Systemic-onset juvenile idiopathic arthritis

Summary

Systemic-onset juvenile idiopathic arthritis (MONDO:0019434) is a disease with 71 cohort genes (56 GWAS associations across 2 studies) and 26 clinical trials. The dominant Reactome pathway is MAPK1 (ERK2) activation (3 cohort genes). Top therapeutic interventions include canakinumab, anakinra, and baricitinib.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 71
• GWAS associations: 56
• Phenotypes (HPO): 22
• Clinical trials: 26

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 1 000 000	0.6	Worldwide	Validated
Point prevalence	1-9 / 100 000	3.1	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

22 HPO clinical features (Orphanet curated; top 22 by frequency):

HPO ID	Term	Frequency
HP:0000988	Skin rash	Very frequent (80-99%)
HP:0001369	Arthritis	Very frequent (80-99%)
HP:0001386	Joint swelling	Very frequent (80-99%)
HP:0001945	Fever	Very frequent (80-99%)
HP:0002829	Arthralgia	Very frequent (80-99%)
HP:0002960	Autoimmunity	Very frequent (80-99%)
HP:0003565	Elevated erythrocyte sedimentation rate	Very frequent (80-99%)
HP:0005681	Juvenile rheumatoid arthritis	Very frequent (80-99%)
HP:0011227	Elevated circulating C-reactive protein concentration	Very frequent (80-99%)
HP:0002716	Lymphadenopathy	Frequent (30-79%)
HP:0000099	Glomerulonephritis	Occasional (5-29%)
HP:0000938	Osteopenia	Occasional (5-29%)
HP:0001510	Growth delay	Occasional (5-29%)
HP:0001701	Pericarditis	Occasional (5-29%)
HP:0001744	Splenomegaly	Occasional (5-29%)
HP:0002027	Abdominal pain	Occasional (5-29%)
HP:0002202	Pleural effusion	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0003281	Increased circulating ferritin concentration	Occasional (5-29%)
HP:0004890	Elevated pulmonary artery pressure	Occasional (5-29%)
HP:0012122	Anterior uveitis	Occasional (5-29%)
HP:0033430	Non-infectious meningitis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	systemic-onset juvenile idiopathic arthritis
Mondo ID	MONDO:0019434
EFO	EFO:1001999
MeSH	C565798
Orphanet	85414
ICD-11	504387587
NCIT	C119031
SNOMED CT	201796004
UMLS	C1858558
MedGen	346934
GARD	0010966
Is cancer (heuristic)	no

Also known as: sJIA · SoJIA · Still disease · Still’s disease (formerly) · systemic juvenile idiopathic arthritis · systemic onset juvenile idiopathic arthritis · systemic onset juvenile rheumatoid arthritis · systemic polyarthritis · systemic-onset JIA

Data availability: 56 GWAS associations (2 studies).

Disease family

Classification path: disease › human disease › disease by body system or component › connective tissue disorder › rheumatic disorder › juvenile idiopathic arthritis › systemic-onset juvenile idiopathic arthritis

Related subtypes (5): polyarticular juvenile idiopathic arthritis, oligoarticular juvenile idiopathic arthritis, psoriasis-related juvenile idiopathic arthritis, enthesitis-related juvenile idiopathic arthritis, unspecified juvenile idiopathic arthritis

Genetics & variants

GWAS landscape

56 GWAS associations across 2 studies. Top hits map to 33 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs7775055	3e-174	HLA-DQB1 - MTCO3P1	G	6.01
rs6679677	3e-25	PHTF1 - RSBN1	A	1.59
rs41291794	4e-15	HLA-DRA - HLA-DRB9	?	2.1
rs10174238	1e-13	STAT4	G	1.29
rs2847293	1e-12	LINC01882 - PTPN2	A	1.31
rs10213692	3e-11	ANKRD55	?	1.27
rs1479924	6e-11	IL2 - IL21	?	1.27
rs34536443	1e-10	TYK2	?	1.79
rs7909519	8e-10	IL2RA	?	1.39
rs6894249	1e-09	CARINH, IRF1	?	1.32
rs7137828	2e-09	ATXN2	C	1.2
rs72632736	3e-09	EEF1DP6 - LINC01777	?	2.4
rs8129030	5e-09	RUNX1	?	1.28
rs10849448	5e-09	LTBR	A	1.24
rs2266959	6e-09	UBE2L3	A	1.24
rs27293	7e-09	LNPEP	A	1.31
rs72698115	1e-08	IL6R	C	1.36
rs3825568	1e-08	ZFP36L1	?	1.3
rs2284033	2e-08	IL2RB	?	1.19
rs7127214	2e-08	PRR5L	?	1.28
rs7069750	3e-08	FAS	C	1.18
rs6946509	3e-08	MTCYBP42 - TOMM7	T	1.19
rs9532434	5e-08	COG6	?	1.19
rs45539732	7e-08	STAT1	?	1.53
rs73300638	1e-07	JAZF1	C	1.28
rs34132030	2e-07	LINC02341	A	1.18
rs79893749	2e-07	CCR3	?	1.28
rs11074967	2e-07	RMI2	?	1.18
rs1823549	3e-07	OLFM3 - COL11A1	?	2.5
rs1178121	3e-07	HDAC9	?	1.6

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST005528	Hinks A	2013	2,816	13,056	Dense genotyping of immune-related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis.
GCST004025	Ombrello MJ	2016	178	0	Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: clinical and therapeutic implications.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	1
Tier 2: splice/UTR	2
Tier 3: regulatory	2
Tier 4: intronic/intergenic	45

