Ankylosing spondylitis

Summary

Ankylosing spondylitis (MONDO:0005306) is a disease with 75 cohort genes (452 GWAS associations across 43 studies) and 384 clinical trials. The dominant Reactome pathway is Interleukin-23 signaling (5 cohort genes). Top therapeutic interventions include etanercept, golimumab, and adalimumab.

At a glance

• Cohort genes: 75
• GWAS associations: 452
• Clinical trials: 384

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	ankylosing spondylitis
Mondo ID	MONDO:0005306
EFO	EFO:0003898
MeSH	D013167
Orphanet	825
DOID	DOID:7147
ICD-10-CM	M45
NCIT	C84564
SNOMED CT	9631008
UMLS	C0038013
MedGen	11561
Is cancer (heuristic)	no

Also known as: ankylosing spondylarthritis

Data availability: 452 GWAS associations (43 studies) · 2 GenCC gene-disease records · 12 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by developmental or physiological process › inflammatory disease › spondylitis › ankylosing spondylitis

Related subtypes (2): inflammatory spondylopathy, gonococcal spondylitis

Subtypes (2): juvenile ankylosing spondylitis, juvenile spondyloarthropathy

Genetics & variants

GWAS landscape

452 GWAS associations across 43 studies. Top hits map to 27 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
chr6:31265376	1e-323		G	1.97
rs17190120	1e-323	MUC22 - HCG22	G	2.14
rs5743293	1e-320	NOD2, CYLD-AS1	?
rs9265982	1e-320	LINC02571 - HLA-B	?
rs7743761	5e-304	HLA-B - RNU6-283P	?
rs4349859	1e-200	MICA-AS1	A
rs80174646	1e-143	IL23R	?
rs17192932	6e-120	HLA-B	?	22.84
rs116488202	1e-100	RNU6-283P - FGFR3P1	?	46
rs7517847	1e-98	IL23R, C1orf141	?
rs2066845	6e-94	NOD2	?
rs117486637	9e-91	HLA-B	?	31.08
HLA-B*2705	1e-88		?	34.31
rs1992661	1e-74	RNU1-150P - TTC33	?
rs35300242	5e-67	ATG16L1	?
rs6426833	7e-62	RNF186-AS1 - OTUD3	?
rs146683910	3e-59	HLA-B - RNU6-283P	?	7.09
rs17622378	2e-55	IRF1, CARINH	?
rs3197999	7e-55	MST1	?
rs9977672	5e-54	LINC02940 - RPL23AP12	?
rs469758	6e-54	ERAP1	?
rs4672505	2e-52	RN7SL51P - RN7SL18P	?
rs10748781	6e-51	LINC01475	?
rs2394250	8e-51	HCG9, POLR1HASP, POLR1HASP	?	1.54
rs10995271	3e-48	LINC02929 - ALDH7A1P4	?
rs2357623	4e-48	NKD1 - SNX20	?
rs6759298	5e-47	RN7SL51P - RN7SL18P	C	1.29
rs30187	4e-45	ERAP1	T	1.29
rs10870077	6e-45	CARD9	?
rs56167332	3e-43	IL12B-AS1	?

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST005529	Cortes A	2013	9,069	13,578	Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci.
GCST005530	Cortes A	2013	9,069	13,578	Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci.
GCST005537	Ellinghaus D	2016	8,726	34,213	Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci.
GCST90435163	Khrom M	2024	3,255	8,572	Comprehensive association analyses of extraintestinal manifestations in inflammatory bowel disease.
GCST001149	Evans DM	2011	3,023	8,779	Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility.
GCST90474065	UK Biobank Whole-Genome Sequencing Consortium	2025	2,076	456,364	Whole-genome sequencing of 490,640 UK Biobank participants.
GCST000563	Reveille JD	2010	2,053	5,140	Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci.
GCST001345	Lin Z	2011	1,837	4,231	A genome-wide association study in Han Chinese identifies new susceptibility loci for ankylosing spondylitis.
GCST008910	Trochet H	2019	1,787	23,008	Bayesian meta-analysis across genome-wide association studies of diverse phenotypes.
GCST90435162	Khrom M	2024	1,704	10,190	Comprehensive association analyses of extraintestinal manifestations in inflammatory bowel disease.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	5
Tier 2: splice/UTR	1
Tier 3: regulatory	2
Tier 4: intronic/intergenic	42

MAF distribution

Bucket	Variants
common (>=0.05)	42
low_freq (0.01-0.05)	3
rare (<0.01)	0
unknown	5

