Rheumatoid arthritis

Summary

Rheumatoid arthritis (MONDO:0008383) is a disease (an umbrella term covering 7 Mondo subtypes) with 75 cohort genes (3,183 GWAS associations across 159 studies) and 2,644 clinical trials. The dominant Reactome pathway is Interferon gamma signaling (10 cohort genes). Top therapeutic interventions include etanercept, tocilizumab, and abatacept.

At a glance

• Umbrella term: 7 Mondo subtypes
• Cohort genes: 75
• GWAS associations: 3,183
• ClinVar variants: 60
• Clinical trials: 2,644

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	rheumatoid arthritis
Mondo ID	MONDO:0008383
EFO	EFO:0000685
MeSH	D001172
OMIM	180300
Orphanet	284130
DOID	DOID:7148
ICD-11	576319925
NCIT	C2884
SNOMED CT	69896004
UMLS	C0003873
MedGen	2078
Is cancer (heuristic)	no

Also known as: RA · rheumatoid arthritis

Data availability: 60 ClinVar variants · 3,183 GWAS associations (159 studies) · 1 GenCC gene-disease record · 1 HPO phenotype · 14 cell lines.

Disease family

An umbrella term covering 7 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › autoimmune disorder of musculoskeletal system › rheumatoid arthritis

Related subtypes (2): neonatal dermatomyositis, autoimmune cardiomyopathy

Subtypes (7): rheumatoid arthritis-associated interstitial lung disease, chronic childhood arthritis, ankylosing spondylitis, Felty syndrome, psoriatic arthritis, polyarticular juvenile rheumatoid arthritis, rheumatoid vasculitis

Genetics & variants

GWAS landscape

3,183 GWAS associations across 159 studies. Top hits map to 23 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs660895	1e-300	HLA-DRB1 - HLA-DQA1	G	3.03
rs6910071	1e-299	TSBP1, TSBP1-AS1	G	2.88
rs35139284	4e-287	HLA-DRB1 - HLA-DQA1	T	0.54
rs9268839	1e-250	HLA-DRB9	G	2.47
rs112062732	6e-227	HLA-DRB9 - HLA-DRB5	?	2.44
rs6457620	4e-186	HLA-DQB1 - MTCO3P1	?	2.55
rs2476601	9e-170	AP4B1-AS1, PTPN22	A	1.8
rs6679677	4e-161	PHTF1 - RSBN1	A	1.59
rs532322163	2e-152	HLA-DRB1 - HLA-DQA1	T	0.86
rs3763309	2e-124	TSBP1-AS1 - HLA-DRA	?	2.3
rs6457617	5e-75	HLA-DQB1 - MTCO3P1	T	2.36
rs13192471	2e-58	HLA-DQB1 - MTCO3P1	G	1.97
rs12194148	5e-58	HLA-DRB9 - HLA-DRB5	?
rs2157337	9e-52	HLA-DRB5 - RNU1-61P	?
rs7517847	5e-43	IL23R, C1orf141	?	0.11
rs10174238	3e-42	STAT4	?	1.37
rs1571878	4e-40	CCR6	T	0.86
rs7731626	1e-39	ANKRD55	A	0.88
rs13238352	1e-38	TNPO3	T	1.44
rs9296015	2e-38	NOTCH4 - TSBP1-AS1	?
Asn120HLA-DRB1	2e-34		?	2.46
rs11889341	4e-30	STAT4	T	1.16
rs7752903	2e-29	TNFAIP3 - LINC02865	G	1.38
rs34536443	3e-29	TYK2	C	0.75
rs7749323	4e-29	TNFAIP3 - LINC02865	A	1.33
rs17264332	3e-27	LINC03004	?	1.19
rs615672	8e-27	HLA-DRB1 - HLA-DQA1	?
rs2301888	4e-26	PADI4	A	0.88
rs2233424	7e-26	NFKBIE - TMEM151B	T	1.22
rs3087243	3e-25	CTLA4 - ICOS	G	1.14

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST009877	Marquez A	2018	15,523	22,308	Meta-analysis of Immunochip data of four autoimmune diseases reveals novel single-disease and cross-phenotype associations.
GCST002318	Okada Y	2013	14,361	42,923	Genetics of rheumatoid arthritis contributes to biology and drug discovery.
GCST005569	Eyre S	2012	13,838	33,742	High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis.
GCST005321	Broce I	2018	12,577	23,475	Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies.
GCST005568	Eyre S	2012	9,585	33,742	High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis.
GCST005563	Liu JZ	2013	6,333	106,357	Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis.
GCST010730	Leng RX	2020	5,900	20,521	Identification of new susceptibility loci associated with rheumatoid arthritis.
GCST000679	Stahl EA	2010	5,539	20,169	Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci.
GCST007278	Acosta-Herrera M	2018	4,595	19,704	Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases.
GCST001454	Okada Y	2012	4,074	16,891	Meta-analysis identifies nine new loci associated with rheumatoid arthritis in the Japanese population.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	2
Tier 2: splice/UTR	2
Tier 3: regulatory	2
Tier 4: intronic/intergenic	44

MAF distribution

Bucket	Variants
common (>=0.05)	48
low_freq (0.01-0.05)	2
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intergenic_variant	22
intron_variant	21
regulatory_region_variant	2
missense_variant	2
3_prime_UTR_variant	2
unknown	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs660895	6	32609603	A>G	0.05	regulatory_region_variant	HLA-DRB1 - HLA-DQA1	1e-300	Tier 3: regulatory
rs6910071	6	32315077	A>G	0.22	intron_variant	TSBP1, TSBP1-AS1	1e-299	Tier 4: intronic/intergenic
rs35139284	6	32593593	C>T	0.05	intergenic_variant	HLA-DRB1 - HLA-DQA1	4e-287	Tier 4: intronic/intergenic
rs9268839	6	32460995	A>C,G	0.45	intron_variant	HLA-DRB9	1e-250	Tier 4: intronic/intergenic
rs112062732	6	32486159	T>C,G	0.05	intron_variant	HLA-DRB9 - HLA-DRB5	6e-227	Tier 4: intronic/intergenic
rs6457620	6	32696222	G>C,T	0.5	intergenic_variant	HLA-DQB1 - MTCO3P1	4e-186	Tier 4: intronic/intergenic
rs2476601	1	113834946	A>G,T	0.09	missense_variant	AP4B1-AS1, PTPN22	9e-170	Tier 1: coding
rs6679677	1	113761186	C>A,T	0.12	intergenic_variant	PHTF1 - RSBN1	4e-161	Tier 4: intronic/intergenic
rs532322163	6	32626378	A>T	0.133	intergenic_variant	HLA-DRB1 - HLA-DQA1	2e-152	Tier 4: intronic/intergenic
rs3763309	6	32408196	C>A,G,T	0.05	intergenic_variant	TSBP1-AS1 - HLA-DRA	2e-124	Tier 4: intronic/intergenic
rs6457617	6	32696074	C>A,T	0.49	intergenic_variant	HLA-DQB1 - MTCO3P1	5e-75	Tier 4: intronic/intergenic
rs13192471	6	32703326	T>C	0.22	intergenic_variant	HLA-DQB1 - MTCO3P1	2e-58	Tier 4: intronic/intergenic
rs12194148	6	32476421	G>C,T	0.05	intron_variant	HLA-DRB9 - HLA-DRB5	5e-58	Tier 4: intronic/intergenic
rs2157337	6	32533367	C>G,T	0.05	intergenic_variant	HLA-DRB5 - RNU1-61P	9e-52	Tier 4: intronic/intergenic
rs7517847	1	67215986	T>A,C,G	0.05	intron_variant	IL23R, C1orf141	5e-43	Tier 4: intronic/intergenic
rs10174238	2	191108308	G>A,T	0.05	intron_variant	STAT4	3e-42	Tier 4: intronic/intergenic
rs1571878	6	167127354	C>G,T	0.05	intron_variant	CCR6	4e-40	Tier 4: intronic/intergenic
rs7731626	5	56148856	G>A,C	0.367	intron_variant	ANKRD55	1e-39	Tier 4: intronic/intergenic
rs13238352	7	129007888	C>A,T	0.05	intron_variant	TNPO3	1e-38	Tier 4: intronic/intergenic
rs9296015	6	32251212	G>A	0.05	intergenic_variant	NOTCH4 - TSBP1-AS1	2e-38	Tier 4: intronic/intergenic
Asn120HLA-DRB1				0.12			2e-34	Tier 4: intronic/intergenic
rs11889341	2	191079016	C>T	0.05	intron_variant	STAT4	4e-30	Tier 4: intronic/intergenic
rs7752903	6	137906227	T>G	0.04	intergenic_variant	TNFAIP3 - LINC02865	2e-29	Tier 4: intronic/intergenic
rs34536443	19	10352442	G>C,T	0.044	missense_variant	TYK2	3e-29	Tier 1: coding
rs7749323	6	137909252	G>A	0.05	intergenic_variant	TNFAIP3 - LINC02865	4e-29	Tier 4: intronic/intergenic
rs17264332	6	137684378	A>G,T	0.05	intron_variant	LINC03004	3e-27	Tier 4: intronic/intergenic
rs615672	6	32606394	G>A,C	0.05	intergenic_variant	HLA-DRB1 - HLA-DQA1	8e-27	Tier 4: intronic/intergenic
rs2301888	1	17346235	G>A	0.05	intron_variant	PADI4	4e-26	Tier 4: intronic/intergenic
rs2233424	6	44266184	C>A,G,T	0.05	regulatory_region_variant	NFKBIE - TMEM151B	7e-26	Tier 3: regulatory
rs3087243	2	203874196	G>A,T	0.4	intergenic_variant	CTLA4 - ICOS	3e-25	Tier 4: intronic/intergenic