MAF distribution

Bucket	Variants
common (>=0.05)	49
low_freq (0.01-0.05)	1
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	28
intergenic_variant	16
5_prime_UTR_variant	2
regulatory_region_variant	2
non_coding_transcript_exon_variant	1
missense_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs7775055	6	32690139	T>C	0.02	non_coding_transcript_exon_variant	HLA-DQB1 - MTCO3P1	3e-174	Tier 4: intronic/intergenic
rs6679677	1	113761186	C>A,T	0.1	intergenic_variant	PHTF1 - RSBN1	3e-25	Tier 4: intronic/intergenic
rs41291794	6	32457985	A>T	0.05	intron_variant	HLA-DRA - HLA-DRB9	4e-15	Tier 4: intronic/intergenic
rs10174238	2	191108308	G>A,T	0.23	intron_variant	STAT4	1e-13	Tier 4: intronic/intergenic
rs2847293	18	12782449	A>G,T	0.17	intergenic_variant	LINC01882 - PTPN2	1e-12	Tier 4: intronic/intergenic
rs10213692	5	56146422	T>C,G	0.25	intron_variant	ANKRD55	3e-11	Tier 4: intronic/intergenic
rs1479924	4	122466445	G>A	0.29	intergenic_variant	IL2 - IL21	6e-11	Tier 4: intronic/intergenic
rs34536443	19	10352442	G>C,T	0.05	missense_variant	TYK2	1e-10	Tier 1: coding
rs7909519	10	6047878	T>G	0.11	intron_variant	IL2RA	8e-10	Tier 4: intronic/intergenic
rs6894249	5	132461855	A>C,G,T	0.39	intron_variant	CARINH, IRF1	1e-09	Tier 4: intronic/intergenic
rs7137828	12	111494996	C>A,G,T	0.49	intron_variant	ATXN2	2e-09	Tier 4: intronic/intergenic
rs72632736	1	4389144	A>G,T	0.05	intergenic_variant	EEF1DP6 - LINC01777	3e-09	Tier 4: intronic/intergenic
rs8129030	21	35340290	T>A,G	0.37	intergenic_variant	RUNX1	5e-09	Tier 4: intronic/intergenic
rs10849448	12	6384185	A>G	0.24	5_prime_UTR_variant	LTBR	5e-09	Tier 2: splice/UTR
rs2266959	22	21568615	G>A,T	0.19	intron_variant	UBE2L3	6e-09	Tier 4: intronic/intergenic
rs27293	5	97021474	A>G,T	0.44	intron_variant	LNPEP	7e-09	Tier 4: intronic/intergenic
rs72698115	1	154406893	A>C	0.1	intron_variant	IL6R	1e-08	Tier 4: intronic/intergenic
rs3825568	14	68793871	C>G,T	0.44	5_prime_UTR_variant	ZFP36L1	1e-08	Tier 2: splice/UTR
rs2284033	22	37137994	G>A,C	0.44	intron_variant	IL2RB	2e-08	Tier 4: intronic/intergenic
rs7127214	11	36322143	C>G,T	0.35	intron_variant	PRR5L	2e-08	Tier 4: intronic/intergenic
rs7069750	10	89002619	G>C,T	0.44	intron_variant	FAS	3e-08	Tier 4: intronic/intergenic
rs6946509	7	22769871	T>A,C	0.45	intergenic_variant	MTCYBP42 - TOMM7	3e-08	Tier 4: intronic/intergenic
rs9532434	13	39781776	T>A,C	0.36	intergenic_variant	COG6	5e-08	Tier 4: intronic/intergenic
rs45539732	2	191009521	T>C	0.05	intron_variant	STAT1	7e-08	Tier 4: intronic/intergenic
rs73300638	7	28147725	A>C,G	0.11	intron_variant	JAZF1	1e-07	Tier 4: intronic/intergenic
rs34132030	13	42481900	C>T	0.32	intergenic_variant	LINC02341	2e-07	Tier 4: intronic/intergenic
rs79893749	3	46212159	C>T	0.15	intron_variant	CCR3	2e-07	Tier 4: intronic/intergenic
rs11074967	16	11377557	C>G,T	0.42	intron_variant	RMI2	2e-07	Tier 4: intronic/intergenic
rs1823549	1	102682275	T>A,C,G	0.05	intergenic_variant	OLFM3 - COL11A1	3e-07	Tier 4: intronic/intergenic
rs1178121	7	18723029	C>A,T	0.05	intron_variant	HDAC9	3e-07	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 71 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 11

Dual-evidence genes (GWAS + Mendelian — highest-confidence targets)

Gene	HGNC	Evidence routes
RUNX1	RUNX1	GWAS, Orphanet
STAT4	STAT4	GWAS, Orphanet
UBE2L3	UBE2L3	GWAS, Orphanet
ANKRD55	ANKRD55	GWAS, Orphanet
JAZF1	JAZF1	GWAS, Orphanet
HLA-DQB1	HLA-DQB1	GWAS, Orphanet
IL2RA	IL2RA	GWAS, Orphanet
IL2RB	IL2RB	GWAS, Orphanet
IL6	IL6	GWAS, Orphanet
PTPN2	PTPN2	GWAS, Orphanet
PTPN22	PTPN22	GWAS, Orphanet

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RUNX1	Orphanet:102724	Acute myeloid leukemia with t(8;21)(q22;q22) translocation
RUNX1	Orphanet:521	Chronic myeloid leukemia
RUNX1	Orphanet:71290	Familial platelet disorder with associated myeloid malignancy
RUNX1	Orphanet:98850	Aggressive systemic mastocytosis
ATXN2	Orphanet:803	Amyotrophic lateral sclerosis
ATXN2	Orphanet:98756	Spinocerebellar ataxia type 2
SS18	Orphanet:3273	Synovial sarcoma
STAT4	Orphanet:117	Behçet disease
STAT4	Orphanet:536	Systemic lupus erythematosus
STAT4	Orphanet:85408	Rheumatoid factor-negative polyarticular juvenile idiopathic arthritis
STAT4	Orphanet:85410	Oligoarticular juvenile idiopathic arthritis
STAT4	Orphanet:93552	Pediatric systemic lupus erythematosus
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
WWOX	Orphanet:251510	46,XY partial gonadal dysgenesis
WWOX	Orphanet:284282	Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to WWOX deficiency
WWOX	Orphanet:708171	Facial dysmorphism-corpus callosum hypoplasia-infantile epileptic encephalopathy
WWOX	Orphanet:99977	Squamous cell carcinoma of the esophagus
TIMMDC1	Orphanet:2609	Isolated complex I deficiency
JPH3	Orphanet:98934	Huntington disease-like 2
CCR1	Orphanet:117	Behçet disease
CYSLTR2	Orphanet:39044	Uveal melanoma
COG6	Orphanet:363523	Hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome
COG6	Orphanet:464443	COG6-CGD
PRICKLE2	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
PRICKLE2	Orphanet:402082	Progressive myoclonic epilepsy type 5
COL11A1	Orphanet:2021	Fibrochondrogenesis
COL11A1	Orphanet:440354	Autosomal dominant myopia-midfacial retrusion-sensorineural hearing loss-rhizomelic dysplasia syndrome
COL11A1	Orphanet:560	Marshall syndrome
COL11A1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
COL11A1	Orphanet:90654	Stickler syndrome type 2
COL12A1	Orphanet:536516	Myopathic Ehlers-Danlos syndrome
COL12A1	Orphanet:610	Bethlem muscular dystrophy
COL12A1	Orphanet:75840	Ullrich congenital muscular dystrophy
ANKRD55	Orphanet:85408	Rheumatoid factor-negative polyarticular juvenile idiopathic arthritis
ANKRD55	Orphanet:85410	Oligoarticular juvenile idiopathic arthritis
FBLN7	Orphanet:684742	2q13 microdeletion syndrome
TAPT1	Orphanet:457378	Complex lethal osteochondrodysplasia
RMI2	Orphanet:508512	Intrauterine growth restriction-congenital multiple café-au-lait macules-increased sister chromatid exchange syndrome
JAZF1	Orphanet:213711	Endometrial stromal sarcoma
JAZF1	Orphanet:536	Systemic lupus erythematosus
SH2B3	Orphanet:3318	Essential thrombocythemia
SH2B3	Orphanet:391366	Growth retardation-mild developmental delay-chronic hepatitis syndrome
FOXC2	Orphanet:33001	Lymphedema-distichiasis syndrome
HLA-DQB1	Orphanet:2073	Narcolepsy type 1
HLA-DQB1	Orphanet:477738	Pediatric multiple sclerosis
HLA-DQB1	Orphanet:703	Bullous pemphigoid
HLA-DQB1	Orphanet:83465	Narcolepsy type 2