Functional consequences

Consequence	Count
intron_variant	29
intergenic_variant	10
missense_variant	4
unknown	2
frameshift_variant	1
TF_binding_site_variant	1
non_coding_transcript_exon_variant	1
regulatory_region_variant	1
splice_donor_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
chr6:31265376				0.069			1e-323	Tier 4: intronic/intergenic
rs17190120	6	31045710	G>T	0.014	intron_variant	MUC22 - HCG22	1e-323	Tier 4: intronic/intergenic
rs5743293	16	50729868			frameshift_variant	NOD2, CYLD-AS1	1e-320	Tier 1: coding
rs9265982	6	31348303	C>T	0.05	intron_variant	LINC02571 - HLA-B	1e-320	Tier 4: intronic/intergenic
rs7743761	6	31368323	C>A	0.05	intron_variant	HLA-B - RNU6-283P	5e-304	Tier 4: intronic/intergenic
rs4349859	6	31398010	G>A,C	0.04	intron_variant	MICA-AS1	1e-200	Tier 4: intronic/intergenic
rs80174646	1	67242472	G>T	0.05	intron_variant	IL23R	1e-143	Tier 4: intronic/intergenic
rs17192932	6	31354352	C>G	0.05	intron_variant	HLA-B	6e-120	Tier 4: intronic/intergenic
rs116488202	6	31377139	C>A,T	0.05	intron_variant	RNU6-283P - FGFR3P1	1e-100	Tier 4: intronic/intergenic
rs7517847	1	67215986	T>A,C,G	0.05	intron_variant	IL23R, C1orf141	1e-98	Tier 4: intronic/intergenic
rs2066845	16	50722629	G>C,T		missense_variant	NOD2	6e-94	Tier 1: coding
rs117486637	6	31358156			intron_variant	HLA-B	9e-91	Tier 4: intronic/intergenic
HLA-B*2705				0.026			1e-88	Tier 4: intronic/intergenic
rs1992661	5	40414887	G>A	0.05	intron_variant	RNU1-150P - TTC33	1e-74	Tier 4: intronic/intergenic
rs35300242	2	233260144	G>A,C	0.05	intron_variant	ATG16L1	5e-67	Tier 4: intronic/intergenic
rs6426833	1	19845367	G>A,C,T	0.05	TF_binding_site_variant	RNF186-AS1 - OTUD3	7e-62	Tier 3: regulatory
rs146683910	6	31368220	C>T	0.05	intron_variant	HLA-B - RNU6-283P	3e-59	Tier 4: intronic/intergenic
rs17622378	5	132442760	A>G	0.05	intron_variant	IRF1, CARINH	2e-55	Tier 4: intronic/intergenic
rs3197999	3	49684099	G>A,C,T	0.05	missense_variant	MST1	7e-55	Tier 1: coding
rs9977672	21	39091357	G>A	0.05	intergenic_variant	LINC02940 - RPL23AP12	5e-54	Tier 4: intronic/intergenic
rs469758	5	96786011	C>T	0.05	intron_variant	ERAP1	6e-54	Tier 4: intronic/intergenic
rs4672505	2	62333197	A>C,G,T	0.05	intron_variant	RN7SL51P - RN7SL18P	2e-52	Tier 4: intronic/intergenic
rs10748781	10	99523573	C>A,G	0.05	non_coding_transcript_exon_variant	LINC01475	6e-51	Tier 4: intronic/intergenic
rs2394250	6	29975879	G>T	0.421	intron_variant	HCG9, POLR1HASP, POLR1HASP	8e-51	Tier 4: intronic/intergenic
rs10995271	10	62678726	G>A,C	0.05	intergenic_variant	LINC02929 - ALDH7A1P4	3e-48	Tier 4: intronic/intergenic
rs2357623	16	50660100	A>G,T	0.05	intergenic_variant	NKD1 - SNX20	4e-48	Tier 4: intronic/intergenic
rs6759298	2	62341310	G>A,C	0.378	intron_variant	RN7SL51P - RN7SL18P	5e-47	Tier 4: intronic/intergenic
rs30187	5	96788627	T>A,C	0.338	missense_variant	ERAP1	4e-45	Tier 1: coding
rs10870077	9	136369439	C>G,T	0.05	intron_variant	CARD9	6e-45	Tier 4: intronic/intergenic
rs56167332	5	159400761	C>A,T	0.05	intergenic_variant	IL12B-AS1	3e-43	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 57 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ANKDD1B	Limited	Autosomal dominant	ankylosing spondylitis
RELN	Limited	Autosomal dominant	ankylosing spondylitis	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RELN	Orphanet:101046	Epilepsy with auditory features
RELN	Orphanet:89844	Lissencephaly syndrome, Norman-Roberts type
RORC	Orphanet:477857	Mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency
STAT3	Orphanet:2314	Autosomal dominant hyper-IgE syndrome due to STAT3 deficiency
STAT3	Orphanet:438159	STAT3-related early-onset multisystem autoimmune disease
STAT3	Orphanet:512017	Chronic lymphoproliferative disorder of natural killer cells
STAT3	Orphanet:520	Acute promyelocytic leukemia
STAT3	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
STAT3	Orphanet:86872	T-cell large granular lymphocyte leukemia
STAT3	Orphanet:99885	Isolated permanent neonatal diabetes mellitus
STK11	Orphanet:2869	Peutz-Jeghers syndrome
SUOX	Orphanet:99731	Isolated sulfite oxidase deficiency
MYRF	Orphanet:647811	Cardiac-urogenital syndrome
TLR4	Orphanet:117	Behçet disease
TNFAIP3	Orphanet:536	Systemic lupus erythematosus
TNFAIP3	Orphanet:674762	Early-onset autoinflammatory syndrome due to A20 haploinsufficiency
TNFRSF1A	Orphanet:32960	Tumor necrosis factor receptor 1 associated periodic syndrome
TNFRSF1A	Orphanet:329967	Intermittent hydrarthrosis
CD40	Orphanet:101090	Hyper-IgM syndrome type 3
TNFSF15	Orphanet:186	Primary biliary cholangitis
CD40LG	Orphanet:101088	X-linked hyper-IgM syndrome
TYK2	Orphanet:300865	Primary cutaneous anaplastic large cell lymphoma
TYK2	Orphanet:331226	Susceptibility to infection due to TYK2 deficiency
TYK2	Orphanet:98842	Lymphomatoid papulosis
UBE2L3	Orphanet:536	Systemic lupus erythematosus
USP8	Orphanet:401795	Autosomal recessive spastic paraplegia type 59
USP8	Orphanet:96253	Cushing disease
ACTA2	Orphanet:2573	Moyamoya disease
ACTA2	Orphanet:404463	Multisystemic smooth muscle dysfunction syndrome
ACTA2	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
IKZF3	Orphanet:67038	B-cell chronic lymphocytic leukemia
IKZF3	Orphanet:699590	Immune dysregulation with immunodeficiency due to AIOLOS haploinsufficiency
IKZF3	Orphanet:699593	Combined immunodeficiency-lymphopenia-cancer predisposing syndrome due to AIOLOS deficiency
BACH2	Orphanet:714472	Inflammatory bowel disease-autoimmunity-sinopulmonary infections-lymphadenopathy syndrome
PARK7	Orphanet:2828	Young-onset Parkinson disease
PARK7	Orphanet:90020	Parkinson-dementia complex of Guam
CARD9	Orphanet:457088	Predisposition to invasive fungal disease due to CARD9 deficiency
ZMIZ1	Orphanet:528084	Non-specific syndromic intellectual disability
CD28	Orphanet:2584	Classic mycosis fungoides
CD28	Orphanet:3162	Sézary syndrome
TNIP1	Orphanet:536	Systemic lupus erythematosus
ICOSLG	Orphanet:695191	Late-onset combined immunodeficiency due to ICOSL deficiency
CHSY1	Orphanet:363417	Temtamy preaxial brachydactyly syndrome
PPP2R3C	Orphanet:171709	Male infertility due to globozoospermia
PPP2R3C	Orphanet:1770	XY type gonadal dysgenesis-associated anomalies syndrome
ERAP1	Orphanet:117	Behçet disease
ZNF365	Orphanet:2073	Narcolepsy type 1
ZNF365	Orphanet:83465	Narcolepsy type 2
BANK1	Orphanet:536	Systemic lupus erythematosus
HHAT	Orphanet:1422	Chondrodysplasia-difference of sex development syndrome