ClinVar germline variants

60 retrieved; paginated sample, class counts are floors:

27 uncertain significance, 7 conflicting classifications of pathogenicity, 6 association, 5 likely pathogenic, 5 risk factor, 4 benign; association, 2 pathogenic/likely pathogenic, 2 pathogenic, 1 affects, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1076559	NM_000246.4(CIITA):c.632del (p.Pro211fs)	CIITA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
420718	NM_000246.4(CIITA):c.2290del (p.Gln764fs)	CIITA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
983492	NM_003263.4(TLR1):c.2036T>C (p.Ile679Thr)	TLR1	Pathogenic	no assertion criteria provided
983493	NM_003263.4(TLR1):c.1324T>C (p.Cys442Arg)	TLR1	Pathogenic	no assertion criteria provided
1496695	NM_000246.4(CIITA):c.199+1G>A	CIITA	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3578232	NM_000246.4(CIITA):c.492del (p.Thr165fs)	CIITA	Likely pathogenic	criteria provided, single submitter
3578233	NM_000246.4(CIITA):c.628+1G>A	CIITA	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3578234	NM_000246.4(CIITA):c.2382_2439delinsTGTATTCAGGTACCCAA (p.Lys794fs)	CIITA	Likely pathogenic	criteria provided, single submitter
666964	NM_000246.4(CIITA):c.338dup (p.Leu114fs)	CIITA	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4895	NM_016382.4(CD244):c.834+526A>G	CD244	risk factor	no assertion criteria provided
9546	NC_000016.10:g.10877045=	CIITA	risk factor	no assertion criteria provided
8475	NM_001144962.2(NFKBIL1):c.-13+590T>A	NFKBIL1	risk factor	no assertion criteria provided
5749	NM_003059.3(SLC22A4):c.393+6607C>T	SLC22A4	risk factor	no assertion criteria provided
565291	NM_001014286.3(SUPT20H):c.73A>T (p.Lys25Ter)	SUPT20H	risk factor	no assertion criteria provided
983491	NM_005199.5(CHRNG):c.994C>T (p.Arg332Trp)	CHRNG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
317716	NM_000246.4(CIITA):c.2651G>A (p.Arg884His)	CIITA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
528781	NM_000246.4(CIITA):c.170C>A (p.Ala57Asp)	CIITA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
625921	NM_000246.4(CIITA):c.931A>G (p.Met311Val)	CIITA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
827997	NM_000246.4(CIITA):c.2817-8C>G	CIITA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
971840	NM_000246.4(CIITA):c.3197G>A (p.Arg1066His)	CIITA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
456662	NM_000572.3(IL10):c.43G>A (p.Gly15Arg)	LOC128462409	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
801021	Multiple alleles		Affects	no assertion criteria provided
2585350	NM_015967.8(PTPN22):c.1894+2T>C	AP4B1-AS1	Uncertain significance	criteria provided, single submitter
3393418	NM_015967.8(PTPN22):c.841del (p.Leu281fs)	AP4B1-AS1	Uncertain significance	criteria provided, single submitter
1410833	NM_000246.4(CIITA):c.631C>T (p.Pro211Ser)	CIITA	Uncertain significance	criteria provided, multiple submitters, no conflicts
1413877	NM_000246.4(CIITA):c.2515C>G (p.Arg839Gly)	CIITA	Uncertain significance	criteria provided, multiple submitters, no conflicts
2585349	NM_000246.4(CIITA):c.673G>A (p.Gly225Arg)	CIITA	Uncertain significance	criteria provided, single submitter
317704	NM_000246.4(CIITA):c.2096C>T (p.Pro699Leu)	CIITA	Uncertain significance	criteria provided, multiple submitters, no conflicts
317729	NM_000246.4(CIITA):c.*125C>T	CIITA	Uncertain significance	criteria provided, multiple submitters, no conflicts
317738	NM_000246.4(CIITA):c.*465G>A	CIITA	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 60 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 5

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

Gene	HGNC	Evidence routes
PADI2	PADI2	GWAS
PADI4	PADI4	GWAS
IRF5	IRF5	GWAS, Orphanet
PTPN22	PTPN22	GWAS, GenCC, Orphanet
STAT4	STAT4	GWAS, Orphanet

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
PTPN22	Limited	Unknown	rheumatoid arthritis	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IRF5	Orphanet:186	Primary biliary cholangitis
IRF5	Orphanet:220393	Diffuse cutaneous systemic sclerosis
IRF5	Orphanet:220402	Limited cutaneous systemic sclerosis
IRF5	Orphanet:536	Systemic lupus erythematosus
PTPN22	Orphanet:3437	Vogt-Koyanagi-Harada disease
PTPN22	Orphanet:397	Giant cell arteritis
PTPN22	Orphanet:536	Systemic lupus erythematosus
PTPN22	Orphanet:85408	Rheumatoid factor-negative polyarticular juvenile idiopathic arthritis
PTPN22	Orphanet:85410	Oligoarticular juvenile idiopathic arthritis
PTPN22	Orphanet:900	Granulomatosis with polyangiitis
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
BLK	Orphanet:536	Systemic lupus erythematosus
BLK	Orphanet:552	MODY
SRC	Orphanet:480851	Hereditary thrombocytopenia with early-onset myelofibrosis
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
TBX1	Orphanet:1727	22q11.2 duplication syndrome
TBX1	Orphanet:3303	Tetralogy of Fallot
TBX1	Orphanet:567	22q11.2 deletion syndrome
TBX1	Orphanet:665044	Common arterial trunk with aortic dominance
TBX1	Orphanet:665058	Common arterial trunk with pulmonary dominance and interrupted aortic arch
TBX1	Orphanet:685017	Combined immunodeficiency due to TBX1 deficiency
TGFA	Orphanet:99798	Oligodontia
TNFAIP3	Orphanet:536	Systemic lupus erythematosus
TNFAIP3	Orphanet:674762	Early-onset autoinflammatory syndrome due to A20 haploinsufficiency
CD40	Orphanet:101090	Hyper-IgM syndrome type 3
TNFRSF9	Orphanet:664726	EBV-induced lymphoproliferative disease due to CD137 deficiency
TNFSF4	Orphanet:2073	Narcolepsy type 1
TNFSF4	Orphanet:536	Systemic lupus erythematosus
TRAF6	Orphanet:1810	Autosomal dominant hypohidrotic ectodermal dysplasia
TRPC3	Orphanet:458798	Spinocerebellar ataxia type 41
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
UBE4A	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability
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
C5	Orphanet:169150	Immunodeficiency due to a late component of complement deficiency
PRDM16	Orphanet:154	Familial isolated dilated cardiomyopathy
PRDM16	Orphanet:1606	1p36 deletion syndrome
PRDM16	Orphanet:54260	Left ventricular noncompaction
BACH2	Orphanet:714472	Inflammatory bowel disease-autoimmunity-sinopulmonary infections-lymphadenopathy syndrome