Cohort genes → proteins

71 cohort genes, 63 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	71

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RUNX1	HGNC:10471	ENSG00000159216	Q01196	Runt-related transcription factor 1	gwas
RUNX3	HGNC:10473	ENSG00000020633	Q13761	Runt-related transcription factor 3	gwas
ATXN2	HGNC:10555	ENSG00000204842	Q99700	Ataxin-2	gwas
ZFP36L1	HGNC:1107	ENSG00000185650	Q07352	mRNA decay activator protein ZFP36L1	gwas
SS18	HGNC:11340	ENSG00000141380	Q15532	Protein SSXT	gwas
STAT4	HGNC:11365	ENSG00000138378	Q14765	Signal transducer and activator of transcription 4	gwas
TYK2	HGNC:12440	ENSG00000105397	P29597	Non-receptor tyrosine-protein kinase TYK2	gwas
UBE2L3	HGNC:12488	ENSG00000185651	P68036	Ubiquitin-conjugating enzyme E2 L3	gwas
WWOX	HGNC:12799	ENSG00000186153	Q9NZC7	WW domain-containing oxidoreductase	gwas
ZNF33B	HGNC:13097	ENSG00000196693	Q06732	Zinc finger protein 33B	gwas
ZNF37BP	HGNC:13103	ENSG00000234420		zinc finger protein 37B, pseudogene	gwas
TIMMDC1	HGNC:1321	ENSG00000113845	Q9NPL8	Complex I assembly factor TIMMDC1, mitochondrial	gwas
ATP8B2	HGNC:13534	ENSG00000143515	P98198	Phospholipid-transporting ATPase ID	gwas
HDAC9	HGNC:14065	ENSG00000048052	Q9UKV0	Histone deacetylase 9	gwas
JPH3	HGNC:14203	ENSG00000154118	Q8WXH2	Junctophilin-3	gwas
CCR1	HGNC:1602	ENSG00000163823	P32246	C-C chemokine receptor type 1	gwas
CCR3	HGNC:1604	ENSG00000183625	P51677	C-C chemokine receptor type 3	gwas
SORCS1	HGNC:16697	ENSG00000108018	Q8WY21	VPS10 domain-containing receptor SorCS1	gwas
CD80	HGNC:1700	ENSG00000121594	P33681	T-lymphocyte activation antigen CD80	gwas
CYSLTR2	HGNC:18274	ENSG00000152207	Q9NS75	Cysteinyl leukotriene receptor 2	gwas
COG6	HGNC:18621	ENSG00000133103	Q9Y2V7	Conserved oligomeric Golgi complex subunit 6	gwas
RIN3	HGNC:18751	ENSG00000100599	Q8TB24	Ras and Rab interactor 3	gwas
KLF17	HGNC:18830	ENSG00000171872	Q5JT82	Krueppel-like factor 17	gwas
PRICKLE2	HGNC:20340	ENSG00000163637	Q7Z3G6	Prickle-like protein 2	gwas
COL11A1	HGNC:2186	ENSG00000060718	P12107	Collagen alpha-1(XI) chain	gwas
COL12A1	HGNC:2188	ENSG00000111799	Q99715	Collagen alpha-1(XII) chain	gwas
TRIM58	HGNC:24150	ENSG00000162722	Q8NG06	E3 ubiquitin-protein ligase TRIM58	gwas
ZNF521	HGNC:24605	ENSG00000198795	Q96K83	Zinc finger protein 521	gwas
LONRF2	HGNC:24788	ENSG00000170500	Q1L5Z9	LON peptidase N-terminal domain and RING finger protein 2	gwas
ANKRD55	HGNC:25681	ENSG00000164512	Q3KP44	Ankyrin repeat domain-containing protein 55	gwas
MTHFSD	HGNC:25778	ENSG00000103248	Q2M296	Methenyltetrahydrofolate synthase domain-containing protein	gwas
PRR5L	HGNC:25878	ENSG00000135362	Q6MZQ0	Proline-rich protein 5-like	gwas
FBLN7	HGNC:26740	ENSG00000144152	Q53RD9	Fibulin-7	gwas
TAPT1	HGNC:26887	ENSG00000169762	Q6NXT6	Transmembrane anterior posterior transformation protein 1 homolog	gwas
LINC01020	HGNC:27968	ENSG00000215231		long intergenic non-protein coding RNA 1020	gwas
RMI2	HGNC:28349	ENSG00000175643	Q96E14	RecQ-mediated genome instability protein 2	gwas
JAZF1	HGNC:28917	ENSG00000153814	Q86VZ6	Juxtaposed with another zinc finger protein 1	gwas
ERAP2	HGNC:29499	ENSG00000164308	Q6P179	Endoplasmic reticulum aminopeptidase 2	gwas
SH2B3	HGNC:29605	ENSG00000111252	Q9UQQ2	SH2B adapter protein 3	gwas
AJAP1	HGNC:30801	ENSG00000196581	Q9UKB5	Adherens junction-associated protein 1	gwas
ZBTB7C	HGNC:31700	ENSG00000184828	A1YPR0	Zinc finger and BTB domain-containing protein 7C	gwas
EIF3H	HGNC:3273	ENSG00000147677	O15372	Eukaryotic translation initiation factor 3 subunit H	gwas
ZEB2P1	HGNC:33346	ENSG00000249506		zinc finger E-box binding homeobox 2 pseudogene 1	gwas
ENC1	HGNC:3345	ENSG00000171617	O14682	Ectoderm-neural cortex protein 1	gwas
CARINH	HGNC:33838	ENSG00000197536		colitis associated IRF1 antisense regulator of intestinal homeostasis	gwas
FASN	HGNC:3594	ENSG00000169710	P49327	Fatty acid synthase	gwas
FOXC2	HGNC:3801	ENSG00000176692	Q99958	Forkhead box protein C2	gwas
FOXL1	HGNC:3817	ENSG00000176678	Q12952	Forkhead box protein L1	gwas
PGAM4P2	HGNC:42466	ENSG00000248488		phosphoglycerate mutase family member 4 pseudogene 2	gwas
LINC00536	HGNC:43645	ENSG00000249917		long intergenic non-protein coding RNA 536	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RUNX1	Runt-related transcription factor 1	Forms the heterodimeric complex core-binding factor (CBF) with CBFB.
RUNX3	Runt-related transcription factor 3	Forms the heterodimeric complex core-binding factor (CBF) with CBFB.
ATXN2	Ataxin-2	Involved in EGFR trafficking, acting as negative regulator of endocytic EGFR internalization at the plasma membrane.
ZFP36L1	mRNA decay activator protein ZFP36L1	Zinc-finger RNA-binding protein that destabilizes several cytoplasmic AU-rich element (ARE)-containing mRNA transcripts by promoting their poly(A) tail removal or deadenylation, and hence provide a mechanism for attenuating protein synthes…
SS18	Protein SSXT	Appears to function synergistically with RBM14 as a transcriptional coactivator.
STAT4	Signal transducer and activator of transcription 4	Transcriptional regulator mainly expressed in hematopoietic cells that plays a critical role in cellular growth, differentiation and immune response.
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.
UBE2L3	Ubiquitin-conjugating enzyme E2 L3	Ubiquitin-conjugating enzyme E2 that specifically acts with HECT-type and RBR family E3 ubiquitin-protein ligases.
WWOX	WW domain-containing oxidoreductase	Putative oxidoreductase.
ZNF33B	Zinc finger protein 33B	May be involved in transcriptional regulation.
TIMMDC1	Complex I assembly factor TIMMDC1, mitochondrial	Chaperone protein involved in the assembly of the mitochondrial NADH:ubiquinone oxidoreductase complex (complex I).