Cohort genes → proteins

75 cohort genes, 75 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	73
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ANKDD1B	HGNC:32525	ENSG00000189045	A6NHY2	Ankyrin repeat and death domain-containing protein 1B	gencc
RELN	HGNC:9957	ENSG00000189056	P78509	Reelin	gencc
RORC	HGNC:10260	ENSG00000143365	P51449	Nuclear receptor ROR-gamma	gwas
RPS6KB1	HGNC:10436	ENSG00000108443	P23443	Ribosomal protein S6 kinase beta-1	gwas
RUNX3	HGNC:10473	ENSG00000020633	Q13761	Runt-related transcription factor 3	gwas
CCL21	HGNC:10620	ENSG00000137077	O00585	C-C motif chemokine 21	gwas
BSN	HGNC:1117	ENSG00000164061	Q9UPA5	Protein bassoon	gwas
STAT3	HGNC:11364	ENSG00000168610	P40763	Signal transducer and activator of transcription 3	gwas
STK11	HGNC:11389	ENSG00000118046	Q15831	Serine/threonine-protein kinase STK11	gwas
SULT1A1	HGNC:11453	ENSG00000196502	P50225	Sulfotransferase 1A1	gwas
SUOX	HGNC:11460	ENSG00000139531	P51687	Sulfite oxidase, mitochondrial	gwas
TBX21	HGNC:11599	ENSG00000073861	Q9UL17	T-box transcription factor TBX21	gwas
MYRF	HGNC:1181	ENSG00000124920	Q9Y2G1	Myelin regulatory factor	gwas
TLR4	HGNC:11850	ENSG00000136869	O00206	Toll-like receptor 4	gwas
TNFAIP3	HGNC:11896	ENSG00000118503	P21580	Tumor necrosis factor alpha-induced protein 3	gwas
TNFRSF14	HGNC:11912	ENSG00000157873	Q92956	Tumor necrosis factor receptor superfamily member 14	gwas
TNFRSF1A	HGNC:11916	ENSG00000067182	P19438	Tumor necrosis factor receptor superfamily member 1A	gwas
CD40	HGNC:11919	ENSG00000101017	P25942	Tumor necrosis factor receptor superfamily member 5	gwas
TNFRSF6B	HGNC:11921	ENSG00000243509	O95407	Tumor necrosis factor receptor superfamily member 6B	gwas
TNFSF15	HGNC:11931	ENSG00000181634	O95150	Tumor necrosis factor ligand superfamily member 15	gwas
TNFSF18	HGNC:11932	ENSG00000120337	Q9UNG2	Tumor necrosis factor ligand superfamily member 18	gwas
CD40LG	HGNC:11935	ENSG00000102245	P29965	CD40 ligand	gwas
TNFSF8	HGNC:11938	ENSG00000106952	P32971	Tumor necrosis factor ligand superfamily member 8	gwas
TNP2	HGNC:11952	ENSG00000178279	Q05952	Nuclear transition protein 2	gwas
EIPR1	HGNC:12383	ENSG00000032389	Q53HC9	EARP and GARP complex-interacting protein 1	gwas
TYK2	HGNC:12440	ENSG00000105397	P29597	Non-receptor tyrosine-protein kinase TYK2	gwas
UBASH3A	HGNC:12462	ENSG00000160185	P57075	Ubiquitin-associated and SH3 domain-containing protein A	gwas
UBE2E3	HGNC:12479	ENSG00000170035	Q969T4	Ubiquitin-conjugating enzyme E2 E3	gwas
UBE2L3	HGNC:12488	ENSG00000185651	P68036	Ubiquitin-conjugating enzyme E2 L3	gwas
USP8	HGNC:12631	ENSG00000138592	P40818	Ubiquitin carboxyl-terminal hydrolase 8	gwas
ACTA2	HGNC:130	ENSG00000107796	P62736	Actin, aortic smooth muscle	gwas
SIRAL2	HGNC:1313	ENSG00000100376	Q9NWS6	Protein FAM118A	gwas
IKZF3	HGNC:13178	ENSG00000161405	Q9UKT9	Zinc finger protein Aiolos	gwas
RASSF8	HGNC:13232	ENSG00000123094	Q8NHQ8	Ras association domain-containing protein 8	gwas
PTTG1IP	HGNC:13524	ENSG00000183255	P53801	Pituitary tumor-transforming gene 1 protein-interacting protein	gwas
GLYAT	HGNC:13734	ENSG00000149124	Q6IB77	Glycine N-acyltransferase	gwas
HDAC7	HGNC:14067	ENSG00000061273	Q8WUI4	Histone deacetylase 7	gwas
BACH2	HGNC:14078	ENSG00000112182	Q9BYV9	Transcription regulator protein BACH2	gwas
SLC39A11	HGNC:14463	ENSG00000133195	Q8N1S5	Zinc transporter ZIP11	gwas
B3GNT2	HGNC:15629	ENSG00000170340	Q9NY97	N-acetyllactosaminide beta-1,3-N-acetylglucosaminyltransferase 2	gwas
SKAP2	HGNC:15687	ENSG00000005020	O75563	Src kinase-associated phosphoprotein 2	gwas
ZNF831	HGNC:16167	ENSG00000124203	Q5JPB2	Zinc finger protein 831	gwas
PARK7	HGNC:16369	ENSG00000116288	Q99497	Parkinson disease protein 7	gwas
CARD9	HGNC:16391	ENSG00000187796	Q9H257	Caspase recruitment domain-containing protein 9	gwas
ZMIZ1	HGNC:16493	ENSG00000108175	Q9ULJ6	Zinc finger MIZ domain-containing protein 1	gwas
CD28	HGNC:1653	ENSG00000178562	P10747	T-cell-specific surface glycoprotein CD28	gwas
TNIP1	HGNC:16903	ENSG00000145901	Q15025	TNFAIP3-interacting protein 1	gwas
CD6	HGNC:1691	ENSG00000013725	P30203	T-cell differentiation antigen CD6	gwas
MYDGF	HGNC:16948	ENSG00000074842	Q969H8	Myeloid-derived growth factor	gwas
CD226	HGNC:16961	ENSG00000150637	Q15762	CD226 antigen	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RELN	Reelin	Extracellular matrix serine protease secreted by pioneer neurons that plays a role in layering of neurons in the cerebral cortex and cerebellum by coordinating cell positioning during neurodevelopment.
RORC	Nuclear receptor ROR-gamma	Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5’-AGGTCA-3’ preceded by a short A-T-rich sequence.
RPS6KB1	Ribosomal protein S6 kinase beta-1	Serine/threonine-protein kinase that acts downstream of mTOR signaling in response to growth factors and nutrients to promote cell proliferation, cell growth and cell cycle progression.
RUNX3	Runt-related transcription factor 3	Forms the heterodimeric complex core-binding factor (CBF) with CBFB.
CCL21	C-C motif chemokine 21	Inhibits hemopoiesis and stimulates chemotaxis.
BSN	Protein bassoon	Scaffold protein of the presynaptic cytomatrix at the active zone (CAZ) which is the place in the synapse where neurotransmitter is released.
STAT3	Signal transducer and activator of transcription 3	Signal transducer and transcription activator that mediates cellular responses to interleukins, KITLG/SCF, LEP and other growth factors.
STK11	Serine/threonine-protein kinase STK11	Tumor suppressor serine/threonine-protein kinase that controls the activity of AMP-activated protein kinase (AMPK) family members, thereby playing a role in various processes such as cell metabolism, cell polarity, apoptosis and DNA damage…
SULT1A1	Sulfotransferase 1A1	Sulfotransferase that utilizes 3’-phospho-5’-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the sulfate conjugation of a wide variety of acceptor molecules bearing a hydroxyl or an amine group.
SUOX	Sulfite oxidase, mitochondrial	Catalyzes the oxidation of sulfite to sulfate, the terminal reaction in the oxidative degradation of sulfur-containing amino acids.
TBX21	T-box transcription factor TBX21	Lineage-defining transcription factor which initiates Th1 lineage development from naive Th precursor cells both by activating Th1 genetic programs and by repressing the opposing Th2 and Th17 genetic programs.
MYRF	Myelin regulatory factor	Constitutes a precursor of the transcription factor.
TLR4	Toll-like receptor 4	Transmembrane receptor that functions as a pattern recognition receptor recognizing pathogen- and damage-associated molecular patterns (PAMPs and DAMPs) to induce innate immune responses via downstream signaling pathways.
TNFAIP3	Tumor necrosis factor alpha-induced protein 3	Ubiquitin-editing enzyme that contains both ubiquitin ligase and deubiquitinase activities.
TNFRSF14	Tumor necrosis factor receptor superfamily member 14	Receptor for four distinct ligands: The TNF superfamily members TNFSF14/LIGHT and homotrimeric LTA/lymphotoxin-alpha and the immunoglobulin superfamily members BTLA and CD160, altogether defining a complex stimulatory and inhibitory signal…
TNFRSF1A	Tumor necrosis factor receptor superfamily member 1A	Receptor for TNFSF2/TNF and homotrimeric TNFSF1/lymphotoxin-alpha.
CD40	Tumor necrosis factor receptor superfamily member 5	Receptor for TNFSF5/CD40LG.
TNFRSF6B	Tumor necrosis factor receptor superfamily member 6B	Decoy receptor that can neutralize the cytotoxic ligands TNFS14/LIGHT, TNFSF15 and TNFSF6/FASL.
TNFSF15	Tumor necrosis factor ligand superfamily member 15	Receptor for TNFRSF25 and TNFRSF6B.
TNFSF18	Tumor necrosis factor ligand superfamily member 18	Cytokine that binds to TNFRSF18/AITR/GITR.
CD40LG	CD40 ligand	Cytokine that acts as a ligand to CD40/TNFRSF5.
TNFSF8	Tumor necrosis factor ligand superfamily member 8	Cytokine that binds to TNFRSF8/CD30.
TNP2	Nuclear transition protein 2	Plays a key role in the replacement of histones to protamine in the elongating spermatids of mammals.
EIPR1	EARP and GARP complex-interacting protein 1	Acts as a component of endosomal retrieval machinery that is involved in protein transport from early endosomes to either recycling endosomes or the trans-Golgi network.
TYK2	Non-receptor tyrosine-protein kinase TYK2	Tyrosine kinase of the non-receptor type involved in numerous cytokines and interferons signaling, which regulates cell growth, development, cell migration, innate and adaptive immunity.
UBASH3A	Ubiquitin-associated and SH3 domain-containing protein A	Interferes with CBL-mediated down-regulation and degradation of receptor-type tyrosine kinases.
UBE2E3	Ubiquitin-conjugating enzyme E2 E3	Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins.
UBE2L3	Ubiquitin-conjugating enzyme E2 L3	Ubiquitin-conjugating enzyme E2 that specifically acts with HECT-type and RBR family E3 ubiquitin-protein ligases.
USP8	Ubiquitin carboxyl-terminal hydrolase 8	Hydrolase that can remove conjugated ubiquitin from proteins and therefore plays an important regulatory role at the level of protein turnover by preventing degradation.
ACTA2	Actin, aortic smooth muscle	Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells.
IKZF3	Zinc finger protein Aiolos	Transcription factor that plays an important role in the regulation of lymphocyte differentiation.
PTTG1IP	Pituitary tumor-transforming gene 1 protein-interacting protein	May facilitate PTTG1 nuclear translocation.
GLYAT	Glycine N-acyltransferase	Mitochondrial acyltransferase which transfers an acyl group to the N-terminus of glycine and glutamine, although much less efficiently.
HDAC7	Histone deacetylase 7	Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4).
BACH2	Transcription regulator protein BACH2	Transcriptional regulator that acts as a repressor or activator.
SLC39A11	Zinc transporter ZIP11	Zinc importer that regulates cytosolic zinc concentrations either via zinc influx from the extracellular compartment or efflux from intracellular organelles such as Golgi apparatus.
B3GNT2	N-acetyllactosaminide beta-1,3-N-acetylglucosaminyltransferase 2	Beta-1,3-N-acetylglucosaminyltransferase involved in the synthesis of poly-N-acetyllactosamine.
SKAP2	Src kinase-associated phosphoprotein 2	May be involved in B-cell and macrophage adhesion processes.
PARK7	Parkinson disease protein 7	Multifunctional protein with controversial molecular function which plays an important role in cell protection against oxidative stress and cell death acting as oxidative stress sensor and redox-sensitive chaperone and protease.
CARD9	Caspase recruitment domain-containing protein 9	Adapter protein that plays a key role in innate immune response against fungi by forming signaling complexes downstream of C-type lectin receptors.
ZMIZ1	Zinc finger MIZ domain-containing protein 1	Acts as a transcriptional coactivator.
CD28	T-cell-specific surface glycoprotein CD28	Receptor that plays a role in T-cell activation, proliferation, survival and the maintenance of immune homeostasis.
TNIP1	TNFAIP3-interacting protein 1	Inhibits NF-kappa-B activation and TNF-induced NF-kappa-B-dependent gene expression by regulating TAX1BP1 and A20/TNFAIP3-mediated deubiquitination of IKBKG; proposed to link A20/TNFAIP3 to ubiquitinated IKBKG.
CD6	T-cell differentiation antigen CD6	Cell adhesion molecule that mediates cell-cell contacts and regulates T-cell responses via its interaction with ALCAM/CD166.
MYDGF	Myeloid-derived growth factor	Bone marrow-derived monocyte and paracrine-acting protein that promotes cardiac myocyte survival and adaptive angiogenesis for cardiac protection and/or repair after myocardial infarction (MI).
CD226	CD226 antigen	Cell surface receptor that plays an important role in the immune system, particularly in intercellular adhesion, lymphocyte signaling, cytotoxicity and lymphokine secretion mediated by cytotoxic T-cells and NK cells.
CEP43	Centrosomal protein 43	Required for anchoring microtubules to the centrosomes.
FNBP1	Formin-binding protein 1	May act as a link between RND2 signaling and regulation of the actin cytoskeleton.
ICOSLG	ICOS ligand	Ligand for the T-cell-specific cell surface receptor ICOS.
SP140	Nuclear body protein SP140	Component of the nuclear body, also known as nuclear domain 10, PML oncogenic domain, and KR body.