Cohort genes → proteins

75 cohort genes, 75 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	69
gwas_and_gencc	1
gwas_and_clinvar	3
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PADI2	HGNC:18341	ENSG00000117115	Q9Y2J8	Protein-arginine deiminase type-2	gwas,clinvar
PADI4	HGNC:18368	ENSG00000159339	Q9UM07	Protein-arginine deiminase type-4	gwas,clinvar
IRF5	HGNC:6120	ENSG00000128604	Q13568	Interferon regulatory factor 5	gwas,clinvar
PTPN22	HGNC:9652	ENSG00000134242	Q9Y2R2	Tyrosine-protein phosphatase non-receptor type 22	gwas,gencc
RUNX1	HGNC:10471	ENSG00000159216	Q01196	Runt-related transcription factor 1	gwas
SALL3	HGNC:10527	ENSG00000256463	Q9BXA9	Sal-like protein 3	gwas
BLCAP	HGNC:1055	ENSG00000166619	P62952	Apoptosis inducing factor BLCAP	gwas
BLK	HGNC:1057	ENSG00000136573	P51451	Tyrosine-protein kinase Blk	gwas
CXCR5	HGNC:1060	ENSG00000160683	P32302	C-X-C chemokine receptor type 5	gwas
CCL19	HGNC:10617	ENSG00000172724	Q99731	C-C motif chemokine 19	gwas
CCL21	HGNC:10620	ENSG00000137077	O00585	C-C motif chemokine 21	gwas
CXCL13	HGNC:10639	ENSG00000156234	O43927	C-X-C motif chemokine 13	gwas
SDF2L1	HGNC:10676	ENSG00000128228	Q9HCN8	Stromal cell-derived factor 2-like protein 1	gwas
SFTPD	HGNC:10803	ENSG00000133661	P35247	Pulmonary surfactant-associated protein D	gwas
SLC22A4	HGNC:10968	ENSG00000197208	Q9H015	Solute carrier family 22 member 4	clinvar
ZFP36L1	HGNC:1107	ENSG00000185650	Q07352	mRNA decay activator protein ZFP36L1	gwas
SRC	HGNC:11283	ENSG00000197122	P12931	Proto-oncogene tyrosine-protein kinase Src	gwas
STAT4	HGNC:11365	ENSG00000138378	Q14765	Signal transducer and activator of transcription 4	gwas
SYNGR1	HGNC:11498	ENSG00000100321	O43759	Synaptogyrin-1	gwas
TBX1	HGNC:11592	ENSG00000184058	O43435	T-box transcription factor TBX1	gwas
TCF7	HGNC:11639	ENSG00000081059	P36402	Transcription factor 7	gwas
TEC	HGNC:11719	ENSG00000135605	P42680	Tyrosine-protein kinase Tec	gwas
TGFA	HGNC:11765	ENSG00000163235	P01135	Protransforming growth factor alpha	gwas
TLE1	HGNC:11837	ENSG00000196781	Q04724	Transducin-like enhancer protein 1	gwas
TLE3	HGNC:11839	ENSG00000140332	Q04726	Transducin-like enhancer protein 3	gwas
TLR1	HGNC:11847	ENSG00000174125	Q15399	Toll-like receptor 1	clinvar
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
CD40	HGNC:11919	ENSG00000101017	P25942	Tumor necrosis factor receptor superfamily member 5	gwas
TNFRSF9	HGNC:11924	ENSG00000049249	Q07011	Tumor necrosis factor receptor superfamily member 9	gwas
TNFSF4	HGNC:11934	ENSG00000117586	P23510	Tumor necrosis factor ligand superfamily member 4	gwas
TPD52	HGNC:12005	ENSG00000076554	P55327	Tumor protein D52	gwas
TRAF1	HGNC:12031	ENSG00000056558	Q13077	TNF receptor-associated factor 1	gwas
TRAF6	HGNC:12036	ENSG00000175104	Q9Y4K3	TNF receptor-associated factor 6	gwas
TRPC3	HGNC:12335	ENSG00000138741	Q13507	Short transient receptor potential channel 3	gwas
C1QBP	HGNC:1243	ENSG00000108561	Q07021	Complement component 1 Q subcomponent-binding protein, mitochondrial	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
UBE4A	HGNC:12499	ENSG00000110344	Q14139	Ubiquitin conjugation factor E4 A	gwas
LINC00158	HGNC:1283	ENSG00000185433	P58513	Putative uncharacterized protein encoded by LINC00158	gwas
IKZF3	HGNC:13178	ENSG00000161405	Q9UKT9	Zinc finger protein Aiolos	gwas
C5	HGNC:1331	ENSG00000106804	P01031	Complement C5	gwas
SMIM29	HGNC:1340	ENSG00000186577	Q86T20	Small integral membrane protein 29	gwas
FBXW8	HGNC:13597	ENSG00000174989	Q8N3Y1	F-box/WD repeat-containing protein 8	gwas
TMEM187	HGNC:13705	ENSG00000177854	Q14656	Transmembrane protein 187	gwas
ADGRA3	HGNC:13839	ENSG00000152990	Q8IWK6	Adhesion G protein-coupled receptor A3	gwas
LZTS1	HGNC:13861	ENSG00000061337	Q9Y250	Leucine zipper putative tumor suppressor 1	gwas
APOM	HGNC:13916	ENSG00000204444	O95445	Apolipoprotein M	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PADI2	Protein-arginine deiminase type-2	Catalyzes the deimination of arginine residues of proteins.
PADI4	Protein-arginine deiminase type-4	Catalyzes the citrullination/deimination of arginine residues of proteins such as histones, thereby playing a key role in histone code and regulation of stem cell maintenance.
IRF5	Interferon regulatory factor 5	Transcription factor that plays a critical role in innate immunity by activating expression of type I interferon (IFN) IFNA and INFB and inflammatory cytokines downstream of endolysosomal toll-like receptors TLR7, TLR8 and TLR9.
PTPN22	Tyrosine-protein phosphatase non-receptor type 22	Acts as a negative regulator of T-cell receptor (TCR) signaling by direct dephosphorylation of the Src family kinases LCK and FYN, ITAMs of the TCRz/CD3 complex, as well as ZAP70, VAV, VCP and other key signaling molecules.
RUNX1	Runt-related transcription factor 1	Forms the heterodimeric complex core-binding factor (CBF) with CBFB.
SALL3	Sal-like protein 3	Probable transcription factor.
BLCAP	Apoptosis inducing factor BLCAP	Acts as a tumor suppressor; induces growth arrest at G(1)/S checkpoint and apoptosis via RB1-dependent and p53/TP53- and NF-kappa-B-independent mechanisms.
BLK	Tyrosine-protein kinase Blk	Non-receptor tyrosine kinase involved in B-lymphocyte development, differentiation and signaling.
CXCR5	C-X-C chemokine receptor type 5	Cytokine receptor that binds to B-lymphocyte chemoattractant (BLC).
CCL19	C-C motif chemokine 19	May play a role not only in inflammatory and immunological responses but also in normal lymphocyte recirculation and homing.
CCL21	C-C motif chemokine 21	Inhibits hemopoiesis and stimulates chemotaxis.
CXCL13	C-X-C motif chemokine 13	Chemotactic for B-lymphocytes but not for T-lymphocytes, monocytes and neutrophils.
SFTPD	Pulmonary surfactant-associated protein D	Contributes to the lung’s defense against inhaled microorganisms, organic antigens and toxins.
SLC22A4	Solute carrier family 22 member 4	Transporter that mediates the transport of endogenous and microbial zwitterions and organic cations.
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…
SRC	Proto-oncogene tyrosine-protein kinase Src	Non-receptor protein tyrosine kinase which is activated following engagement of many different classes of cellular receptors including immune response receptors, integrins and other adhesion receptors, receptor protein tyrosine kinases, G…
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.
SYNGR1	Synaptogyrin-1	May play a role in regulated exocytosis.
TBX1	T-box transcription factor TBX1	Transcription factor that plays a key role in cardiovascular development by promoting pharyngeal arch segmentation during embryonic development.
TCF7	Transcription factor 7	Transcriptional activator involved in T-cell lymphocyte differentiation.
TEC	Tyrosine-protein kinase Tec	Non-receptor tyrosine kinase that contributes to signaling from many receptors and participates as a signal transducer in multiple downstream pathways, including regulation of the actin cytoskeleton.
TGFA	Protransforming growth factor alpha	TGF alpha is a mitogenic polypeptide that is able to bind to the EGF receptor/EGFR and to act synergistically with TGF beta to promote anchorage-independent cell proliferation in soft agar.
TLE1	Transducin-like enhancer protein 1	Transcriptional corepressor that binds to a number of transcription factors.
TLE3	Transducin-like enhancer protein 3	Transcriptional coregulator that binds to a number of transcription factors.
TLR1	Toll-like receptor 1	Participates in the innate immune response to microbial agents.
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…
CD40	Tumor necrosis factor receptor superfamily member 5	Receptor for TNFSF5/CD40LG.
TNFRSF9	Tumor necrosis factor receptor superfamily member 9	Receptor for TNFSF9/4-1BBL.
TNFSF4	Tumor necrosis factor ligand superfamily member 4	Cytokine that binds to TNFRSF4.
TRAF1	TNF receptor-associated factor 1	Adapter molecule that regulates the activation of NF-kappa-B and JNK.
TRAF6	TNF receptor-associated factor 6	E3 ubiquitin ligase that, together with UBE2N and UBE2V1, mediates the synthesis of ‘Lys-63’-linked-polyubiquitin chains conjugated to proteins, such as ECSIT, IKBKG, IRAK1, AKT1 and AKT2.
TRPC3	Short transient receptor potential channel 3	Forms a receptor-activated non-selective calcium permeant cation channel.
C1QBP	Complement component 1 Q subcomponent-binding protein, mitochondrial	Multifunctional and multicompartmental protein involved in inflammation and infection processes, ribosome biogenesis, protein synthesis in mitochondria, regulation of apoptosis, transcriptional regulation and pre-mRNA splicing.
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.
UBE4A	Ubiquitin conjugation factor E4 A	Ubiquitin-protein ligase that probably functions as an E3 ligase in conjunction with specific E1 and E2 ligases.
IKZF3	Zinc finger protein Aiolos	Transcription factor that plays an important role in the regulation of lymphocyte differentiation.
C5	Complement C5	Precursor of the C5a anaphylatoxin and complement C5b components of the complement pathways, which consist in a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive immune sy…
FBXW8	F-box/WD repeat-containing protein 8	Substrate-recognition component of the Cul7-RING(FBXW8) ubiquitin ligase complex, which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.
ADGRA3	Adhesion G protein-coupled receptor A3	Orphan receptor that may have a role in planar cell polarity pathway.
LZTS1	Leucine zipper putative tumor suppressor 1	Involved in the regulation of cell growth.
APOM	Apolipoprotein M	Probably involved in lipid transport.
PRDM16	Histone-lysine N-methyltransferase PRDM16	Transcription regulator that acts both as a histone methyltransferase or chromatin adapter, depending on the context.
BACH2	Transcription regulator protein BACH2	Transcriptional regulator that acts as a repressor or activator.
BOLL	Protein boule-like	Probable RNA-binding protein, which may be required during spermatogenesis.
MMEL1	Membrane metallo-endopeptidase-like 1	Metalloprotease involved in sperm function, possibly by modulating the processes of fertilization and early embryonic development.
IL22	Interleukin-22	Cytokine that plays a critical role in modulating tissue responses during inflammation.

