chloro-7,13,15-trihydroxy-5,6,10-trimethyl-4-oxabicyclo[10.4.0]hexadeca-1(12),9,13,15-tetraene-3,11-dione	1985589: Inhibition of IL-4 induced STAT6 signaling in human HepG2 cells harboring pRL-EF1alpha, pGL3-TK-7xN4 and TOPO-Stat6 plasmid assessed as luciferase activity incubated for 24 hrs	ic50	0.0500	uM
(5R,6S,7R,9E)-16-chloro-7,13,15-trihydroxy-5,6,10-trimethyl-4-oxabicyclo[10.4.0]hexadeca-1(12),9,13,15-tetraene-3,11-dione	1954728: Inhibition of IL-4 induced STAT6 signaling in human HepG2 cells harboring pRL-EF1alpha, pGL3-TK-7xN4 and TOPO-Stat6 plasmid assessed as luciferase activity incubated for 24 hrs by Promega reporter rene assay	ic50	0.0560	uM
[[2-[[(2S)-3,3-dimethyl-1-oxo-1-[(2S)-2-[(3R)-3-phenylpiperidine-1-carbonyl]pyrrolidin-1-yl]butan-2-yl]carbamoyl]-1-benzothiophen-5-yl]-difluoromethyl]phosphonic acid	2231010: Binding affinity to N-terminal his6-tgged STAT6 (unknown origin) (113 to 658 residues) assessed as inhibition constant incubated for 1 hr by fluorescence polarization assay	ki	0.0570	uM
4-(benzylamino)-2-[2-(3,5-dichloro-4-hydroxyphenyl)ethylamino]pyrimidine-5-carboxamide	343057: Inhibition of STAT6 activation in FW4 reporter cells	ic50	0.0610	uM
(5R,6S,7S,9Z)-16-chloro-7,13,15-trihydroxy-5,6,10-trimethyl-4-oxabicyclo[10.4.0]hexadeca-1(12),9,13,15-tetraene-3,11-dione	1985589: Inhibition of IL-4 induced STAT6 signaling in human HepG2 cells harboring pRL-EF1alpha, pGL3-TK-7xN4 and TOPO-Stat6 plasmid assessed as luciferase activity incubated for 24 hrs	ic50	0.0640	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression	6
bisphenol A	decreases expression, increases expression, increases phosphorylation	3
trichostatin A	affects cotreatment, increases expression	3
Air Pollutants	decreases expression, affects cotreatment, increases abundance, increases oxidation, affects expression	3
sodium arsenite	affects cotreatment, increases abundance, increases expression	2
cobaltous chloride	decreases expression	2
entinostat	increases expression, affects cotreatment	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Acetaminophen	decreases expression	2
Vehicle Emissions	affects cotreatment, increases expression, decreases expression, increases abundance	2
Cisplatin	affects cotreatment, increases expression, decreases phosphorylation	2
Lead	decreases expression	2
Ozone	increases abundance, affects expression, affects cotreatment, increases oxidation	2
Plant Extracts	decreases expression, increases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Dronabinol	affects reaction, increases expression, increases phosphorylation, decreases reaction	2
Tretinoin	increases expression	2
alpinumisoflavone	decreases activity, decreases phosphorylation	1
aristolochic acid I	decreases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases abundance, affects cotreatment, increases oxidation	1
pirinixic acid	increases activity, affects binding, decreases expression	1
geraniol	increases expression	1
acetylsalicylic acid lysinate	increases activity, decreases reaction, increases phosphorylation, affects reaction	1
decabromobiphenyl ether	increases expression	1
beta-lapachone	decreases expression	1
isoquercitrin	increases expression	1
tetrabromobisphenol A	decreases expression	1

ChEMBL screening assays

81 unique, capped per target: 77 binding, 4 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4356752	Binding	Protac activity at CRBN/STAT6 in human MOLM16 cells assessed as degradation of STAT6 at 0.01 to 10 uM incubated for 4 hrs by Western blot analysis	Structure-Based Discovery of SD-36 as a Potent, Selective, and Efficacious PROTAC Degrader of STAT3 Protein. — *J Med Chem*
CHEMBL4715506	Functional	In vivo protac activity at CRBN/STAT6 degradation in SCID mouse xenografted with human MOLM16 cells assessed as reduction in STAT6 in tumor tissue at 50 mg/kg, iv measured after 24 hrs by immunoblotting analysis	SD-91 as A Potent and Selective STAT3 Degrader Capable of Achieving Complete and Long-Lasting Tumor Regression. — *ACS Med Chem Lett*

Cellosaurus cell lines

15 cell lines: 12 cancer cell line, 3 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A8BY	HEK-Blue STAT6-hSTING-R232	Transformed cell line	Female
CVCL_A8DA	HEK-Blue IL-4/IL-13	Transformed cell line	Female
CVCL_B8QC	Abcam HCT 116 STAT6 KO	Cancer cell line	Male
CVCL_B9C0	Abcam MCF-7 STAT6 KO	Cancer cell line	Female
CVCL_B9ST	Abcam A-549 STAT6 KO	Cancer cell line	Male
CVCL_C6JI	SFT-T1	Cancer cell line	Male
CVCL_C6JJ	SFT-T2	Cancer cell line	Female
CVCL_D4AC	SFT-S1	Cancer cell line	Female
CVCL_D8BP	Ubigene A-549 STAT6 KO	Cancer cell line	Male
CVCL_D8WI	Ubigene HCT 116 STAT6 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for STAT6 across ~30M SureChEMBL compounds — explore on Sugi Predict.