Protein-family classification

Druggable: 27 · Difficult: 18 · Unknown: 30 · Druggable fraction: 0.36

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Antibody/Immunoglobulin	6	2.3×	0.267
Kinase	6	2.2×	0.267
Nuclear receptor	1	5.2×	0.384
Enzyme (other)	9	1.4×	0.384
Transcription factor	12	1.3×	0.384
Scaffold/PPI	6	1.4×	0.443
Phosphatase	1	1.1×	0.764
Protease	2	1.0×	0.764
GPCR	2	0.6×	0.918
Other/Unknown	30	0.7×	0.998

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ANKDD1B	Scaffold/PPI	no		Death_dom, Ankyrin_rpt, DEATH-like_dom_sf
RELN	Other/Unknown	no		EGF, Reeler_dom, EGF_extracell
RORC	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
RPS6KB1	Kinase	yes	2.7.11.1	Prot_kinase_dom, AGC-kinase_C, Ser/Thr_kinase_AS
RUNX3	Transcription factor	no		AML1_Runt, p53-like_TF_DNA-bd_sf, p53/RUNT-type_TF_DNA-bd_sf
CCL21	Other/Unknown	no		Chemokine_IL8-like_dom, Chemokine_CC_DCCL, Interleukin_8-like_sf
BSN	Transcription factor	no		Znf_piccolo, Znf_FYVE_PHD, Znf_RING/FYVE/PHD
STAT3	Transcription factor	no		SH2, STAT, p53-like_TF_DNA-bd_sf
STK11	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
SULT1A1	Enzyme (other)	yes	2.8.2.1	Sulfotransferase_dom, P-loop_NTPase
SUOX	Enzyme (other)	yes	1.8.3.1	OxRdtase_Mopterin-bd_dom, Cyt_B5-like_heme/steroid-bd, MoCF_OxRdtse_dimer
TBX21	Transcription factor	no		TF_T-box, p53-like_TF_DNA-bd_sf, TF_T-box_CS
MYRF	Transcription factor	no		p53-like_TF_DNA-bd_sf, NDT80_DNA-bd_dom, MYRF_C2
TLR4	Other/Unknown	no		TIR_dom, Cys-rich_flank_reg_C, Leu-rich_rpt
TNFAIP3	Transcription factor	no		Znf_A20, OTU_dom, OTU_Deubiquitinase
TNFRSF14	Other/Unknown	no		TNFR/NGFR_Cys_rich_reg, TNFR_14, TNFRSF14/UL144_N
TNFRSF1A	Other/Unknown	no		Death_dom, TNFR/NGFR_Cys_rich_reg, DEATH-like_dom_sf
CD40	Other/Unknown	no		TNFR/NGFR_Cys_rich_reg, TNFR_5, TNFRSF5_N
TNFRSF6B	Other/Unknown	no		TNFR/NGFR_Cys_rich_reg, TNFRSF6B_N, TNFRSF_decoy_receptor
TNFSF15	Other/Unknown	no		TNF_dom, TNF, Tumour_necrosis_fac-like_dom
TNFSF18	Other/Unknown	no		TNF_dom, Tumour_necrosis_fac-like_dom, TNFSF18
CD40LG	Other/Unknown	no		CD40L, TNF_dom, Tumour_necrosis_fac-like_dom
TNFSF8	Other/Unknown	no		TNF_dom, Tumour_necrosis_fac-like_dom, TNF_CS
TNP2	Other/Unknown	no		TP2
EIPR1	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_CS
TYK2	Kinase	yes	2.7.10.2	FERM_domain, Prot_kinase_dom, SH2
UBASH3A	Phosphatase	yes		SH3_domain, UBA-like_sf, His_Pase_superF_clade-1
UBE2E3	Enzyme (other)	yes	2.3.2.23	UBC, UBQ-conjugating_enzyme/RWD, UBQ-conjugating_AS
UBE2L3	Enzyme (other)	yes	2.3.2.23	UBC, UBQ-conjugating_enzyme/RWD, UBQ-conjugating_AS
USP8	Protease	yes	3.4.19.12	Peptidase_C19_UCH, Rhodanese-like_dom, USP8_dimer
ACTA2	Other/Unknown	no		Actin, Actin_CS, Actin/actin-like_CS
SIRAL2	Other/Unknown	no		FAM118
IKZF3	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Ikaros_C2H2-ZF
RASSF8	Other/Unknown	no		RA_dom, Ubiquitin-like_domsf, N-RASSF
PTTG1IP	Other/Unknown	no		PSI, PTTG1IP
GLYAT	Enzyme (other)	yes	2.3.1.13	Glycine_N-acyltransferase, Glycine_N-acyltransferase_C, Glycine_N-acyltransferase_N
HDAC7	Enzyme (other)	yes	3.5.1.98	HDACs, Ureohydrolase_dom_sf, His_deacetylse_dom
BACH2	Transcription factor	no		BTB/POZ_dom, bZIP_Maf, bZIP
SLC39A11	Other/Unknown	no		ZIP
B3GNT2	Other/Unknown	no		Glyco_trans_31
SKAP2	Scaffold/PPI	no		SH3_domain, PH_domain, PH-like_dom_sf
ZNF831	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf
PARK7	Enzyme (other)	yes	3.5.1.124	DJ-1/PfpI, DJ-1, Class_I_gatase-like
CARD9	Other/Unknown	no		CARD, DEATH-like_dom_sf, CARD_CARD9
ZMIZ1	Transcription factor	no		Znf_MIZ, Znf_RING/FYVE/PHD, ZMIZ1_N
CD28	Antibody/Immunoglobulin	yes		CD28, Ig_V-set, Ig-like_fold
TNIP1	Other/Unknown	no
CD6	Other/Unknown	no		SRCR, SRCR-like_dom_sf
MYDGF	Other/Unknown	no		MYDGF
CD226	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, Ig-like_dom

Expression context

Cohort genes with no expression data: 0.