ATP8B2	Phospholipid-transporting ATPase ID	Catalytic component of P4-ATPase flippase complex, which catalyzes the hydrolysis of ATP coupled to the transport of phosphatidylcholine (PC) from the outer to the inner leaflet of the plasma membrane.
HDAC9	Histone deacetylase 9	Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4).
JPH3	Junctophilin-3	Junctophilins contribute to the formation of junctional membrane complexes (JMCs) which link the plasma membrane with the endoplasmic or sarcoplasmic reticulum in excitable cells.
CCR1	C-C chemokine receptor type 1	Chemokine receptor that plays a crucial role in regulating immune cell migration, inflammation, and immune responses.
CCR3	C-C chemokine receptor type 3	G protein-coupled receptor (GPCR) that plays a key role in the immune system by regulating the migration and activation of white blood cells in response to chemokines.
CD80	T-lymphocyte activation antigen CD80	Costimulatory molecule that belongs to the immunoglobulin superfamily that plays an important role in T-lymphocyte activation.
CYSLTR2	Cysteinyl leukotriene receptor 2	Receptor for cysteinyl leukotrienes.
COG6	Conserved oligomeric Golgi complex subunit 6	Required for normal Golgi function.
RIN3	Ras and Rab interactor 3	Ras effector protein that functions as a guanine nucleotide exchange (GEF) for RAB5B and RAB31, by exchanging bound GDP for free GTP.
KLF17	Krueppel-like factor 17	Transcription repressor that binds to the promoter of target genes and prevents their expression.
PRICKLE2	Prickle-like protein 2	Is involved in the organization and maintenance of axon initial segment (AIS) architecture, likely cooperating with IGSF9B to regulate ANK3/ANKG localization to AIS.
COL11A1	Collagen alpha-1(XI) chain	May play an important role in fibrillogenesis by controlling lateral growth of collagen II fibrils.
COL12A1	Collagen alpha-1(XII) chain	Type XII collagen interacts with type I collagen-containing fibrils, the COL1 domain could be associated with the surface of the fibrils, and the COL2 and NC3 domains may be localized in the perifibrillar matrix.
TRIM58	E3 ubiquitin-protein ligase TRIM58	E3 ubiquitin ligase induced during late erythropoiesis.
ZNF521	Zinc finger protein 521	Transcription factor that can both act as an activator or a repressor depending on the context.
PRR5L	Proline-rich protein 5-like	Associates with the mTORC2 complex that regulates cellular processes including survival and organization of the cytoskeleton.
FBLN7	Fibulin-7	An adhesion molecule that interacts with extracellular matrix molecules in developing teeth and may play important roles in differentiation and maintenance of odontoblasts as well as in dentin formation.
TAPT1	Transmembrane anterior posterior transformation protein 1 homolog	Plays a role in primary cilia formation.
RMI2	RecQ-mediated genome instability protein 2	Essential component of the RMI complex, a complex that plays an important role in the processing of homologous recombination intermediates.
JAZF1	Juxtaposed with another zinc finger protein 1	Acts as a transcriptional corepressor of orphan nuclear receptor NR2C2.
ERAP2	Endoplasmic reticulum aminopeptidase 2	Aminopeptidase that plays a central role in peptide trimming, a step required for the generation of most HLA class I-binding peptides.
SH2B3	SH2B adapter protein 3	Links T-cell receptor activation signal to phospholipase C-gamma-1, GRB2 and phosphatidylinositol 3-kinase.
AJAP1	Adherens junction-associated protein 1	Plays a role in cell adhesion and cell migration.
ZBTB7C	Zinc finger and BTB domain-containing protein 7C	May be a tumor suppressor gene.
EIF3H	Eukaryotic translation initiation factor 3 subunit H	Component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is required for several steps in the initiation of protein synthesis.
ENC1	Ectoderm-neural cortex protein 1	Actin-binding protein involved in the regulation of neuronal process formation and in differentiation of neural crest cells.
FASN	Fatty acid synthase	Fatty acid synthetase is a multifunctional enzyme that catalyzes the de novo biosynthesis of long-chain saturated fatty acids starting from acetyl-CoA and malonyl-CoA in the presence of NADPH.
FOXC2	Forkhead box protein C2	Transcriptional activator.
FOXL1	Forkhead box protein L1	Transcription factor required for proper proliferation and differentiation in the gastrointestinal epithelium.
HLA-DQA2	HLA class II histocompatibility antigen, DQ alpha 2 chain	Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells.
HLA-DQB1	HLA class II histocompatibility antigen, DQ beta 1 chain	Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells.
HLA-DRA	HLA class II histocompatibility antigen, DR alpha chain	An alpha chain of antigen-presenting major histocompatibility complex class II (MHCII) molecule.
IL2	Interleukin-2	Cytokine produced by activated CD4-positive helper T-cells and to a lesser extend activated CD8-positive T-cells and natural killer (NK) cells that plays pivotal roles in the immune response and tolerance.
IL21	Interleukin-21	Cytokine with immunoregulatory activity.
IL2RA	Interleukin-2 receptor subunit alpha	Receptor for interleukin-2.
IL2RB	Interleukin-2 receptor subunit beta	Receptor for interleukin-2.
IL6	Interleukin-6	Cytokine with a wide variety of biological functions in immunity, tissue regeneration, and metabolism.
IL6R	Interleukin-6 receptor subunit alpha	Part of the receptor for interleukin 6.
IRF1	Interferon regulatory factor 1	Transcriptional regulator which displays a remarkable functional diversity in the regulation of cellular responses.