Protein-family classification

Druggable: 26 · Difficult: 15 · Unknown: 34 · Druggable fraction: 0.35

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
Phosphatase	3	3.4×	0.559
GPCR	6	1.9×	0.559
Complement	1	3.6×	0.711
Kinase	4	1.5×	0.711
Transcription factor	11	1.2×	0.711
Ion channel	1	1.5×	0.765
Transporter	1	1.0×	0.765
Protease	2	1.0×	0.765
Enzyme (other)	6	1.0×	0.765
Scaffold/PPI	4	0.9×	0.765
Antibody/Immunoglobulin	2	0.8×	0.799
Other/Unknown	34	0.8×	0.974

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PADI2	Enzyme (other)	yes	3.5.3.15	PAD, Cupredoxin, PAD_C
PADI4	Enzyme (other)	yes	3.5.3.15	PAD, Cupredoxin, PAD_C
IRF5	Other/Unknown	no		Interferon_reg_fact_DNA-bd_dom, SMAD_FHA_dom_sf, SMAD-like_dom_sf
PTPN22	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, Tyr_Pase_cat
RUNX1	Transcription factor	no		AML1_Runt, p53-like_TF_DNA-bd_sf, p53/RUNT-type_TF_DNA-bd_sf
SALL3	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Sal_C2H2-zinc-finger
BLCAP	Other/Unknown	no		BCALP
BLK	Kinase	yes	2.7.10.2	Prot_kinase_dom, SH2, Ser-Thr/Tyr_kinase_cat_dom
CXCR5	GPCR	yes		GPCR_Rhodpsn, Chemokine_CXCR5, GPCR_Rhodpsn_7TM
CCL19	Other/Unknown	no		Chemokine_CC_CS, Chemokine_IL8-like_dom, Chemokine_CC_DCCL
CCL21	Other/Unknown	no		Chemokine_IL8-like_dom, Chemokine_CC_DCCL, Interleukin_8-like_sf
CXCL13	Other/Unknown	no		Chemokine_CXC, Chemokine_IL8-like_dom, Chemokine_CXC_CS
SDF2L1	Other/Unknown	no		MIR_motif, MIR_dom_sf
SFTPD	Other/Unknown	no		C-type_lectin-like, Collagen, Surfac_D-trimer
SLC22A4	Transporter	yes		Orgcat_transp/SVOP, MFS_sugar_transport-like, Sugar_transporter_CS
ZFP36L1	Transcription factor	no		Znf_CCCH, Tis11B_N, Znf_CCCH_sf
SRC	Kinase	yes	2.7.10.2	Prot_kinase_dom, SH2, Ser-Thr/Tyr_kinase_cat_dom
STAT4	Transcription factor	no		SH2, STAT, p53-like_TF_DNA-bd_sf
SYNGR1	Other/Unknown	no		Marvel, Synaptogyrin
TBX1	Transcription factor	no		TF_T-box, p53-like_TF_DNA-bd_sf, TF_T-box_CS
TCF7	Other/Unknown	no		HMG_box_dom, CTNNB1-bd_N, TCF/LEF
TEC	Kinase	yes	2.7.10.2	Prot_kinase_dom, SH2, Ser-Thr/Tyr_kinase_cat_dom
TGFA	Other/Unknown	no		EGF
TLE1	Scaffold/PPI	no		WD40_rpt, Groucho/TLE_N, Groucho_enhance
TLE3	Scaffold/PPI	no		WD40_rpt, Groucho/TLE_N, Groucho_enhance
TLR1	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
CD40	Other/Unknown	no		TNFR/NGFR_Cys_rich_reg, TNFR_5, TNFRSF5_N
TNFRSF9	Other/Unknown	no		TNFR/NGFR_Cys_rich_reg, Growth_fac_rcpt_cys_sf, TNFR_9
TNFSF4	Other/Unknown	no		TNF_dom, Tumour_necrosis_fac-like_dom, TNF_CS
TPD52	Other/Unknown	no		TPD52
TRAF1	Other/Unknown	no		MATH/TRAF_dom, TRAF-like, TNF_rcpt-assoc_TRAF_met
TRAF6	Transcription factor	no		Znf_TRAF, Znf_RING, MATH/TRAF_dom
TRPC3	Ion channel	yes		Ankyrin_rpt, TRPC_channel, TRPC3_channel
C1QBP	Other/Unknown	no		MAM33, MAM33_sf
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
UBE4A	Transcription factor	no	2.3.2.27	Ubox_domain, Znf_RING/FYVE/PHD, Ub_conjug_fac_E4_core
LINC00158	Other/Unknown	no
IKZF3	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Ikaros_C2H2-ZF
C5	Complement	yes	3.4.21.43	Anaphylatoxin/fibulin, Netrin_domain, Macroglobln_a2
SMIM29	Other/Unknown	no		SMIM29
FBXW8	Scaffold/PPI	no		WD40_rpt, F-box_dom, Quinoprotein_ADH-like_sf
TMEM187	Other/Unknown	no		TMEM187
ADGRA3	GPCR	yes		GPS, Cys-rich_flank_reg_C, GPCR_2_secretin-like
LZTS1	Other/Unknown	no		LZTS
APOM	Other/Unknown	no		Calycin, ApoM

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	75
unknown	0

Top tissues across cohort

Tissue	Cohort genes
lymph node	13
granulocyte	12
monocyte	9
blood	7
secondary oocyte	7
mononuclear cell	6
oocyte	6
spleen	6
vermiform appendix	6
bone marrow cell	5
ganglionic eminence	5
male germ line stem cell (sensu Vertebrata) in testis	5
right lobe of liver	5
primordial germ cell in gonad	5
cortical plate	5
leukocyte	5
ventricular zone	4
buccal mucosa cell	4
bone marrow	3
mucosa of paranasal sinus	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PADI2	251	broad	marker	medial globus pallidus, globus pallidus, C1 segment of cervical spinal cord
PADI4	123	tissue_specific	marker	blood, bone marrow, bone marrow cell
IRF5	214	broad	marker	monocyte, mononuclear cell, granulocyte
PTPN22	190	broad	marker	bone marrow cell, bone marrow, monocyte
RUNX1	253	ubiquitous	marker	olfactory segment of nasal mucosa, epithelium of bronchus, mucosa of paranasal sinus
SALL3	74	broad	marker	ventricular zone, ganglionic eminence, amygdala
BLCAP	294	ubiquitous	marker	secondary oocyte, oocyte, nucleus accumbens
BLK	145	tissue_specific	marker	spleen, male germ line stem cell (sensu Vertebrata) in testis, lymph node
CXCR5	172	tissue_specific	marker	granulocyte, spleen, lymph node
CCL19	207	broad	marker	vermiform appendix, lymph node, caecum
CCL21	206	tissue_specific	marker	lymph node, right lobe of thyroid gland, vermiform appendix
CXCL13	190	tissue_specific	marker	spleen, lymph node, vermiform appendix
SDF2L1	199	ubiquitous	marker	mucosa of transverse colon, adenohypophysis, right lobe of liver
SFTPD	180	tissue_specific	marker	lower lobe of lung, visceral pleura, upper lobe of lung
SLC22A4	201	ubiquitous	marker	bronchial epithelial cell, epithelium of bronchus, bronchus
ZFP36L1	289	ubiquitous	marker	mucosa of paranasal sinus, endocervix, mucosa of stomach
SRC	236	ubiquitous	marker	body of stomach, gall bladder, rectum
STAT4	201	broad	marker	granulocyte, sperm, middle temporal gyrus
SYNGR1	298	ubiquitous	marker	Brodmann (1909) area 10, right hemisphere of cerebellum, cerebellar hemisphere
TBX1	220	broad	marker	hindlimb stylopod muscle, gastrocnemius, muscle of leg
TCF7	279	ubiquitous	marker	thymus, olfactory bulb, periodontal ligament
TEC	159	ubiquitous	marker	primordial germ cell in gonad, lower esophagus mucosa, bone marrow cell
TGFA	252	broad	yes	esophagus squamous epithelium, epithelium of esophagus, squamous epithelium
TLE1	293	ubiquitous	marker	ventricular zone, adrenal tissue, sural nerve
TLE3	248	ubiquitous	marker	blood, cortical plate, ganglionic eminence
TLR1	218	broad	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
CD40	242	ubiquitous	marker	lymph node, right lung, spleen
TNFRSF9	133	broad	marker	buccal mucosa cell, lymph node, cartilage tissue