67 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	1
moderate (6-20)	0
broad (>20)	74
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	11
lymph node	11
male germ line stem cell (sensu Vertebrata) in testis	7
monocyte	6
blood	5
leukocyte	5
spleen	5
jejunal mucosa	5
secondary oocyte	5
calcaneal tendon	4
vermiform appendix	4
left testis	4
mononuclear cell	4
stromal cell of endometrium	4
sperm	4
tibia	4
ileal mucosa	4
olfactory segment of nasal mucosa	3
right uterine tube	3
cerebellar vermis	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ANKDD1B	132		marker	right uterine tube, male germ line stem cell (sensu Vertebrata) in testis, olfactory segment of nasal mucosa
RELN	254	broad	marker	olfactory bulb, cerebellar vermis, cerebellum
RORC	209	broad	marker	gastrocnemius, male germ line stem cell (sensu Vertebrata) in testis, hindlimb stylopod muscle
RPS6KB1	275	ubiquitous	marker	endothelial cell, Brodmann (1909) area 23, calcaneal tendon
RUNX3	220	broad	marker	granulocyte, buccal mucosa cell, lymph node
CCL21	206	tissue_specific	marker	lymph node, right lobe of thyroid gland, vermiform appendix
BSN	156	broad	marker	frontal pole, paraflocculus, middle temporal gyrus
STAT3	301	ubiquitous	marker	type B pancreatic cell, pericardium, lower lobe of lung
STK11	238	ubiquitous	marker	left testis, right testis, hindlimb stylopod muscle
SULT1A1	177	ubiquitous	marker	mucosa of transverse colon, right lobe of liver, right adrenal gland cortex
SUOX	267	ubiquitous	marker	right lobe of liver, right adrenal gland, right adrenal gland cortex
TBX21	149	broad	marker	granulocyte, blood, male germ line stem cell (sensu Vertebrata) in testis
MYRF	223	ubiquitous	marker	middle frontal gyrus, C1 segment of cervical spinal cord, inferior vagus X ganglion
TLR4	233	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
TNFAIP3	274	ubiquitous	marker	vena cava, mucosa of paranasal sinus, vermiform appendix
TNFRSF14	134	ubiquitous	marker	granulocyte, spleen, right uterine tube
TNFRSF1A	292	ubiquitous	marker	tendon of biceps brachii, gall bladder, left uterine tube
CD40	242	ubiquitous	marker	lymph node, right lung, spleen
TNFRSF6B	127	broad	yes	olfactory segment of nasal mucosa, spleen, subcutaneous adipose tissue
TNFSF15	149	broad	marker	cartilage tissue, jejunal mucosa, duodenum
TNFSF18	98	broad	yes	male germ line stem cell (sensu Vertebrata) in testis, gall bladder, stromal cell of endometrium
CD40LG	124	tissue_specific	marker	granulocyte, lymph node, blood
TNFSF8	179	broad	marker	monocyte, leukocyte, mononuclear cell
TNP2	32	tissue_specific	yes	sperm, male germ cell, left testis
EIPR1	249	ubiquitous	marker	prefrontal cortex, adenohypophysis, nucleus accumbens
TYK2	288	ubiquitous	marker	granulocyte, right hemisphere of cerebellum, adenohypophysis
UBASH3A	133	broad	marker	granulocyte, blood, lymph node
UBE2E3	134	ubiquitous	marker	ganglionic eminence, cortical plate, stromal cell of endometrium
UBE2L3	287	ubiquitous	marker	oocyte, secondary oocyte, mucosa of transverse colon
USP8	284	ubiquitous	marker	calcaneal tendon, sural nerve, colonic epithelium

Protein interactions among cohort

Intra-cohort edges: 47.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
STAT3	10,108
LRRK2	7,628
TLR4	6,974
PARK7	5,722
RPS6KB1	5,474
STK11	5,146
TNFRSF1A	4,523
TYK2	3,932
CD40	3,765
TNFAIP3	3,716

Intra-cohort edges

A	B	Sources
BACH2	UBASH3A	string_interaction
BANK1	TNFAIP3	string_interaction
CARD9	IFIH1	string_interaction
CD226	THADA	intact
CD28	CD40	string_interaction
CD28	CD40LG	string_interaction
CD28	ICOSLG	intact, string_interaction
CD28	TNFSF18	string_interaction
CD40	CD40LG	biogrid_interaction, intact, string_interaction
CD40	ICOSLG	string_interaction
CD40	SLC39A11	intact
CD40	THADA	intact
CD40	TNFSF8	string_interaction
CD40LG	ICOSLG	string_interaction
CD40LG	TNFSF8	string_interaction
CD6	UBASH3A	string_interaction
CEP43	PPP2R3C	biogrid_interaction
ERAP1	IL23R	string_interaction
ERAP1	TNFRSF1A	string_interaction
ERAP1	TNIP1	string_interaction
ICOSLG	TNFSF18	string_interaction
IFNLR1	TYK2	string_interaction
IKZF3	RUNX3	string_interaction
IL23R	RORC	string_interaction
IL23R	TBX21	string_interaction
IL23R	TNIP1	string_interaction
IL23R	TYK2	string_interaction
LRRK2	MYDGF	intact
LRRK2	PARK7	string_interaction
NDFIP1	UBE2L3	biogrid_interaction
OR5B21	TNP2	string_interaction
RORC	TBX21	string_interaction
RUNX3	TBX21	string_interaction
STAT3	TYK2	string_interaction
TNFAIP3	TNFRSF1A	biogrid_interaction
TNFAIP3	TNIP1	biogrid_interaction, intact, string_interaction
TNFRSF14	TNFRSF6B	string_interaction
TNFRSF14	TNFSF15	string_interaction
TNFRSF14	TNFSF18	string_interaction
TNFRSF14	TNFSF8	string_interaction
TNFRSF1A	TNFRSF6B	string_interaction
TNFRSF1A	TNFSF15	string_interaction
TNFRSF1A	TNFSF8	string_interaction
TNFRSF6B	TNFSF15	biogrid_interaction, intact, string_interaction
TNFRSF6B	TNFSF8	string_interaction
TNFSF15	TNFSF18	string_interaction
TNFSF15	TNFSF8	string_interaction