Protein-family classification

Druggable: 24 · Difficult: 19 · Unknown: 28 · Druggable fraction: 0.34

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	8	3.3×	0.029
Complement	2	7.5×	0.096
Transcription factor	15	1.7×	0.096
Protease	4	2.1×	0.323
Phosphatase	2	2.4×	0.415
GPCR	3	1.0×	0.848
Scaffold/PPI	4	1.0×	0.848
Other/Unknown	28	0.7×	0.998
Enzyme (other)	4	0.7×	0.998
Kinase	1	0.4×	0.998

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RUNX1	Transcription factor	no		AML1_Runt, p53-like_TF_DNA-bd_sf, p53/RUNT-type_TF_DNA-bd_sf
RUNX3	Transcription factor	no		AML1_Runt, p53-like_TF_DNA-bd_sf, p53/RUNT-type_TF_DNA-bd_sf
ATXN2	Other/Unknown	no		LsmAD_domain, PAM2_motif, LSM_dom_sf
ZFP36L1	Transcription factor	no		Znf_CCCH, Tis11B_N, Znf_CCCH_sf
SS18	Other/Unknown	no		SS18_N
STAT4	Transcription factor	no		SH2, STAT, p53-like_TF_DNA-bd_sf
TYK2	Kinase	yes	2.7.10.2	FERM_domain, Prot_kinase_dom, SH2
UBE2L3	Enzyme (other)	yes	2.3.2.23	UBC, UBQ-conjugating_enzyme/RWD, UBQ-conjugating_AS
WWOX	Scaffold/PPI	no		WW_dom, SDR_fam, WW_dom_sf
ZNF33B	Transcription factor	no		KRAB, Znf_C2H2_type, KRAB_dom_sf
ZNF37BP	Other/Unknown	no
TIMMDC1	Other/Unknown	no		TIMMDC1
ATP8B2	Transcription factor	no	7.6.2.1	P_typ_ATPase, P-type_ATPase_IV, ATPase_P-typ_transduc_dom_A_sf
HDAC9	Enzyme (other)	yes	3.5.1.98	HDACs, Ureohydrolase_dom_sf, His_deacetylse_dom
JPH3	Other/Unknown	no		MORN, Junctophilin
CCR1	GPCR	yes		GPCR_Rhodpsn, Chemokine_rcpt, Chemokine_CCR1
CCR3	GPCR	yes		GPCR_Rhodpsn, Chemokine_rcpt, Chemokine_CCR3
SORCS1	Antibody/Immunoglobulin	yes		PKD_dom, VPS10, Ig-like_fold
CD80	Antibody/Immunoglobulin	yes		Ig_sub, Ig-like_dom, Ig_V-set
CYSLTR2	GPCR	yes		GPCR_Rhodpsn, Cyst_leuk_rcpt, CLT2_recept
COG6	Other/Unknown	no		COG6, COG6_N, COG6_C
RIN3	Scaffold/PPI	no		RA_dom, SH2, VPS9
KLF17	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf
PRICKLE2	Transcription factor	no		Znf_LIM, PET_domain, PET_prickle
COL11A1	Other/Unknown	no		Fib_collagen_C, Laminin_G, Collagen
COL12A1	Antibody/Immunoglobulin	yes		VWF_A, FN3_dom, Collagen
TRIM58	Transcription factor	no		Znf_B-box, Znf_RING, B30.2/SPRY
ZNF521	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf
LONRF2	Transcription factor	no		Znf_RING, Lon_prtase_N, TPR-like_helical_dom_sf
ANKRD55	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf
MTHFSD	Other/Unknown	no		RRM_dom, FTHF_cligase, Nucleotide-bd_a/b_plait_sf
PRR5L	Other/Unknown	no		Bit61/PRR5
FBLN7	Complement	yes		EGF-type_Asp/Asn_hydroxyl_site, Sushi_SCR_CCP_dom, EGF
TAPT1	Other/Unknown	no		Tatp1
LINC01020	Other/Unknown	no
RMI2	Other/Unknown	no		NA-bd_OB-fold, RMI2
JAZF1	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, ZnF-Chromatin_assoc
ERAP2	Protease	yes	3.4.11.1	Peptidase_M1, Peptidase_M1_dom, ERAP1-like_C_dom
SH2B3	Scaffold/PPI	no		SH2, PH_domain, PH-like_dom_sf
AJAP1	Other/Unknown	no		AJAP1_PANP_C, AJAP1
ZBTB7C	Transcription factor	no		BTB/POZ_dom, SKP1/BTB/POZ_sf, Znf_C2H2_type
EIF3H	Protease	yes		JAMM/MPN+_dom, eIF3h, MPN
ZEB2P1	Other/Unknown	no
ENC1	Other/Unknown	no		BTB/POZ_dom, Kelch_1, SKP1/BTB/POZ_sf
CARINH	Other/Unknown	no
FASN	Enzyme (other)	yes	2.3.1.39	Thioesterase, Ac_transferase_dom_sf, Ppantetheine_attach_site
FOXC2	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_1, TF_fork_head_CS_2
FOXL1	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_1, TF_fork_head_CS_2
PGAM4P2	Other/Unknown	no
LINC00536	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	2
moderate (6-20)	0
broad (>20)	69
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	11
monocyte	11
male germ line stem cell (sensu Vertebrata) in testis	11
leukocyte	7
primordial germ cell in gonad	7
buccal mucosa cell	6
secondary oocyte	6
oocyte	5
cortical plate	5
colonic epithelium	4
right adrenal gland cortex	4
calcaneal tendon	4
tibia	4
cartilage tissue	4
Brodmann (1909) area 23	4
lymph node	3
middle temporal gyrus	3
sperm	3
mononuclear cell	3
sural nerve	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RUNX1	253	ubiquitous	marker	olfactory segment of nasal mucosa, epithelium of bronchus, mucosa of paranasal sinus
RUNX3	220	broad	marker	granulocyte, buccal mucosa cell, lymph node
ATXN2	286	ubiquitous	marker	buccal mucosa cell, colonic epithelium, olfactory bulb
ZFP36L1	289	ubiquitous	marker	mucosa of paranasal sinus, endocervix, mucosa of stomach
SS18	291	ubiquitous	marker	adrenal tissue, right adrenal gland cortex, right adrenal gland
STAT4	201	broad	marker	granulocyte, sperm, middle temporal gyrus
TYK2	288	ubiquitous	marker	granulocyte, right hemisphere of cerebellum, adenohypophysis
UBE2L3	287	ubiquitous	marker	oocyte, secondary oocyte, mucosa of transverse colon
WWOX	286	ubiquitous	marker	parotid gland, cervix squamous epithelium, cranial nerve II
ZNF33B	235	ubiquitous	marker	body of pancreas, cortical plate, pancreas
ZNF37BP	254	ubiquitous	marker	body of uterus, left ovary, calcaneal tendon
TIMMDC1	259	ubiquitous	marker	left ventricle myocardium, cardiac muscle of right atrium, myocardium
ATP8B2	250	ubiquitous	marker	mucosa of stomach, right coronary artery, stromal cell of endometrium
HDAC9	277	ubiquitous	marker	oocyte, monocyte, secondary oocyte
JPH3	166	broad	yes	right frontal lobe, postcentral gyrus, parietal lobe
CCR1	244	broad	marker	monocyte, mononuclear cell, leukocyte
CCR3	100	tissue_specific	yes	secondary oocyte, blood, oocyte
SORCS1	188	broad	marker	cortical plate, sural nerve, trigeminal ganglion
CD80	143	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, lower lobe of lung, pancreatic ductal cell
CYSLTR2	166	broad	marker	right adrenal gland cortex, monocyte, leukocyte
COG6	254	ubiquitous	marker	secondary oocyte, tibia, calcaneal tendon
RIN3	210	ubiquitous	marker	granulocyte, monocyte, leukocyte
KLF17	83	broad	marker	left testis, male germ line stem cell (sensu Vertebrata) in testis, right testis
PRICKLE2	233	ubiquitous	marker	oviduct epithelium, cauda epididymis, colonic epithelium
COL11A1	209	broad	marker	tibia, cartilage tissue, periodontal ligament
COL12A1	240	ubiquitous	marker	tibia, calcaneal tendon, cartilage tissue
TRIM58	169	broad	marker	trabecular bone tissue, monocyte, mononuclear cell
ZNF521	240	ubiquitous	marker	cerebellar vermis, buccal mucosa cell, calcaneal tendon
LONRF2	235	broad	marker	corpus epididymis, Brodmann (1909) area 23, middle temporal gyrus
ANKRD55	169	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, sperm, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 27.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IL6	9,239
FASN	6,551
WWOX	5,892
RUNX1	4,994
IRF1	4,076
TYK2	3,932
CD80	3,664
ATXN2	3,360
RUNX3	3,293
HLA-DRA	3,244