Protein interactions among cohort

Intra-cohort edges: 61.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SRC	11,608
TRAF6	6,163
CASP8	5,040
RUNX1	4,994
C1QBP	4,534
TYK2	3,932
CD40	3,765
TNFAIP3	3,716
TRAF1	3,557
CCR2	3,331

Intra-cohort edges

A	B	Sources
ACTN1	SRC	string_interaction
APOM	B3GNT2	intact
BACH2	TAGAP	string_interaction
BACH2	TCF7	string_interaction
BACH2	UBASH3A	string_interaction
BLK	IRF5	string_interaction
BLK	STAT4	string_interaction
BLK	TAGAP	biogrid_interaction
BLK	TNFAIP3	string_interaction
C1QBP	PTPN22	string_interaction
C5	TRAF1	string_interaction
CASP10	CASP8	biogrid_interaction, intact, string_interaction
CCL19	CCL21	string_interaction
CCL19	CCR2	string_interaction
CCL19	CCR6	string_interaction
CCL19	CXCL13	string_interaction
CCL19	CXCR5	string_interaction
CCL21	CXCL13	string_interaction
CCL21	CXCR5	string_interaction
CCR1	CCR3	string_interaction
CCR2	CCR6	string_interaction
CCR2	SRC	intact
CCR6	CXCL13	string_interaction
CD2	CD28	string_interaction
CD2	CD5	biogrid_interaction, string_interaction
CD28	CD40	string_interaction
CD28	TNFRSF9	string_interaction
CD28	TNFSF4	string_interaction
CD40	TNFRSF9	string_interaction
CD40	TNFSF4	string_interaction
CD40	TRAF1	biogrid_interaction, string_interaction
CD40	TRAF6	biogrid_interaction, intact, string_interaction
CXCL13	CXCR5	string_interaction
IKZF3	ORMDL3	string_interaction
IKZF3	RUNX1	string_interaction
IRF5	PTPN22	string_interaction
IRF5	STAT4	string_interaction
IRF5	TNFAIP3	string_interaction
IRF5	TRAF6	biogrid_interaction, string_interaction
IRF5	TYK2	string_interaction
LZTS1	UBASH3A	intact
PADI4	PTPN22	string_interaction
PADI4	SLC22A4	string_interaction
PADI4	TRAF1	string_interaction
PRDM16	TLE3	string_interaction
PTPN22	SLC22A4	string_interaction
PTPN22	STAT4	string_interaction
PTPN22	TNFAIP3	string_interaction
PTPN22	UBASH3A	string_interaction
RUNX1	SLC22A4	string_interaction

Structural data

PDB: 53 · AlphaFold-only: 22 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SRC	P12931	79
TYK2	P29597	52
C5	P01031	42
CASP8	Q14790	36
SFTPD	P35247	31
PADI4	Q9UM07	28
PADI2	Q9Y2J8	24
UBE2L3	P68036	21
TRPC3	Q13507	19
ELMO1	Q92556	18
TNFAIP3	P21580	17
PTPN22	Q9Y2R2	14
CD40	P25942	14
TNFRSF9	Q07011	14
TRAF6	Q9Y4K3	13
ORMDL3	Q8N138	13
B3GNT2	Q9NY97	12
TGFA	P01135	11
CD28	P10747	10
TNFRSF14	Q92956	8
PPIL4	Q8WUA2	7
CCR2	P41597	7
CD2	P06729	7
TLE1	Q04724	6
TLR1	Q15399	6
IL22	Q9GZX6	6
RUNX1	Q01196	5
CCL19	Q99731	5
CCL21	O00585	5
CPA4	Q9UI42	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TMEM187	Q14656	92.12
MMEL1	Q495T6	90.34
PPM1L	Q5SGD2	89.78
SDF2L1	Q9HCN8	89.30
STAT4	Q14765	86.87
SLC22A4	Q9H015	85.07
BLK	P51451	81.89
CXCR5	P32302	80.85
PTX4	Q96A99	78.83
SMIM29	Q86T20	71.70
ADGRA3	Q8IWK6	70.20
CASP10	Q92851	69.54
TPD52	P55327	69.11
TLE3	Q04726	68.65
PHACTR3	Q96KR7	64.19
BOLL	Q8N9W6	64.18
BLCAP	P62952	63.24
TCF7	P36402	58.11
TAGAP	Q8N103	57.36
LINC00158	P58513	57.23
IKZF3	Q9UKT9	48.06
TSBP1	Q5SRN2	45.58

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 710. Enrichment computed across 250 evidence-associated genes (163 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 163 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interferon gamma signaling	10	7.7×	4e-04	IRF5, HLA-B, HLA-DQA1, HLA-DQA2, HLA-DQB1, HLA-DRB1, IRF8, IFNGR2 (+2 more)
Chemokine receptors bind chemokines	8	9.2×	8e-04	CXCR5, CCL19, CCL21, CXCL13, CCR1, CCR2, CCR3, CCR6
RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs)	4	28.0×	0.001	RUNX1, CTLA4, IL2, IL2RA
Signal Transduction	35	2.2×	0.001	RUNX1, CCL19, CCL21, SRC, TCF7, TEC, TGFA, C1QBP (+27 more)
Immune System	29	2.3×	0.002	IRF5, BLK, CCL19, SFTPD, SRC, STAT4, SYNGR1, TEC (+21 more)
Interleukin receptor SHC signaling	5	12.5×	0.005	CSF2, IL2, IL2RA, IL2RB, IL3
Cytokine Signaling in Immune system	14	3.5×	0.005	IRF5, CCL19, SRC, STAT4, TEC, CASP8, CCR1, CCR2 (+6 more)
Interleukin-10 signaling	6	8.6×	0.006	CCL19, TYK2, CCR1, CCR2, CSF2, CSF3
RHO GTPase cycle	11	4.1×	0.007	SRC, C1QBP, TAGAP, ACTN1, ARAP1, CDC42EP3, SWAP70, SENP1 (+3 more)
Translocation of ZAP-70 to Immunological synapse	4	15.6×	0.007	PTPN22, HLA-DQA1, HLA-DQA2, HLA-DRB1
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	9	4.8×	0.007	SFTPD, CD40, CD226, SLAMF6, COL2A1, CD200R1, FCGR2B, HLA-B (+1 more)
TRAIL signaling	3	26.3×	0.009	CASP10, CASP8, CFLAR
Phosphorylation of CD3 and TCR zeta chains	4	13.3×	0.011	PTPN22, HLA-DQA1, HLA-DQA2, HLA-DRB1
Diseases of Cellular Senescence	2	46.7×	0.019	CDK4, CDK6
Evasion of Oncogene Induced Senescence Due to p16INK4A Defects	2	46.7×	0.019	CDK4, CDK6
Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6	2	46.7×	0.019	CDK4, CDK6
Evasion of Oxidative Stress Induced Senescence Due to p16INK4A Defects	2	46.7×	0.019	CDK4, CDK6
Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6	2	46.7×	0.019	CDK4, CDK6
Diseases of cellular response to stress	2	46.7×	0.019	CDK4, CDK6
Interleukin-35 Signalling	3	17.5×	0.019	STAT4, TYK2, IL12RB2
Interleukin-2 signaling	3	17.5×	0.019	IL2, IL2RA, IL2RB
Interleukin-20 family signaling	4	10.4×	0.019	STAT4, TYK2, IL22, IL20RB
Aberrant regulation of mitotic G1/S transition in cancer due to RB1 defects	3	16.2×	0.022	CDK2, CDK4, CDK6
Differentiation of naive CD4+ T cells to T helper 1 cells (Th1 cells)	3	16.2×	0.022	RUNX1, STAT4, IL12RB2
Regulation of TNFR1 signaling	5	6.9×	0.022	TNFAIP3, TRAF1, UBE2L3, CASP8, CFLAR
Signaling by Rho GTPases	13	2.7×	0.027	SRC, C1QBP, TAGAP, ACTN1, ARAP1, CDC42EP3, SWAP70, SENP1 (+5 more)
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	13	2.7×	0.031	SRC, C1QBP, TAGAP, ACTN1, ARAP1, CDC42EP3, SWAP70, SENP1 (+5 more)
Repression of WNT target genes	3	13.1×	0.035	TCF7, TLE1, TLE3
RAF/MAP kinase cascade	9	3.4×	0.035	SRC, TGFA, SPRED2, CSF2, IL2, IL2RA, IL2RB, IL3 (+1 more)
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	7	4.2×	0.035	SRC, TGFA, TRAF6, CD28, PIP4K2C, ICOS, IRAK1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 220 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	36	7.7×	1e-18	CXCR5, CCL19, CCL21, CXCL13, TCF7, TLR1, TNFRSF14, TNFSF4 (+28 more)
positive regulation of type II interferon production	13	13.3×	1e-08	PTPN22, TNFSF4, TYK2, CCR2, CD2, CD226, CD244, SLAMF6 (+5 more)
humoral immune response	9	11.5×	4e-05	CCR2, CCR6, CD28, CD83, AIRE, GATA3, HLA-DQB1, HLA-DRB1 (+1 more)
T cell costimulation	8	13.6×	4e-05	CCL19, CCL21, SRC, TNFRSF14, CD28, CD5, DPP4, ICOS
cytokine-mediated signaling pathway	11	6.5×	3e-04	IRF5, STAT4, TYK2, CCR1, CCR2, CSF3, IFNGR2, IL12RB2 (+3 more)
dendritic cell chemotaxis	5	22.5×	4e-04	CCL19, CCL21, CCR1, CCR2, CCR6
inflammatory response	20	3.4×	4e-04	IRF5, CCL19, CCL21, CXCL13, TLR1, TNFAIP3, CD40, TNFSF4 (+12 more)
antigen processing and presentation of exogenous peptide antigen via MHC class II	6	14.8×	5e-04	TRAF6, FCGR2B, HLA-DQA1, HLA-DQA2, HLA-DQB1, HLA-DRB1
positive regulation of interleukin-2 production	6	12.8×	0.001	RUNX1, TRAF6, CCR2, CD28, CD83, IRF4
regulation of T-helper cell differentiation	3	57.5×	0.001	GATA3, HLA-DRB1, IRF4
positive regulation of T cell activation	6	12.1×	0.001	CCR2, CYRIB, HLA-DQA1, HLA-DQA2, HLA-DQB1, HLA-DRB1
cell surface receptor signaling pathway	14	4.1×	0.001	CXCL13, TGFA, TNFRSF14, C5, ADGRA3, CCR1, CD2, CD28 (+6 more)
T cell receptor signaling pathway	9	6.2×	0.002	PTPN22, TEC, TRAF6, CD28, ICOSLG, CTLA4, GATA3, HLA-DQB1 (+1 more)
positive regulation of interleukin-10 production	6	10.9×	0.002	TNFSF4, CD28, CD83, IL20RB, IL21, IRF4
regulation of G2/M transition of mitotic cell cycle	4	23.6×	0.002	CDK2, CDK4, CDK6, RNASEH2B
positive regulation of interleukin-12 production	6	10.7×	0.002	IRF5, CCL19, CD40, TNFSF4, TRAF6, IRF8
T cell activation	7	8.2×	0.002	CASP8, CD2, CD28, ICOSLG, SLAMF6, DPP4, IRF4
positive regulation of interleukin-4 production	5	12.8×	0.003	TNFSF4, CD28, GATA3, IL20RB, IRF4
peptide antigen assembly with MHC class II protein complex	4	19.1×	0.004	HLA-DQA1, HLA-DQA2, HLA-DQB1, HLA-DRB1
negative regulation of T cell proliferation	6	9.0×	0.004	SFTPD, TNFRSF14, CTLA4, HLA-DRB1, IL20RB, IL2RA
chemokine-mediated signaling pathway	6	8.8×	0.004	CCL19, CCL21, CXCL13, CCR1, CCR2, CCR3
adaptive immune response	11	4.2×	0.005	TEC, TNFRSF14, ICOSLG, CD244, CTLA4, EOMES, HLA-B, HLA-DQA1 (+3 more)
inflammatory response to antigenic stimulus	4	17.0×	0.005	HLA-DRB1, RBPJ, IL20RB, IL2RA
myeloid dendritic cell differentiation	4	17.0×	0.005	TRAF6, CSF2, RBPJ, IRF4
defense response	7	6.9×	0.005	STAT4, TNIP1, CD83, ICOSLG, FCGR2B, GATA3, HLA-B
cellular response to lipopolysaccharide	10	4.5×	0.005	CXCL13, TNFAIP3, CD40, TNFSF4, TRAF6, TNIP1, CDK4, CSF2 (+2 more)
macrophage differentiation	5	10.6×	0.006	CASP8, CFLAR, CSF2, GATA3, HLA-DRB1
negative regulation of immunoglobulin production	3	28.7×	0.006	FCRL3, ZPBP2, FCGR2B
interleukin-2-mediated signaling pathway	3	28.7×	0.006	IL2, IL2RA, IL2RB
positive regulation of cytosolic calcium ion concentration	9	4.8×	0.006	CXCR5, CXCL13, CCR1, CCR2, CCR3, CCR6, SWAP70, GRM5 (+1 more)