Structural data

PDB: 54 · AlphaFold-only: 21 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RORC	P51449	161
PARK7	Q99497	88
TYK2	P29597	52
LRRK2	Q5S007	44
ERAP1	Q9NZ08	23
RPS6KB1	P23443	22
UBE2L3	P68036	21
TNFAIP3	P21580	17
TLR4	O00206	15
CD40	P25942	14
TNFRSF1A	P19438	13
B3GNT2	Q9NY97	12
SULT1A1	P50225	11
CD28	P10747	10
HHAT	Q5VTY9	10
USP8	P40818	9
IFIH1	Q9BYX4	9
TNFRSF14	Q92956	8
TNFRSF6B	O95407	8
CD40LG	P29965	8
CARD9	Q9H257	8
TNIP1	Q15025	8
IFNLR1	Q8IU57	8
TNFSF15	O95150	7
TNFSF18	Q9UNG2	7
STAT3	P40763	6
HDAC7	Q8WUI4	6
FNDC3A	Q9Y2H6	6
CCL21	O00585	5
SP140	Q13342	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GLYAT	Q6IB77	95.71
ACTA2	P62736	95.43
PPP2R3C	Q969Q6	90.08
EIPR1	Q53HC9	89.26
OR5B21	A6NL26	88.83
CHSY1	Q86X52	84.20
ANKDD1B	A6NHY2	83.90
SIRAL2	Q9NWS6	83.77
TNFSF8	P32971	80.07
SBK1	Q52WX2	77.87
PTTG1IP	P53801	77.51
SLC39A11	Q8N1S5	76.64
UBAC2	Q8NBM4	72.34
NDFIP1	Q9BT67	63.27
TBX21	Q9UL17	61.95
BANK1	Q8NDB2	61.25
TNP2	Q05952	59.17
HIPK1	Q86Z02	52.62
IKZF3	Q9UKT9	48.06
ZNF365	Q70YC4	30.21
BSN	Q9UPA5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 618. Enrichment computed across 204 evidence-associated genes (135 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 135 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interleukin-23 signaling	5	47.0×	2e-05	STAT3, TYK2, IL23R, IL12B, JAK2
TNFs bind their physiological receptors	6	17.5×	3e-04	TNFRSF14, TNFRSF1A, TNFRSF6B, TNFSF15, TNFSF18, TNFSF8
Interleukin-10 signaling	7	12.1×	3e-04	STAT3, TNFRSF1A, TYK2, IL10, IL12B, IL1R1, IL1R2
Interleukin-4 and Interleukin-13 signaling	9	6.9×	1e-03	RORC, STAT3, TYK2, IL23R, FOS, IL10, IL12B, IL6R (+1 more)
Interleukin-6 signaling	4	28.2×	0.001	STAT3, TYK2, IL6R, JAK2
RUNX3 Regulates Immune Response and Cell Migration	3	42.3×	0.003	RORC, RUNX3, ITGAL
Interleukin-37 signaling	4	15.4×	0.010	STAT3, IL18R1, SMAD3, PTPN2
MAPK1 (ERK2) activation	3	25.4×	0.013	TYK2, IL6R, JAK2
Activation of STAT3 by cadherin engagement	6	7.2×	0.013	STAT3, TYK2, ACTA2, IL6R, JAK2, NFKB1
MAPK3 (ERK1) activation	3	23.1×	0.014	TYK2, IL6R, JAK2
Interleukin-27 signaling	3	23.1×	0.014	STAT3, TYK2, JAK2
Interleukin-20 family signaling	4	12.5×	0.014	STAT3, TYK2, IFNLR1, JAK2
Interleukin-35 Signalling	3	21.1×	0.015	STAT3, TYK2, JAK2
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	6	6.5×	0.015	TBX21, HDAC7, ETS1, FOS, IL5, NOTCH1
Differentiation of naive CD4+ T cells to T helper 1 cells (Th1 cells)	3	19.5×	0.017	RUNX3, TBX21, NFATC1
Regulation of IFNG signaling	3	18.1×	0.021	IFNGR2, JAK2, PTPN2
TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway	3	14.9×	0.035	CD40, CD40LG, LTBR
IL-6-type cytokine receptor ligand interactions	3	14.1×	0.036	TYK2, JAK2, OSMR
FCGR3A-mediated IL10 synthesis	4	8.7×	0.036	ADCY3, ADCY7, FCGR2A, IL10
Potential therapeutics for SARS	6	5.1×	0.036	TYK2, KEAP1, IFNGR2, IL1R1, IL6R, JAK2
RUNX3 regulates BCL2L11 (BIM) transcription	2	33.8×	0.038	RUNX3, SMAD3
Ovarian tumor domain proteases	4	8.2×	0.038	TNFAIP3, TNIP1, IFIH1, NOD2
NOTCH4 Intracellular Domain Regulates Transcription	3	12.7×	0.041	ACTA2, SMAD3, NOTCH1
Signaling by CSF3 (G-CSF)	3	12.7×	0.041	STAT3, TYK2, JAK2
IkBA variant leads to EDA-ID	2	24.2×	0.064	NFKB1, NFKBIA
RUNX3 regulates CDKN1A transcription	2	24.2×	0.064	RUNX3, SMAD3
G alpha (z) signalling events	4	6.9×	0.064	ADCY3, ADCY7, PRKCB, PRKCQ
TRAF6 mediated NF-kB activation	3	10.2×	0.068	IFIH1, NFKB1, NFKBIA
Interleukin-6 family signaling	2	21.1×	0.069	STAT3, JAK2
IFNG signaling activates MAPKs	2	21.1×	0.069	IFNGR2, JAK2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 181 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
immune response	22	5.7×	7e-08	CCL21, TLR4, TNFRSF14, TNFSF15, TNFSF8, TYK2, ETS1, GPR65 (+14 more)
inflammatory response	24	5.0×	7e-08	CCL21, STAT3, TLR4, TNFAIP3, TNFRSF1A, CD40, CD40LG, PARK7 (+16 more)
nucleotide-binding oligomerization domain containing 2 signaling pathway	6	50.8×	2e-07	TLR4, INAVA, IRGM, NOD2, IRF5, NFKBIA
positive regulation of interleukin-17 production	8	26.6×	2e-07	TYK2, CARD9, IL23R, NOD2, IL12B, IL21, JAK2, PRKCQ
negative regulation of inflammatory response	13	9.8×	2e-07	TNFAIP3, TNFRSF1A, NDFIP1, IRGM, IL10, IL2RA, SMAD3, MEFV (+5 more)
positive regulation of canonical NF-kappaB signal transduction	17	6.8×	2e-07	CCL21, STAT3, TLR4, TNFRSF1A, CD40, TNFSF15, CD40LG, CARD9 (+9 more)
response to muramyl dipeptide	6	46.5×	3e-07	TNFAIP3, CARD9, INAVA, NOD2, NFKBIA, NOTCH1
positive regulation of T-helper 17 type immune response	6	46.5×	3e-07	TYK2, CARD9, IL23R, IL12B, JAK2, PRKCQ
positive regulation of type II interferon production	10	12.4×	1e-06	TLR4, TYK2, CD226, IL23R, IL12B, IL18R1, IL1R1, IL21 (+2 more)
positive regulation of interleukin-10 production	8	17.7×	2e-06	STAT3, TLR4, CD40LG, CD28, INAVA, NOD2, IL12B, IL21
cellular response to virus	10	11.1×	3e-06	TYK2, IFNLR1, IFIH1, IRGM, IFNGR2, IL21, IRF5, JAK2 (+2 more)
positive regulation of T cell proliferation	9	12.9×	4e-06	CD40LG, TYK2, CD28, CD6, IL23R, IL12B, IL21, JAK2 (+1 more)
positive regulation of inflammatory response	11	8.8×	6e-06	STAT3, TLR4, TNFRSF1A, TNFSF18, TNIP1, ETS1, IL12B, IL21 (+3 more)
interleukin-23-mediated signaling pathway	4	62.1×	2e-05	STAT3, TYK2, IL23R, JAK2
negative regulation of cytokine production involved in inflammatory response	7	16.3×	2e-05	STAT3, ADCY7, IL1R2, JAK2, MEFV, NFKB1, NFKBIA
adaptive immune response	13	6.0×	3e-05	TNFRSF14, TNFSF18, CD6, ICOSLG, ERAP1, ERAP2, EOMES, HLA-B (+5 more)
positive regulation of transcription by RNA polymerase II	32	2.6×	4e-05	STAT3, TBX21, TLR4, TNFRSF1A, CD40, TNFSF8, PARK7, ZMIZ1 (+24 more)
cytokine-mediated signaling pathway	10	7.2×	1e-04	STAT3, TNFRSF1A, TYK2, IFNLR1, IL23R, IFNGR2, IL6R, IRF5 (+2 more)
cellular response to lipopolysaccharide	11	6.0×	2e-04	TLR4, TNFAIP3, CD40, TNIP1, SBNO2, IRGM, EFNB2, NOD2 (+3 more)
cell surface receptor signaling pathway via JAK-STAT	7	11.2×	2e-04	STAT3, TNFRSF1A, CD40, TYK2, IL23R, IL12B, JAK2
positive regulation of tumor necrosis factor production	9	7.6×	2e-04	STAT3, TLR4, CARD9, LRRK2, IFIH1, FCGR2A, NOD2, IL12B (+1 more)
positive regulation of receptor signaling pathway via JAK-STAT	6	14.3×	3e-04	TYK2, IL10, IL5, IL7R, JAK2, NOTCH1
positive regulation of natural killer cell proliferation	4	31.0×	4e-04	TYK2, IL23R, IL12B, JAK2
positive regulation of interleukin-12 production	6	13.0×	4e-04	TLR4, CD40, CD40LG, IL23R, IL12B, IRF5
positive regulation of interleukin-1 beta production	7	10.0×	4e-04	STAT3, TLR4, INAVA, NOD2, JAK2, SMAD3, MEFV
T-helper cell differentiation	3	55.9×	8e-04	RORC, IL12B, PTGER4
positive regulation of MAPK cascade	11	4.9×	0.001	CD40, MYDGF, BANK1, LRRK2, INAVA, GPR37, NOD2, IL6R (+3 more)
positive regulation of cytokine production involved in inflammatory response	5	15.0×	0.001	STAT3, TLR4, CARD9, CD6, NOD2
cellular response to mechanical stimulus	7	8.4×	0.001	TLR4, TNFRSF1A, CD40, DAG1, LTBR, NFKB1, PTGER4
lipopolysaccharide-mediated signaling pathway	5	14.6×	0.001	TLR4, CD6, JAK2, NFKBIA, PTPN22

Therapeutics

Drugs indicated or in trials for this disease

13 approved drugs — disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Status
Adalimumab	Approved (phase 4)
Celecoxib	Approved (phase 4)
Certolizumab Pegol	Approved (phase 4)
Dexamethasone	Approved (phase 4)
Etanercept	Approved (phase 4)
Golimumab	Approved (phase 4)
Indomethacin	Approved (phase 4)
Infliximab	Approved (phase 4)
Isopropyl Alcohol	Approved (phase 4)
Naproxen	Approved (phase 4)
Prednisolone	Approved (phase 4)
Prednisone	Approved (phase 4)
Secukinumab	Approved (phase 4)

29 drugs in clinical trials for this disease (phase 2–3, investigational): efficacy not established — a trial record, not an indication.