Intra-cohort edges

A	B	Sources
AFF3	ANKRD55	string_interaction
AFF3	LONRF2	string_interaction
AFF3	PTPN22	string_interaction
ANKRD55	PTPN22	string_interaction
ATXN2	SH2B3	string_interaction
CCR1	CCR3	string_interaction
CD80	ENC1	intact
FOXC2	MTHFSD	string_interaction
FOXL1	MTHFSD	string_interaction
HLA-DRA	LNPEP	biogrid_interaction, intact
IL2	IL2RA	intact
IL2	IL2RB	intact
IL2RA	IL2RB	string_interaction
IL2RA	PTPN2	string_interaction
IL6	IL6R	biogrid_interaction, intact, string_interaction
IL6	STAT4	string_interaction
IL6	TYK2	string_interaction
IL6R	TYK2	string_interaction
JPH3	LONRF2	intact
LDB2	RUNX1	string_interaction
LDB2	TAPT1	string_interaction
LONRF2	PRR5L	string_interaction
PTPN2	SH2B3	string_interaction
PTPN2	STAT4	string_interaction
PTPN22	STAT4	string_interaction
RUNX1	RUNX3	string_interaction
STAT4	TYK2	string_interaction

Structural data

PDB: 36 · AlphaFold-only: 27 · No structure: 8

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HLA-DRA	P01903	140
TYK2	P29597	52
IL2	P60568	37
FASN	P49327	34
EIF3H	O15372	27
UBE2L3	P68036	21
LGMN	Q99538	18
IL6	P05231	17
ERAP2	Q6P179	14
PTPN2	P17706	14
PTPN22	Q9Y2R2	14
LNPEP	Q9UIQ6	11
HLA-DQB1	P01920	10
IL2RA	P01589	10
IL6R	P08887	10
CYSLTR2	Q9NS75	9
IL2RB	P14784	8
CD80	P33681	6
RMI2	Q96E14	6
FOXC2	Q99958	6
RUNX1	Q01196	5
CCR1	P32246	3
IL21	Q9HBE4	3
ZFP36L1	Q07352	2
HDAC9	Q9UKV0	2
RIN3	Q8TB24	2
TRIM58	Q8NG06	2
LTBR	P36941	2
MOCS2	O96007	2
RUNX3	Q13761	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HLA-DQA2	P01906	89.29
ENC1	O14682	88.22
STAT4	Q14765	86.87
COG6	Q9Y2V7	86.62
FBLN7	Q53RD9	82.78
ATP8B2	P98198	82.24
LONRF2	Q1L5Z9	78.97
SORCS1	Q8WY21	77.77
LDB2	O43679	73.80
TIMMDC1	Q9NPL8	72.08
TAPT1	Q6NXT6	71.98
JAZF1	Q86VZ6	70.25
PRR5L	Q6MZQ0	68.40
IRF1	P10914	66.65
ZNF33B	Q06732	65.80
FOXL1	Q12952	64.30
SH2B3	Q9UQQ2	63.45
ANKRD55	Q3KP44	63.43
ZNF521	Q96K83	61.75
JPH3	Q8WXH2	61.52
ZBTB7C	A1YPR0	56.80
PRICKLE2	Q7Z3G6	56.41
KLF17	Q5JT82	54.30
PRM1	P04553	54.01
COL11A1	P12107	53.06
AFF3	P51826	52.20
AJAP1	Q9UKB5	50.22

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 246. Enrichment computed across 71 evidence-associated genes (44 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 44 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
MAPK1 (ERK2) activation	3	77.9×	6e-04	TYK2, IL6, IL6R
RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs)	3	77.9×	6e-04	RUNX1, IL2, IL2RA
MAPK3 (ERK1) activation	3	70.8×	6e-04	TYK2, IL6, IL6R
Interleukin-6 signaling	3	64.9×	6e-04	TYK2, IL6, IL6R
Interleukin-2 signaling	3	64.9×	6e-04	IL2, IL2RA, IL2RB
Differentiation of naive CD4+ T cells to T helper 1 cells (Th1 cells)	3	59.9×	6e-04	RUNX1, RUNX3, STAT4
RUNX3 regulates RUNX1-mediated transcription	2	173.0×	0.001	RUNX1, RUNX3
Translocation of ZAP-70 to Immunological synapse	3	43.3×	0.001	HLA-DQA2, HLA-DRA, PTPN22
Interleukin-10 signaling	4	21.2×	0.001	TYK2, CCR1, CD80, IL6
Phosphorylation of CD3 and TCR zeta chains	3	37.1×	0.002	HLA-DQA2, HLA-DRA, PTPN22
Interleukin receptor SHC signaling	3	27.8×	0.004	IL2, IL2RA, IL2RB
Interferon gamma signaling	4	11.4×	0.008	HLA-DQA2, HLA-DQB1, HLA-DRA, IRF1
Interleukin-23 signaling	2	57.7×	0.010	STAT4, TYK2
RUNX3 regulates p14-ARF	2	51.9×	0.010	RUNX1, RUNX3
Interleukin-21 signaling	2	51.9×	0.010	STAT4, IL21
Interleukin-35 Signalling	2	43.3×	0.014	STAT4, TYK2
Activation of STAT3 by cadherin engagement	3	11.1×	0.035	TYK2, IL6, IL6R
Co-inhibition by PD-1	2	23.6×	0.044	HLA-DQA2, HLA-DRA
Cytokine Signaling in Immune system	5	4.6×	0.055	STAT4, CCR1, CD80, SH2B3, IRF1
Interleukin-20 family signaling	2	19.2×	0.059	STAT4, TYK2
Interleukin-12 signaling	2	18.5×	0.060	STAT4, TYK2
Generation of second messenger molecules	2	15.7×	0.079	HLA-DQA2, HLA-DRA
Interleukin-4 and Interleukin-13 signaling	3	7.0×	0.095	TYK2, IL6, IL6R
Transcriptional regulation by RUNX3	2	12.4×	0.116	RUNX1, RUNX3
Collagen chain trimerization	2	11.8×	0.122	COL11A1, COL12A1
MHC class II antigen presentation	3	6.1×	0.123	HLA-DQA2, HLA-DRA, LGMN
RUNX1 regulates expression of components of tight junctions	1	51.9×	0.149	RUNX1
RUNX1 regulates transcription of genes involved in interleukin signaling	1	51.9×	0.149	RUNX1
RUNX2 regulates genes involved in differentiation of myeloid cells	1	51.9×	0.149	RUNX1
RUNX3 regulates BCL2L11 (BIM) transcription	1	51.9×	0.149	RUNX3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 61 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	11	8.5×	3e-05	TYK2, CCR1, CCR3, CD80, CYSLTR2, HLA-DQA2, HLA-DQB1, HLA-DRA (+3 more)
interleukin-2-mediated signaling pathway	3	103.6×	6e-04	IL2, IL2RA, IL2RB
positive regulation of interleukin-17 production	4	39.5×	6e-04	TYK2, IL2, IL21, IL6
antigen processing and presentation of exogenous peptide antigen via MHC class II	4	35.6×	6e-04	HLA-DQA2, HLA-DQB1, HLA-DRA, LGMN
cytokine-mediated signaling pathway	6	12.8×	8e-04	STAT4, TYK2, CCR1, IL2RB, IL6, IL6R
regulation of CD4-positive, alpha-beta T cell proliferation	2	276.3×	0.001	IL2, IL2RA
peptide antigen assembly with MHC class II protein complex	3	51.8×	0.002	HLA-DQA2, HLA-DQB1, HLA-DRA
hepatic immune response	2	184.2×	0.002	IL6, IL6R
regulation of T cell homeostatic proliferation	2	184.2×	0.002	IL2, IL2RA
negative regulation of CD4-positive, alpha-beta T cell differentiation	2	138.1×	0.004	RUNX1, RUNX3
positive regulation of T cell proliferation	4	17.0×	0.005	TYK2, CD80, IL21, IL6
positive regulation of CD8-positive, alpha-beta T cell differentiation	2	110.5×	0.006	RUNX1, RUNX3
monocyte chemotaxis	3	28.6×	0.006	CCR1, IL6, IL6R
ossification	4	14.9×	0.006	RUNX1, RUNX3, TAPT1, FOXC2
positive regulation of type II interferon production	4	14.7×	0.006	TYK2, IL2, IL21, PTPN22
cell surface receptor signaling pathway via STAT	3	27.6×	0.006	IL2, IL6, IL6R
positive regulation of tissue remodeling	2	92.1×	0.006	IL2, IL21
vascular endothelial growth factor production	2	78.9×	0.008	IL6, IL6R
positive regulation of immunoglobulin production	3	23.7×	0.008	IL2, IL21, IL6
positive regulation of immune response	3	23.7×	0.008	HLA-DQA2, HLA-DQB1, HLA-DRA
positive regulation of T cell activation	3	21.8×	0.009	HLA-DQA2, HLA-DQB1, HLA-DRA
interleukin-12-mediated signaling pathway	2	61.4×	0.011	STAT4, TYK2
activated T cell proliferation	2	61.4×	0.011	IL2, IL2RA
T cell differentiation	3	18.8×	0.013	IL2, PTPN2, PTPN22
germinal center B cell differentiation	2	55.2×	0.013	IL21, IL6
negative regulation of T cell receptor signaling pathway	3	18.0×	0.013	CD80, PTPN2, PTPN22
negative regulation of lipid storage	2	50.2×	0.013	IL6, PTPN2
peripheral nervous system neuron development	2	50.2×	0.013	RUNX1, RUNX3
T-helper 17 cell lineage commitment	2	50.2×	0.013	IL6, IL6R
adaptive immune response	5	6.9×	0.015	ERAP2, HLA-DQA2, HLA-DQB1, HLA-DRA, IL2