Therapeutics

Drugs indicated for this disease

43 approved, 47 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Abatacept	Approved (phase 4)
Adalimumab	Approved (phase 4)
Anakinra	Approved (phase 4)
Auranofin	Approved (phase 4)
Azathioprine	Approved (phase 4)
Baricitinib	Approved (phase 4)
Celecoxib	Approved (phase 4)
Certolizumab Pegol	Approved (phase 4)
Cortisone Acetate	Approved (phase 4)
Cyclosporine	Approved (phase 4)
Dexamethasone	Approved (phase 4)
Diclofenac	Approved (phase 4)
Diflunisal	Approved (phase 4)
Etanercept	Approved (phase 4)
Etodolac	Approved (phase 4)
Famotidine	Approved (phase 4)
Golimumab	Approved (phase 4)
Hydrocortisone	Approved (phase 4)
Ibuprofen	Approved (phase 4)
Indomethacin	Approved (phase 4)
Infliximab	Approved (phase 4)
Isopropyl Alcohol	Approved (phase 4)
Ketoprofen	Approved (phase 4)
Leflunomide	Approved (phase 4)
Meloxicam	Approved (phase 4)
Methotrexate	Approved (phase 4)
Methylprednisolone	Approved (phase 4)
Methylprednisolone Acetate	Approved (phase 4)
Nabumetone	Approved (phase 4)
Naproxen	Approved (phase 4)
Oxaprozin	Approved (phase 4)
Penicillamine	Approved (phase 4)
Piroxicam	Approved (phase 4)
Prasterone	Approved (phase 4)
Prednisolone	Approved (phase 4)
Prednisone	Approved (phase 4)
Rituximab	Approved (phase 4)
Sarilumab	Approved (phase 4)
Sulfasalazine	Approved (phase 4)
Sulindac	Approved (phase 4)
Tocilizumab	Approved (phase 4)
Triamcinolone Acetonide	Approved (phase 4)
Valdecoxib	Approved (phase 4)
Bucillamine	Phase 3 (in late-stage trials)
Certolizumab	Phase 3 (in late-stage trials)
Chloroquine	Phase 3 (in late-stage trials)
Cilostazol	Phase 3 (in late-stage trials)
Clobetasol Propionate	Phase 3 (in late-stage trials)
Corticotropin	Phase 3 (in late-stage trials)
Denosumab	Phase 3 (in late-stage trials)
Diosmin	Phase 3 (in late-stage trials)
Escitalopram	Phase 3 (in late-stage trials)
Etoricoxib	Phase 3 (in late-stage trials)
Filgotinib	Phase 3 (in late-stage trials)
Fish Oil	Phase 3 (in late-stage trials)
Fish Oil Triglycerides	Phase 3 (in late-stage trials)
Folic Acid	Phase 3 (in late-stage trials)
Fostamatinib	Phase 3 (in late-stage trials)
GW-406381	Phase 3 (in late-stage trials)
Gamolenic Acid	Phase 3 (in late-stage trials)
Hesperidin	Phase 3 (in late-stage trials)
Hydroxychloroquine	Phase 3 (in late-stage trials)
Icosapent	Phase 3 (in late-stage trials)
Iguratimod	Phase 3 (in late-stage trials)
Levilimab	Phase 3 (in late-stage trials)
Levocarnitine	Phase 3 (in late-stage trials)
Lumiracoxib	Phase 3 (in late-stage trials)
Minocycline	Phase 3 (in late-stage trials)
Mizoribine	Phase 3 (in late-stage trials)
Montelukast	Phase 3 (in late-stage trials)
Nitazoxanide	Phase 3 (in late-stage trials)
Nitroglycerin	Phase 3 (in late-stage trials)
Ocrelizumab	Phase 3 (in late-stage trials)
Ofatumumab	Phase 3 (in late-stage trials)
Olokizumab	Phase 3 (in late-stage trials)
Otilimab	Phase 3 (in late-stage trials)
Paroxetine	Phase 3 (in late-stage trials)
Peficitinib	Phase 3 (in late-stage trials)
Pelubiprofen	Phase 3 (in late-stage trials)
Piclidenoson	Phase 3 (in late-stage trials)
Pioglitazone	Phase 3 (in late-stage trials)
Rebamipide	Phase 3 (in late-stage trials)
Rupatadine	Phase 3 (in late-stage trials)
Secukinumab	Phase 3 (in late-stage trials)
Sirukumab	Phase 3 (in late-stage trials)
Spironolactone	Phase 3 (in late-stage trials)
Tabalumab	Phase 3 (in late-stage trials)
Tacrolimus Anhydrous	Phase 3 (in late-stage trials)
Tofacitinib	Phase 3 (in late-stage trials)
Upadacitinib	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Acacia, Acalabrutinib, Acetaminophen, Andecaliximab, Anifrolumab, Apremilast, Arginine, Atacicept, Atorvastatin, Belimumab, Bimekizumab, Binimetinib, Brodalumab, Canakinumab, Cannabidiol, Cannabinol, Cetrorelix, Clazakizumab, Dazodalibep, Diacerein, Digoxin, Dimethyl Fumarate, Dipyridamole, Dronabinol, Duvelisib, Efalizumab, Evobrutinib, Fenebrutinib, Gevokizumab, Guselkumab, Imatinib, Itacitinib, Ixekizumab, Keyhole Limpet Hemocyanin, Lenzilumab, Losmapimod, Lovastatin, Loxoprofen, Maraviroc, Masitinib, Metformin, Methoxsalen, Natalizumab, Nipocalimab, Obefazimod, Paclitaxel, Ramipril, Ritlecitinib, Rosiglitazone, Rosuvastatin, Ruxolitinib, Sodium Chloride, TECHNETIUM TC 99M TILMANOCEPT, Temsirolimus, Tetanus Toxoid, Tranilast, Triamcinolone Hexacetonide, Ursodiol, Ustekinumab, Vidofludimus, Zanolimumab.