Drug	Highest phase
Apremilast	Phase 3
Bimekizumab	Phase 3
Brodalumab	Phase 3
Diclofenac	Phase 3
Etoricoxib	Phase 3
Filgotinib	Phase 3
Gumokimab	Phase 3
Ixekizumab	Phase 3
Meloxicam	Phase 3
Methotrexate	Phase 3
Misoprostol	Phase 3
Omeprazole	Phase 3
Rebamipide	Phase 3
Tocilizumab	Phase 3
Tofacitinib	Phase 3
Upadacitinib	Phase 3
Ustekinumab	Phase 3
ARRY-797	Phase 2
Abatacept	Phase 2
Izokibep	Phase 2
Methylprednisolone	Phase 2
Mufemilast	Phase 2
Olsalazine	Phase 2
Risankizumab	Phase 2
Rituximab	Phase 2
Sarilumab	Phase 2
Sulfasalazine	Phase 2
Thalidomide	Phase 2
Vunakizumab	Phase 2

Drug target analysis

Approved (phase 4): 12 · Phase ≥3: 12 · Phased (≥1): 16 · Undrugged: 59

Druggability breadth: 102 of 204 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
RORC	DIGOXIN
RPS6KB1	FEDRATINIB
STAT3	MOMELOTINIB
STK11	FEDRATINIB
SULT1A1	ESTRADIOL
TLR4	METHOTREXATE
TYK2	FEDRATINIB
IKZF3	POMALIDOMIDE
HDAC7	CELECOXIB
SBK1	AFATINIB
LRRK2	PONATINIB
HIPK1	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TYK2	72	4
LRRK2	42	4
RPS6KB1	39	4
HDAC7	28	4
HIPK1	21	4
STAT3	18	4
STK11	17	4
SBK1	14	4
RORC	9	4
TLR4	6	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DIGOXIN	4	RORC, STAT3
TRETINOIN	4	RORC
ALITRETINOIN	4	RORC
FEDRATINIB	4	HIPK1, LRRK2, RPS6KB1, SBK1, STK11, TYK2
SORAFENIB	4	HIPK1, RPS6KB1
VANDETANIB	4	LRRK2, RPS6KB1
BOSUTINIB	4	HIPK1, LRRK2, RPS6KB1, TYK2
NINTEDANIB	4	HIPK1, LRRK2, RPS6KB1, SBK1, STK11, TYK2
SUNITINIB	4	HIPK1, LRRK2, RPS6KB1, SBK1, STK11, TYK2
CRIZOTINIB	4	RPS6KB1, SBK1, TYK2
MIDOSTAURIN	4	LRRK2, RPS6KB1, STK11, TYK2
MOMELOTINIB	4	STAT3, TYK2
NITAZOXANIDE	4	STAT3
NICLOSAMIDE	4	STAT3
BARICITINIB	4	STAT3, TYK2
DIGITOXIN	4	STAT3
DEUCRAVACITINIB	4	STAT3, TYK2
PACRITINIB	4	STK11, TYK2
ESTRADIOL	4	SULT1A1
ETHINYL ESTRADIOL	4	SULT1A1
METHOTREXATE	4	TLR4
POLYMYXIN B	4	TLR4
CARVEDILOL	4	TLR4
RUXOLITINIB	4	HIPK1, LRRK2, SBK1, TYK2
TOFACITINIB	4	LRRK2, TYK2
UPADACITINIB	4	TYK2
FILGOTINIB	4	TYK2
ABROCITINIB	4	TYK2
AXITINIB	4	LRRK2, TYK2
RUXOLITINIB PHOSPHATE	4	TYK2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 14.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
HDAC7	1,710	Binding:1695, ADMET:10, Functional:4, Toxicity:1
STAT3	1,319	Binding:1304, Functional:12, Unclassified:2, ADMET:1
TYK2	1,083	Binding:1043, Functional:39, ADMET:1
LRRK2	809	Binding:799, ADMET:7, Functional:3
RORC	758	Binding:707, Functional:50, Unclassified:1
RPS6KB1	585	Binding:582, Functional:2, ADMET:1
HIPK1	285	Binding:285
TLR4	267	Binding:254, Functional:10, ADMET:3
STK11	244	Binding:244
IKZF3	101	Binding:100, Functional:1
SBK1	97	Binding:97
ERAP1	88	Binding:85, Functional:2, ADMET:1
PARK7	62	Binding:62
USP8	54	Binding:51, Functional:3
TNFRSF1A	24	Binding:23, Functional:1
SULT1A1	19	ADMET:15, Binding:4
HHAT	14	Binding:14
GBA3	14	Binding:14
IL23R	13	Binding:13
CD40	10	Binding:10
CD40LG	8	Binding:8
SP140	8	Binding:8
ICOSLG	6	Binding:6
BACH2	3	Binding:3
UBE2L3	2	Binding:2
CEP43	2	Binding:2
TNFAIP3	1	Binding:1
UBASH3A	1	Binding:1
SLC39A11	1	Binding:1
B3GNT2	1	Binding:1
CD28	1	Functional:1
IFIH1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RPS6KB1	2.7.11.1	non-specific serine/threonine protein kinase
STK11	2.7.11.1	non-specific serine/threonine protein kinase
SULT1A1	2.8.2.1, 2.8.2.2	aryl sulfotransferase, alcohol sulfotransferase
SUOX	1.8.3.1	sulfite oxidase
TYK2	2.7.10.2	non-specific protein-tyrosine kinase
UBE2E3	2.3.2.23, 2.3.2.24	E2 ubiquitin-conjugating enzyme, (E3-independent) E2 ubiquitin-conjugating enzyme
UBE2L3	2.3.2.23, 2.3.2.24	E2 ubiquitin-conjugating enzyme, (E3-independent) E2 ubiquitin-conjugating enzyme
USP8	3.4.19.12	ubiquitinyl hydrolase 1
GLYAT	2.3.1.13, 2.3.1.71	glycine N-acyltransferase, glycine N-benzoyltransferase
HDAC7	3.5.1.98	histone deacetylase
PARK7	3.5.1.124, 4.2.1.130	protein deglycase, D-lactate dehydratase
CHSY1	2.4.1.175, 2.4.1.226	glucuronosyl-N-acetylgalactosaminyl-proteoglycan 4-beta-N-acetylgalactosaminyltransferase, N-acetylgalactosaminyl-proteoglycan 3-beta-glucuronosyltransferase
ERAP1	3.4.11.1, 3.4.11.22	leucyl aminopeptidase, aminopeptidase I
GBA3	3.2.1.21	beta-glucosidase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
RORC	758
RPS6KB1	585
STAT3	1,319
STK11	244
TLR4	267
TYK2	1,083
IKZF3	101
HDAC7	1,710
LRRK2	809
HIPK1	285

Pharmacogenomics

Cohort genes with a PharmGKB record: 75; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

27 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
DIGOXIN	4	RORC, STAT3
TRETINOIN	4	RORC
ALITRETINOIN	4	RORC
FEDRATINIB	4	HIPK1, LRRK2, RPS6KB1, SBK1, STK11, TYK2
SORAFENIB	4	HIPK1, RPS6KB1
VANDETANIB	4	LRRK2, RPS6KB1
BOSUTINIB	4	HIPK1, LRRK2, RPS6KB1, TYK2
NINTEDANIB	4	HIPK1, LRRK2, RPS6KB1, SBK1, STK11, TYK2
SUNITINIB	4	HIPK1, LRRK2, RPS6KB1, SBK1, STK11, TYK2
CRIZOTINIB	4	RPS6KB1, SBK1, TYK2
MIDOSTAURIN	4	LRRK2, RPS6KB1, STK11, TYK2
MOMELOTINIB	4	STAT3, TYK2
NITAZOXANIDE	4	STAT3
NICLOSAMIDE	4	STAT3
BARICITINIB	4	STAT3, TYK2
DIGITOXIN	4	STAT3
DEUCRAVACITINIB	4	STAT3, TYK2
PACRITINIB	4	STK11, TYK2
ESTRADIOL	4	SULT1A1
ETHINYL ESTRADIOL	4	SULT1A1
POLYMYXIN B	4	TLR4
CARVEDILOL	4	TLR4
RUXOLITINIB	4	HIPK1, LRRK2, SBK1, TYK2
UPADACITINIB	4	TYK2
ABROCITINIB	4	TYK2
AXITINIB	4	LRRK2, TYK2
RUXOLITINIB PHOSPHATE	4	TYK2

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	12	RORC, RPS6KB1, STAT3, STK11, SULT1A1, TLR4, TYK2, IKZF3, HDAC7, SBK1 (+2 more)
B	Phased (≥1) drug, not yet approved	4	TNFRSF1A, PARK7, ERAP1, GBA3
C	Druggable family + PDB, no drug	12	SUOX, UBASH3A, UBE2E3, UBE2L3, USP8, CD28, CD226, ICOSLG, ADGRL2, IFNLR1 (+2 more)
D	Druggable family + AlphaFold only, no drug	3	GLYAT, CHSY1, OR5B21
E	Difficult family or no structure, no drug	44	ANKDD1B, RELN, RUNX3, CCL21, BSN, TBX21, MYRF, TNFAIP3, TNFRSF14, CD40 (+34 more)