Therapeutics

Drug target analysis

Approved (phase 4): 7 · Phase ≥3: 7 · Phased (≥1): 11 · Undrugged: 60

Druggability breadth: 29 of 71 evidence-associated genes (41%) 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
RUNX1	APOMORPHINE HYDROCHLORIDE
TYK2	FEDRATINIB
HDAC9	CELECOXIB
CCR1	ABAMETAPIR
CYSLTR2	PRANLUKAST
FASN	RABEPRAZOLE
IL6	PREDNISOLONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TYK2	72	4
HDAC9	28	4
CCR1	8	4
CYSLTR2	8	4
FASN	8	4
PTPN2	4	2
IL6	3	4
RUNX1	2	4
CCR3	2	2
IL2	2	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
APOMORPHINE HYDROCHLORIDE	4	RUNX1
FEDRATINIB	4	TYK2
RUXOLITINIB	4	TYK2
TOFACITINIB	4	TYK2
UPADACITINIB	4	TYK2
BARICITINIB	4	TYK2
FILGOTINIB	4	TYK2
ABROCITINIB	4	TYK2
DEUCRAVACITINIB	4	TYK2
MOMELOTINIB	4	TYK2
AXITINIB	4	TYK2
RUXOLITINIB PHOSPHATE	4	TYK2
INFIGRATINIB PHOSPHATE	4	TYK2
INFIGRATINIB	4	TYK2
PACRITINIB	4	TYK2
TOFACITINIB CITRATE	4	TYK2
BOSUTINIB	4	TYK2
PEFICITINIB	4	TYK2
CRAVACITINIB	4	TYK2
PAZOPANIB	4	TYK2
NINTEDANIB	4	TYK2
SUNITINIB	4	TYK2
DASATINIB	4	TYK2
ERLOTINIB	4	TYK2
CRIZOTINIB	4	TYK2
MIDOSTAURIN	4	TYK2
IMATINIB	4	TYK2
CELECOXIB	4	HDAC9
PHENYLBUTANOIC ACID	4	HDAC9
SODIUM PHENYLBUTYRATE	4	HDAC9

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 11.

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

Symbol	Assays	Type breakdown
HDAC9	1,625	Binding:1612, ADMET:8, Functional:4, Toxicity:1
TYK2	1,083	Binding:1043, Functional:39, ADMET:1
PTPN2	250	Binding:246, ADMET:4
CCR1	243	Binding:176, Functional:67
CCR3	175	Binding:107, Functional:68
FASN	142	Binding:136, Functional:6
PTPN22	137	Binding:122, Functional:10, ADMET:5
CYSLTR2	74	Functional:47, Binding:27
ERAP2	46	Binding:40, ADMET:4, Functional:2
LGMN	43	Binding:43
IL2	35	Binding:34, ADMET:1
LNPEP	34	Binding:33, ADMET:1
RUNX1	20	Binding:17, Functional:3
STAT4	20	Binding:20
IL6	16	Binding:16
ATXN2	5	Binding:3, Functional:2
IL6R	5	Binding:5
UBE2L3	2	Binding:2
COG6	2	Binding:2
TRIM58	2	Binding:2
FOXC2	2	Binding:2
IL2RA	2	Binding:2
LONRF2	1	Binding:1
EIF3H	1	Binding:1
IL2RB	1	Binding:1
LTBR	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TYK2	2.7.10.2	non-specific protein-tyrosine kinase
UBE2L3	2.3.2.23, 2.3.2.24	E2 ubiquitin-conjugating enzyme, (E3-independent) E2 ubiquitin-conjugating enzyme
ATP8B2	7.6.2.1	P-type phospholipid transporter
HDAC9	3.5.1.98	histone deacetylase
ERAP2	3.4.11.1, 3.4.11.6	leucyl aminopeptidase, aminopeptidase B
FASN	2.3.1.39, 2.3.1.85	[acyl-carrier-protein] S-malonyltransferase, fatty-acid synthase system
LNPEP	3.4.11.3	cystinyl aminopeptidase
MOCS2	2.8.1.12	molybdopterin synthase
LGMN	3.4.22.34	Legumain
PTPN2	3.1.3.48	protein-tyrosine-phosphatase
PTPN22	3.1.3.48	protein-tyrosine-phosphatase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TYK2	1,083
HDAC9	1,625
CCR1	243
CCR3	175
FASN	142
PTPN2	250
PTPN22	137

Pharmacogenomics

Cohort genes with a PharmGKB record: 65; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