Drug target analysis

Approved (phase 4): 12 · Phase ≥3: 12 · Phased (≥1): 17 · Undrugged: 58

Druggability breadth: 105 of 250 evidence-associated genes (42%) 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
PADI4	CHLORTETRACYCLINE
RUNX1	APOMORPHINE HYDROCHLORIDE
BLK	AFATINIB
SRC	PONATINIB
TEC	IBRUTINIB
TYK2	FEDRATINIB
IKZF3	POMALIDOMIDE
C5	OXAPROZIN
CASP8	PRIMAQUINE PHOSPHATE
CCR1	ABAMETAPIR
CCR2	CISPLATIN
CCR6	TEGASEROD MALEATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SRC	103	4
TYK2	72	4
BLK	62	4
TEC	39	4
CCR2	17	4
CCR1	8	4
IKZF3	5	4
C5	4	4
PADI4	3	4
CCR6	3	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CHLORTETRACYCLINE	4	PADI4
APOMORPHINE HYDROCHLORIDE	4	RUNX1
AFATINIB	4	BLK, SRC
FEDRATINIB	4	BLK, SRC, TYK2
AXITINIB	4	BLK, TYK2
SORAFENIB	4	BLK, SRC
NERATINIB	4	BLK, SRC
IBRUTINIB	4	BLK, SRC, TEC
ENTRECTINIB	4	BLK, SRC
BELUMOSUDIL	4	BLK
AFATINIB DIMALEATE	4	BLK
VANDETANIB	4	BLK, SRC
NILOTINIB	4	BLK, SRC
BOSUTINIB	4	BLK, SRC, TEC, TYK2
BRIGATINIB	4	BLK, SRC
ACALABRUTINIB	4	BLK, TEC
ZANUBRUTINIB	4	BLK, TEC
TIRABRUTINIB	4	BLK, TEC
RITLECITINIB	4	BLK, TEC
PAZOPANIB	4	BLK, SRC, TYK2
NINTEDANIB	4	BLK, SRC, TYK2
SUNITINIB	4	BLK, SRC, TYK2
DASATINIB	4	BLK, SRC, TEC, TYK2
ERLOTINIB	4	BLK, SRC, TYK2
QUIZARTINIB	4	BLK
CRIZOTINIB	4	BLK, SRC, TYK2
MIDOSTAURIN	4	BLK, SRC, TYK2
GEFITINIB	4	BLK, SRC
IMATINIB	4	BLK, SRC, TYK2
PONATINIB	4	SRC

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 17.

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

Symbol	Assays	Type breakdown
SRC	1,917	Binding:1858, Functional:43, ADMET:16
TYK2	1,083	Binding:1043, Functional:39, ADMET:1
BLK	483	Binding:477, ADMET:4, Functional:2
CCR2	426	Binding:277, Functional:149
TEC	302	Binding:291, ADMET:11
CCR1	243	Binding:176, Functional:67
CCR3	175	Binding:107, Functional:68
PTPN22	137	Binding:122, Functional:10, ADMET:5
CASP8	116	Binding:106, Functional:10
IKZF3	101	Binding:100, Functional:1
PADI4	86	Binding:84, Functional:2
CCR6	60	Functional:33, Binding:27
TLR1	59	Binding:59
TRPC3	45	Binding:45
CXCR5	33	Binding:21, Functional:12
PADI2	30	Binding:30
SLC22A4	29	Functional:26, ADMET:3
C5	25	Binding:25
CASP10	22	Binding:21, Functional:1
RUNX1	20	Binding:17, Functional:3
STAT4	20	Binding:20
TNFRSF9	11	Binding:11
CD40	10	Binding:10
TCF7	7	Binding:7
TRAF6	6	Binding:6
PPIL4	6	Binding:6
ELMO1	6	Binding:6
CD2	5	Binding:5
TGFA	3	Binding:3
BACH2	3	Binding:3
SFTPD	2	Binding:2
UBE2L3	2	Binding:2
ADGRA3	2	Binding:2
PRDM16	2	Binding:2
MMEL1	2	Binding:2
TNFAIP3	1	Binding:1
C1QBP	1	Binding:1
UBASH3A	1	Binding:1
UBE4A	1	Binding:1
B3GNT2	1	Binding:1
CPA4	1	Binding:1
ORMDL3	1	Binding:1
ACTN1	1	Binding:1
CD28	1	Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PADI2	3.5.3.15, 3.5.3.6	protein-arginine deiminase, arginine deiminase
PADI4	3.5.3.15	protein-arginine deiminase
PTPN22	3.1.3.48	protein-tyrosine-phosphatase
BLK	2.7.10.2	non-specific protein-tyrosine kinase
SRC	2.7.10.2	non-specific protein-tyrosine kinase
TEC	2.7.10.2	non-specific protein-tyrosine kinase
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
UBE4A	2.3.2.27, 2.3.2.B12	RING-type E3 ubiquitin transferase,
C5	3.4.21.43	classical-complement-pathway C3/C5 convertase
PRDM16	2.1.1.367, 2.1.1.370	[histone H3]-lysine9 N-methyltransferase, [histone H3]-lysine4 N-dimethyltransferase
MMEL1	3.4.24.B14
CASP10	3.4.22.63	caspase-10
CASP8	3.4.22.61	caspase-8
CPA4	3.4.17.1	carboxypeptidase A
PPM1L	3.1.3.16	protein-serine/threonine phosphatase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
PTPN22	137
BLK	483
SRC	1,917
TEC	302
TYK2	1,083
IKZF3	101
CASP8	116
CCR1	243
CCR2	426
CCR3	175

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

30 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)
CHLORTETRACYCLINE	4	PADI4
APOMORPHINE HYDROCHLORIDE	4	RUNX1
AFATINIB	4	BLK, SRC
FEDRATINIB	4	BLK, SRC, TYK2
AXITINIB	4	BLK, TYK2
SORAFENIB	4	BLK, SRC
NERATINIB	4	BLK, SRC
IBRUTINIB	4	BLK, SRC, TEC
ENTRECTINIB	4	BLK, SRC
BELUMOSUDIL	4	BLK
AFATINIB DIMALEATE	4	BLK
VANDETANIB	4	BLK, SRC
NILOTINIB	4	BLK, SRC
BOSUTINIB	4	BLK, SRC, TEC, TYK2
BRIGATINIB	4	BLK, SRC
ACALABRUTINIB	4	BLK, TEC
ZANUBRUTINIB	4	BLK, TEC
TIRABRUTINIB	4	BLK, TEC
RITLECITINIB	4	BLK, TEC
PAZOPANIB	4	BLK, SRC, TYK2
NINTEDANIB	4	BLK, SRC, TYK2
SUNITINIB	4	BLK, SRC, TYK2
DASATINIB	4	BLK, SRC, TEC, TYK2
ERLOTINIB	4	BLK, SRC, TYK2
QUIZARTINIB	4	BLK
CRIZOTINIB	4	BLK, SRC, TYK2
MIDOSTAURIN	4	BLK, SRC, TYK2
GEFITINIB	4	BLK, SRC
IMATINIB	4	BLK, SRC, TYK2
PONATINIB	4	SRC