Undrugged target profiles

59 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
TNFRSF6B	0	TNFRSF1A
ANKDD1B	0	—
RELN	0	—
RUNX3	0	—
CCL21	0	—
BSN	0	—
SUOX	0	—
TBX21	0	—
MYRF	0	—
TNFAIP3	1	—
TNFRSF14	0	—
CD40	10	—
TNFSF15	0	—
TNFSF18	0	—
CD40LG	8	—
TNFSF8	0	—
TNP2	0	—
EIPR1	0	—
UBASH3A	1	—
UBE2E3	0	—
UBE2L3	2	—
USP8	54	—
ACTA2	0	—
SIRAL2	0	—
RASSF8	0	—
PTTG1IP	0	—
GLYAT	0	—
BACH2	3	—
SLC39A11	1	—
B3GNT2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 384.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	237
PHASE3	44
PHASE4	42
PHASE2	37
PHASE1	8
PHASE2/PHASE3	7
PHASE1/PHASE2	5
EARLY_PHASE1	4

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05303285	PHASE4	RECRUITING	A Study Evaluating the Efficacy of Secukinumab 300mg in Chinese Adults With Active Ankylosing Spondylitis
NCT06707194	PHASE4	RECRUITING	Effect and Safety of Benzathine Penicillin Combined With Etanercept on Spondyloarthritis
NCT06833112	PHASE4	NOT_YET_RECRUITING	Interleukin-17 (IL-17) Inhibitor in Combination With Tumor Necrosis Factor α (TNFα )Inhibitor for the Treatment of Ankylosing Spondylitis
NCT00133315	PHASE4	COMPLETED	TNFalfa Blocking Treatment of Spondylarthropathies
NCT00247962	PHASE4	COMPLETED	Study Evaluating Etanercept and Sulphasalazine in Ankylosing Spondylitis
NCT00410046	PHASE4	COMPLETED	Extension Study Evaluating Etanercept in Ankylosing Spondylitis
NCT00420238	PHASE4	COMPLETED	Study Evaluating Etanercept for the Treatment of Active, Severe, and Advanced Axial Ankylosing Spondylitis
NCT00432432	PHASE4	COMPLETED	Combination Methotrexate and Infliximab
NCT00444340	PHASE4	COMPLETED	An Open-Label Multicentre Long-Term Extension Study of Etanercept for Ankylosing Spondylitis
NCT00458185	PHASE4	COMPLETED	Study Evaluating Etanercept in Patients With Ankylosing Spondylitis
NCT00507403	PHASE4	COMPLETED	Infliximab and Methotrexate in Ankylosing Spondylitis
NCT00647517	PHASE4	COMPLETED	Tramadol/Acetaminophen(Ultracet) AS add-on Therapy in the Treatment of Patients With Ankylosing Spondylitis
NCT00715091	PHASE4	COMPLETED	Effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) on RAdiographic Damage in Ankylosing Spondylitis
NCT00873730	PHASE4	COMPLETED	Study Evaluating Etanercept in Subjects With Ankylosing Spondylitis in Spain
NCT00910273	PHASE4	TERMINATED	Effects of Etanercept on the Heart, Veins and Thickness of Certain Major Arteries In Ankylosing Spondylitis Patients
NCT00953979	PHASE4	COMPLETED	Efficacy and Safety of Kunxian Capsule in Treatment Patients With Early Ankylosing Spondylitis
NCT01148901	PHASE4	WITHDRAWN	Effectiveness and Safety of Early Treatment With Infliximab for Hip Arthritis Associated With Ankylosing Spondylitis (AS) (P06451)
NCT01212653	PHASE4	COMPLETED	Effect of Anti-TNF (Alpha) Treatment on Vascular Stiffness in Ankylosing Spondylitis (AS)
NCT01422564	PHASE4	TERMINATED	Metal on Metal Versus Metal on Highly Crossed Linked Polyethylene Sytem
NCT01517620	PHASE4	COMPLETED	Total Glucosides Paeony Capsules in Maintaining Clinical Remission in Patients With Ankylosing Spondylitis Which Achieve Clinical Remission After Anti-TNF Therapy
NCT01668004	PHASE4	COMPLETED	The Incidence of Extra-Articular Manifestations in Participants With Ankylosing Spondylitis Treated With Golimumab (MK-8259-012)
NCT01895764	PHASE4	COMPLETED	Effect of the Combination of Methotrexate and Adalimumab on Reduction of Immunization in Ankylosing Spondylitis (COMARIS)
NCT01934933	PHASE4	COMPLETED	Etanercept and Celecoxib Alone/Combined Treatment in Effectiveness and Safety of Active Ankylosing Spondylitis
NCT02132234	PHASE4	UNKNOWN	Effects of Biological Treatment on Blood Pressure and Endothelial Function in Patients With Rheumatoid Arthritis, Psoriatic Arthritis and Ankylosing Spondylitis
NCT02313727	PHASE4	UNKNOWN	Combined Treatment With TNF Inhibitor and Pamidronate in AS Patients: Effect on the Radiographic Progression
NCT02489760	PHASE4	UNKNOWN	Etanercept Versus Adalimumab in the Treatment of Patients With Ankylosing Spondylitis. A Switch Study
NCT02492217	PHASE4	COMPLETED	Biomarkers Identification of Anti-tumor Necrosis Factor (TNF) α Agent’s Efficacy in Ankylosing Spondylitis Patients
NCT02528201	PHASE4	COMPLETED	A Study Of Celecoxib Versus Diclofenac In Patients With Ankylosing Spondylitis
NCT02638896	PHASE4	UNKNOWN	Dose Reduction of Etanercept in Patients With Ankylosing Spondylitis
NCT02758782	PHASE4	COMPLETED	NSAIDs Added to Anti-TNF Therapy Versus Anti-TNF Therapy Alone on Progression of Structural Damage in Ankylosing Spondylitis
NCT02763046	PHASE4	COMPLETED	Study to Examine the Clinical Efficacy and the Nonsteroidal Anti-inflammatory Drug (NSAID)-Sparing Effect of Secukinumab Over 16 Weeks in Patients With Ankylosing Spondylitis
NCT03350815	PHASE4	COMPLETED	Study Estimating the Clinical Difference Between 300 mg and 150 mg of Secukinumab Following Dose Escalation to 300 mg in Patients With Ankylosing Spondylitis
NCT03411798	PHASE4	COMPLETED	Sequential Application of Yisaipu® and DMARDs in Treating Mild-to-Moderate AS
NCT03473665	PHASE4	TERMINATED	Non-Steroidal Anti-inflammatory Drugs in Axial Spondyloarthritis
NCT03639740	PHASE4	UNKNOWN	Treat-to-target With Secukinumab in Axial Spondyloarthritis
NCT03800797	PHASE4	COMPLETED	Efficacy and Safety of Loxoprofen Hydrogel Patch in Patients With Ankylosing Spondylitis
NCT03932006	PHASE4	UNKNOWN	A Multicenter，Double-Blind and Randomized Controlled Trial of Fengshigutong Capsule in the Treatment of Ankylosing Spondylitis
NCT04077957	PHASE4	UNKNOWN	Treat-to-target Strategy in Ankylosing Spondylitis Using Etanercept and Conventional Synthetic DMARDs
NCT04885751	PHASE4	UNKNOWN	Compare the Effect of Eupatilin and Rebamipide on the Prevention of Gastroenteropathy
NCT04934059	PHASE4	UNKNOWN	Efficacy and Safety of Yuxuebi Tablet in Treating Night Pain of Ankylosing Spondylitis (AS).

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ETANERCEPT	4	27
GOLIMUMAB	4	8
ADALIMUMAB	4	7
INFLIXIMAB	4	7
SECUKINUMAB	4	7
TOFACITINIB	4	6
BIMEKIZUMAB	4	5
CELECOXIB	4	5
SULFASALAZINE	4	5
CERTOLIZUMAB PEGOL	4	4
FILGOTINIB	4	4
ENTECAVIR ANHYDROUS	4	3
ETORICOXIB	4	3
DICLOFENAC	4	2
MELOXICAM	4	2
SARILUMAB	4	2
ABATACEPT	4	1
APREMILAST	4	1
HYDROXYCHLOROQUINE	4	1
INDOMETHACIN	4	1
LOXOPROFEN	4	1
METHOTREXATE	4	1
METHYLPREDNISOLONE	4	1
NAPROXEN	4	1
OLSALAZINE	4	1
PAMIDRONIC ACID	4	1
PENICILLIN G BENZATHINE	4	1
RISANKIZUMAB	4	1
TERBINAFINE	4	1
THALIDOMIDE	4	1