29 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)
APOMORPHINE HYDROCHLORIDE	4	RUNX1
FEDRATINIB	4	TYK2
RUXOLITINIB	4	TYK2
TOFACITINIB	4	TYK2
UPADACITINIB	4	TYK2
FILGOTINIB	4	TYK2
ABROCITINIB	4	TYK2
DEUCRAVACITINIB	4	TYK2
MOMELOTINIB	4	TYK2
AXITINIB	4	TYK2
RUXOLITINIB PHOSPHATE	4	TYK2
INFIGRATINIB PHOSPHATE	4	TYK2
INFIGRATINIB	4	TYK2
PACRITINIB	4	TYK2
TOFACITINIB CITRATE	4	TYK2
BOSUTINIB	4	TYK2
PEFICITINIB	4	TYK2
CRAVACITINIB	4	TYK2
PAZOPANIB	4	TYK2
NINTEDANIB	4	TYK2
SUNITINIB	4	TYK2
DASATINIB	4	TYK2
ERLOTINIB	4	TYK2
CRIZOTINIB	4	TYK2
MIDOSTAURIN	4	TYK2
IMATINIB	4	TYK2
CELECOXIB	4	HDAC9
PHENYLBUTANOIC ACID	4	HDAC9
SODIUM PHENYLBUTYRATE	4	HDAC9

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	7	RUNX1, TYK2, HDAC9, CCR1, CYSLTR2, FASN, IL6
B	Phased (≥1) drug, not yet approved	4	CCR3, ERAP2, IL2, PTPN2
C	Druggable family + PDB, no drug	13	UBE2L3, CD80, COL12A1, EIF3H, HLA-DQB1, HLA-DRA, IL2RA, IL2RB, IL6R, LNPEP (+3 more)
D	Druggable family + AlphaFold only, no drug	3	SORCS1, FBLN7, HLA-DQA2
E	Difficult family or no structure, no drug	44	RUNX3, ATXN2, ZFP36L1, SS18, STAT4, WWOX, ZNF33B, ZNF37BP, TIMMDC1, ATP8B2 (+34 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
STAT4	20	TYK2
IL6R	5	IL6
PTPN22	137	—
RUNX3	0	—
ATXN2	5	—
ZFP36L1	0	—
SS18	0	—
UBE2L3	2	—
WWOX	0	—
ZNF33B	0	—
ZNF37BP	0	—
TIMMDC1	0	—
ATP8B2	0	—
JPH3	0	—
SORCS1	0	—
CD80	0	—
COG6	2	—
RIN3	0	—
KLF17	0	—
PRICKLE2	0	—
COL11A1	0	—
COL12A1	0	—
TRIM58	2	—
ZNF521	0	—
LONRF2	1	—
ANKRD55	0	—
MTHFSD	0	—
PRR5L	0	—
FBLN7	0	—
TAPT1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 26.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	11
Not specified	10
PHASE1	2
PHASE2/PHASE3	1
PHASE2	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04088396	PHASE3	RECRUITING	A Study of Baricitinib (LY3009104) in Participants From 1 Year to Less Than 18 Years Old With Systemic Juvenile Idiopathic Arthritis (sJIA)
NCT00144599	PHASE3	COMPLETED	Study of MRA for Systemic Juvenile Idiopathic Arthritis (sJIA)
NCT00144612	PHASE3	COMPLETED	Long-term Treatment Study of MRA for Systemic Juvenile Idiopathic Arthritis (sJIA)
NCT00144664	PHASE3	COMPLETED	Study of MRA for Polyarticular Juvenile Idiopathic Arthritis (pJIA)
NCT00339157	PHASE2/PHASE3	COMPLETED	Interleukin-1 Receptor Antagonist (IL-1RA) (ANAKINRA) IN SEVERE SYSTEMIC-ONSET JUVENILE IDIOPATHIC ARTHRITIS
NCT00886769	PHASE3	TERMINATED	Single-dose Study to Assess Efficacy of Canakinumab (ACZ885) in Patients With Active Juvenile Idiopathic Arthritis (SJIA)
NCT00891046	PHASE3	COMPLETED	An Open-label Extension Study of Canakinumab in Patients With Systemic Juvenile Idiopathic Arthritis and Active Systemic Manifestations Manifestations and Response Characterization Study in Canakinumab Treatment-naïve Patients With Active SJIA With and Without Fever.
NCT01676948	PHASE3	WITHDRAWN	An Open-label, Multi-arm, Non-comparative Safety and Tolerability Study of Canakinumab (ACZ885) in Patients With Active Systemic Juvenile Idiopathic Arthritis (SJIA)
NCT02296424	PHASE3	COMPLETED	ß-SPECIFIC 4 Patients: Study of Pediatric EffiCacy and Safety wIth FIrst-line Use of Canakinumab
NCT02334748	PHASE3	COMPLETED	A Study of Canakinumab in Patients With Systemic Juvenile Idiopathic Arthritis or Hereditary Periodic Fevers Who Participated in the CACZ885G2301E1, CACZ885G2306 or CACZ885N2301 Studies
NCT02396212	PHASE3	COMPLETED	Study of Efficacy and Safety of Canakinumab in Japanese Patients With SJIA
NCT05001737	PHASE3	COMPLETED	Evaluate Efficacy, Safety and Tolerability, PK and PD of Emapalumab in Children and Adults With MAS in Still’s or SLE
NCT01962415	PHASE2	RECRUITING	Reduced Intensity Conditioning for Non-Malignant Disorders Undergoing UCBT, BMT or PBSCT
NCT01803321	PHASE1	COMPLETED	Study to Evaluate the Safety and Tolerability of Two Doses of Rilonacept in Pediatric Subjects With Active Systemic Juvenile Idiopathic Arthritis (SJIA)
NCT05027373	PHASE1	UNKNOWN	Safety, Tolerability and Pharmacokinetic of Recombinant Anti-IL-1β Humanized Monoclonal Antibody Injection
NCT05239702	EARLY_PHASE1	UNKNOWN	Clinical Study of Targeting CD7 CAR-T Cells in the Treatment of Autoimmune Diseases
NCT05200715	Not specified	RECRUITING	AutoInflammatory Disease Alliance Registry (AIDA)
NCT05927454	Not specified	RECRUITING	Acostill ( RaDiCo Cohort) (RaDiCo Acostill)
NCT06718049	Not specified	NOT_YET_RECRUITING	Role of Interleukin 18 (IL-18) and Interleukin 18 Binding Protein (IL-18BP) in the Diagnostic Work-up of Systemic Juvenile Idiopathic Arthritis and Autoinflammatory Diseases: Possible Biomarkers in the Differential Diagnosis of Other Febrile Diseases
NCT06838143	Not specified	RECRUITING	Ilaris NIS in Korea
NCT07077304	Not specified	NOT_YET_RECRUITING	EACVI Study on Multimodality Cardiovascular Imaging of Inflammatory Cardiovascular Diseases
NCT07126145	Not specified	NOT_YET_RECRUITING	Clinical Autoinflammatory Disease Cohort
NCT07517250	Not specified	RECRUITING	A Study on the Use of Canakinumab Among Familial Mediterranean Fever and Still’s Disease Patients
NCT01304420	Not specified	COMPLETED	Ultrasonography in Juvenile Idiopathic Arthritis
NCT05045001	Not specified	UNKNOWN	Pharmacogenetic Studies on Anti-IL-6 Receptor Monoclonal Antibodies on the Treatment of Rheumatic Diseases
NCT05055882	Not specified	UNKNOWN	Auvergne-Rhône-Alpes-Limousin Research Database for Still’s Diseases in Children and Adults

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CANAKINUMAB	4	6
ANAKINRA	4	1
BARICITINIB	4	1
EMAPALUMAB	4	1
HYDROXYUREA	4	1
RILONACEPT	4	1
TOCILIZUMAB	4	1
CHEMBL5220618	0	1
CHEMBL5427854	0	1