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	12	PADI4, RUNX1, BLK, SRC, TEC, TYK2, IKZF3, C5, CASP8, CCR1 (+2 more)
B	Phased (≥1) drug, not yet approved	5	PADI2, TRPC3, PPIL4, CCR3, ELMO1
C	Druggable family + PDB, no drug	7	PTPN22, UBASH3A, UBE2E3, UBE2L3, CPA4, CD2, CD28
D	Druggable family + AlphaFold only, no drug	6	CXCR5, SLC22A4, ADGRA3, MMEL1, CASP10, PPM1L
E	Difficult family or no structure, no drug	45	IRF5, SALL3, BLCAP, CCL19, CCL21, CXCL13, SDF2L1, SFTPD, ZFP36L1, STAT4 (+35 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PTPN22	137	PADI4
IRF5	0	TYK2
SLC22A4	29	RUNX1, PADI4
STAT4	20	TYK2
TLE1	0	RUNX1
CASP10	22	CASP8
SALL3	0	—
BLCAP	0	—
CXCR5	33	—
CCL19	0	—
CCL21	0	—
CXCL13	0	—
SDF2L1	0	—
SFTPD	2	—
ZFP36L1	0	—
SYNGR1	0	—
TBX1	0	—
TCF7	7	—
TGFA	3	—
TLE3	0	—
TLR1	59	—
TNFAIP3	1	—
TNFRSF14	0	—
CD40	10	—
TNFRSF9	11	—
TNFSF4	0	—
TPD52	0	—
TRAF1	0	—
TRAF6	6	—
C1QBP	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2,644.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	356
PHASE3	345
PHASE4	271
PHASE1/PHASE2	51
PHASE1	43
PHASE2/PHASE3	32
EARLY_PHASE1	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02714634	PHASE4	RECRUITING	Clinical Trial Evaluating Methotrexate or Leflunomide + Targeted Therapy Versus Methotrexate or Leflunomide + Sulfasalazine + Hydroxychloroquine in Patients With Rheumatoid Arthritis and Insufficient Response to Methotrexate or Leflunomide
NCT03976245	PHASE4	RECRUITING	Advanced Therapeutics in Rheumatoid Arthritis (RA)
NCT04985435	PHASE4	RECRUITING	Better After CHoosing. Randomly Allocated or Patient Preference Based Treatment With Filgotinib or TNFi in RA (BACH)
NCT05353829	PHASE4	ACTIVE_NOT_RECRUITING	Methotrexate in Patients with Early Rheumatoid Arthritis
NCT05540938	PHASE4	RECRUITING	Post-marketing Re-evaluation of WangBi Granules for Rheumatoid Arthritis
NCT05879419	PHASE4	ACTIVE_NOT_RECRUITING	Recombinant Herpes Zoster Vaccine in Patients With Autoimmune Rheumatic Diseases
NCT05955066	PHASE4	RECRUITING	Effect of JAK Inhibitor on Erosion Healing in RA
NCT06003283	PHASE4	RECRUITING	Tapering of Rituximab Based on Interval Prolongation Compared to Disease Activity-guided Dose Reduction in Patients With Rheumatoid Arthritis
NCT06440629	PHASE4	RECRUITING	Effect of Proactive Therapeutic Drug Monitoring on Maintenance of Sustained Disease Control in Adults With Rheumatoid Arthritis on a Subcutaneous TNF Inhibitor: The Rheumatoid Arthritis Therapeutic DRUg Monitoring Trial (RA-DRUM)
NCT06527534	PHASE4	RECRUITING	Filgotinib Effect on Proteomic Profile and Micro-RNA Expression in Patients With Active Rheumatoid Arthritis (RA)
NCT06641128	PHASE4	NOT_YET_RECRUITING	The Possible Efficacy and Protective Effect of Empagliflozin in Rheumatoid Arthritis Patients Treated with Methotrexate
NCT06649136	PHASE4	RECRUITING	MethMax Trial: MAXimising the METHotrexate Therapy Potential in Patients with Active Rheumatoid Arthritis
NCT06724952	PHASE4	NOT_YET_RECRUITING	Effect of Silymarin in Rheumatoid Arthritis Patients Treated With Methotrexate
NCT06906549	PHASE4	RECRUITING	Evaluation of 200 mg of Rituximab Every 6 Months as Maintenance Treatment of Rituximab-treated Patients With Rheumatoid Arthritis
NCT06913907	PHASE4	RECRUITING	Changes in MTX-PG Concentrations During Subcutaneous MTX Therapy in Patients With Rheumatoid Arthritis(COSMOS Study)
NCT07008196	PHASE4	NOT_YET_RECRUITING	Telitacicept for the Treatment of Refractory RA
NCT07087912	PHASE4	RECRUITING	Safety and Immunogenicity of the Live Attenuated Tetravalent Butantan-Dengue Vaccine in Autoimmune Rheumatic Diseases
NCT07160231	PHASE4	RECRUITING	REDO-JAK: Dose Reduction of Janus Kinase Inhibitors in Patients With Inflammatory Rheumatic Diseases
NCT07227428	PHASE4	NOT_YET_RECRUITING	Comparison of Glucocorticoid Tapering Schedules in Rheumatoid Arthritis
NCT07245732	PHASE4	RECRUITING	Oral Versus Intramuscular Steroid Use to Control Rheumatoid Arthritis Flares
NCT07357649	PHASE4	NOT_YET_RECRUITING	Baricitinib Effects on Procoagulant State in Rheumatoid Arthritis
NCT07452445	PHASE4	NOT_YET_RECRUITING	Efficacy and Safety of Ivarmacitinib Monotherapy in the Treatment of csDMARDs-IR Rheumatoid Arthritis
NCT07554820	PHASE4	RECRUITING	Major Adverse Cardiovascular Events (MACE) in Rheumatoid Arthritis Patient With Moderate to Severe Disease Activity Treated With Tofacitinib and Statins vs TNF Inhibitors: TOFSTAT CLINICAL TRIAL
NCT07582185	PHASE4	NOT_YET_RECRUITING	Tdose Binding and Tocilizumab
NCT07611747	PHASE4	RECRUITING	Carotid Ultrasound-Based Strategy for Primary Prevention of Cardiovascular Events in Inflammatory Rheumatic Disease (PREVENER)
NCT00056667	PHASE4	COMPLETED	Relaxation Response Training for the Treatment of Rheumatoid Arthritis
NCT00094341	PHASE4	COMPLETED	Preference of Rheumatoid Arthritis (RA) Patients of Enbrel® (Etanercept) Auto-Injector Versus Enbrel® Pre-Filled Syringes
NCT00099554	PHASE4	COMPLETED	Effectiveness and Safety of Enbrel® (Etanercept) in Rheumatoid Arthritis Subjects Who Have Failed Remicade® (Infliximab)
NCT00111410	PHASE4	COMPLETED	Evaluating the Effect of Anakinra (r-metHuIL-1ra) on Vaccine AntibodyResponse in Subjects With Rheumatoid Arthritis (RA)
NCT00115219	PHASE4	COMPLETED	Evaluating Efficacy and Safety of Etanercept 50 mg Twice Weekly (BIW) in Rheumatoid Arthritis (RA) Subjects Who Are Sub-Optimal Responders to Etanercept 50 mg Once Weekly (QW)
NCT00121043	PHASE4	COMPLETED	Evaluating Kineret® (Anakinra) in Rheumatoid Arthritis (RA) Subjects Using aSelf-Reported Questionnaire
NCT00132418	PHASE4	COMPLETED	Study of Enbrel in Rheumatoid Arthritis (RA) Subjects With Comorbid Disorders
NCT00157872	PHASE4	COMPLETED	A Study of Rofecoxib Versus Naproxen in the Treatment of Chinese Patient With Rheumatoid Arthritis (0966-231)
NCT00195494	PHASE4	COMPLETED	Study Comparing Etanercept and Methotrexate vs. Methotrexate Alone in Rheumatoid Arthritis
NCT00208364	PHASE4	TERMINATED	A Two Centre Study to Assess the Long-term Performance of the Pinnacle™ Cup With a Metal-on-Metal Bearing in Primary Total Hip Replacement
NCT00208377	PHASE4	TERMINATED	A Multi-centre Study to Assess the Long-term Performance of the DePuy ASR™ System in Primary Hip Resurfacing Surgery
NCT00208390	PHASE4	TERMINATED	A Multi-centre Study to Assess the Long-term Performance of the Summit™ Hip in Primary Total Hip Replacement
NCT00208429	PHASE4	WITHDRAWN	A Multi-centre Study to Assess the Long-term Performance of the Pinnacle™ Cup With a Polyethylene-on-metal Bearing in Primary Total Hip Replacement
NCT00208455	PHASE4	TERMINATED	A Multi-centre Study to Assess the Long-term Performance of the DePuy PROXIMA™ Hip in Primary Total Hip Replacement
NCT00209859	PHASE4	COMPLETED	Methotrexate and Cyclosporine in Treatment of Early Rheumatoid Arthritis

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ETANERCEPT	4	64
TOCILIZUMAB	4	54
ABATACEPT	4	48
ADALIMUMAB	4	43
METHOTREXATE	4	42
TOFACITINIB	4	36
CERTOLIZUMAB PEGOL	4	34
FOSTAMATINIB	4	21
BARICITINIB	4	18
INFLIXIMAB	4	18
SARILUMAB	4	18
LEFLUNOMIDE	4	17
SULFASALAZINE	4	17
UPADACITINIB	4	17
FILGOTINIB	4	16
FOLIC ACID	4	15
HYDROXYCHLOROQUINE	4	14
GOLIMUMAB	4	13
RITUXIMAB	4	9
OCRELIZUMAB	4	8
CANAKINUMAB	4	7
METHYLPREDNISOLONE	4	6
TACROLIMUS ANHYDROUS	4	6
ANAKINRA	4	4
CORTICOTROPIN	4	4
ETORICOXIB	4	4
PREDNISONE	4	4
SECUKINUMAB	4	4
AZATHIOPRINE	4	3
DENOSUMAB	4	3