Graves disease

Summary

Graves disease (MONDO:0005364) is a disease with 41 cohort genes (311 GWAS associations across 29 studies) and 86 clinical trials. The dominant Reactome pathway is Translocation of ZAP-70 to Immunological synapse (3 cohort genes). Top therapeutic interventions include methimazole, doxycycline anhydrous, and efgartigimod alfa.

At a glance

• Cohort genes: 41
• GWAS associations: 311
• Clinical trials: 86

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Graves disease
Mondo ID	MONDO:0005364
EFO	EFO:0004237
MeSH	D006111
DOID	DOID:12361
NCIT	C3071
SNOMED CT	353295004
UMLS	C0018213
MedGen	6677
Is cancer (heuristic)	no

Also known as: Basedow disease · Graves disease · Graves’ hyperthyroidism · parry disease

Data availability: 311 GWAS associations (29 studies).

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › endocrine system disorder › thyroid gland disorder › hyperthyroidism › toxic diffuse goiter › Graves disease

Subtypes (1): pediatric-onset Graves disease

Genetics & variants

GWAS landscape

311 GWAS associations across 29 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
rs1794282	3e-248	HLA-DQB1 - MTCO3P1	T	0.66
rs28414437	3e-137	TSHR	C	0.27
rs2160215	6e-126	TSHR	C	0.32
rs9357156	1e-68	HLA-DPA1	C	0.44
rs4345439	2e-67	HLA-DPA1	T	0.49
rs1521	2e-65	MICA-AS1	T	1.92
rs2281388	2e-65	HLA-DPA2	T	1.64
rs231775	2e-59	CTLA4	G	0.2
rs4947296	4e-51	RNU6-1133P - C6orf15	C	1.77
rs6679677	9e-50	PHTF1 - RSBN1	A	0.28
rs73400009	2e-40	HLA-DPA1	A	0.22
rs201212911	3e-40	HLA-DPA1	A	0.22
rs72870107	1e-39	HLA-DPA1	A	0.22
rs2300519	1e-38	TSHR	A	1.54
rs3087243	1e-37	CTLA4 - ICOS	A	0.21
rs76589166	8e-37	HLA-DPA1	T	0.2
rs9265475	2e-35	LINC02571 - HLA-B	T	0.24
rs7190187	7e-35	MAFTRR, LINC01229	T	0.14
rs5912838	2e-33	CTHRC1P1 - KIF4CP	?	1.32
rs13136820	3e-33	RHOH - LINC02265	T	0.15
rs6457617	7e-33	HLA-DQB1 - MTCO3P1	T	1.4
rs35923382	9e-33	HLA-DRB6, HLA-DRB6	A	0.31
rs2395521	1e-32	HLA-DQA1	C	0.41
rs67640541	3e-30	HLA-DPA1	T	0.23
rs76819459	2e-29	LINC01229, MAFTRR	G	0.16
rs312729	8e-29	CALM2P1 - CASC17	?	2.08
rs759916207	3e-28	B3GALT4	A	0.68
rs4409785	1e-26	LNCRNA-IUR - FAM76B	C	0.16
rs231779	4e-26	CTLA4	T	0.24
rs9265428	3e-24	LINC02571 - HLA-B	T	0.15

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90627744	White SL	2026	12,019	1,869,646	Global multi-ancestry genome-wide analyses identify genes and biological pathways associated with thyroid cancer and benign thyroid diseases.
GCST90627767	White SL	2026	11,220	1,793,565	Global multi-ancestry genome-wide analyses identify genes and biological pathways associated with thyroid cancer and benign thyroid diseases.
GCST90018627	Sakaue S	2021	2,809	172,656	A cross-population atlas of genetic associations for 220 human phenotypes.
GCST005526	Cooper JD	2012	2,285	9,364	Seven newly identified loci for autoimmune thyroid disease.
GCST005524	Cooper JD	2012	2,282	0	Seven newly identified loci for autoimmune thyroid disease.
GCST90627742	White SL	2026	2,270	207,823	Global multi-ancestry genome-wide analyses identify genes and biological pathways associated with thyroid cancer and benign thyroid diseases.
GCST90013683	Ishigaki K	2020	2,176	210,277	Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases.
GCST90428824	Yu X	2024	1,678	473,608	Shared genetic architecture between autoimmune disorders and B-cell acute lymphoblastic leukemia: insights from large-scale genome-wide cross-trait analysis.
GCST90018847	Sakaue S	2021	1,678	456,942	A cross-population atlas of genetic associations for 220 human phenotypes.
GCST90475644	Verma A	2024	1,672	448,997	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	3
Tier 2: splice/UTR	0
Tier 3: regulatory	1
Tier 4: intronic/intergenic	46

MAF distribution

Bucket	Variants
common (>=0.05)	48
low_freq (0.01-0.05)	1
rare (<0.01)	0
unknown	1

Functional consequences

Consequence	Count
intron_variant	26
intergenic_variant	14
non_coding_transcript_exon_variant	3
missense_variant	3
unknown	2
regulatory_region_variant	1
synonymous_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs1794282	6	32698749	C>G,T	0.094	intergenic_variant	HLA-DQB1 - MTCO3P1	3e-248	Tier 4: intronic/intergenic
rs28414437	14	80990913	A>C	0.399	intron_variant	TSHR	3e-137	Tier 4: intronic/intergenic
rs2160215	14	80995128	T>A,C	0.345	intron_variant	TSHR	6e-126	Tier 4: intronic/intergenic
rs9357156	6	33073296	A>C,G,T	0.05	intron_variant	HLA-DPA1	1e-68	Tier 4: intronic/intergenic
rs4345439	6	33072321	C>T	0.47	intron_variant	HLA-DPA1	2e-67	Tier 4: intronic/intergenic
rs1521	6	31382927	C>G,T	0.21	non_coding_transcript_exon_variant	MICA-AS1	2e-65	Tier 4: intronic/intergenic
rs2281388	6	33092341	G>A,C,T	0.32	non_coding_transcript_exon_variant	HLA-DPA2	2e-65	Tier 4: intronic/intergenic
rs231775	2	203867991	A>G,T	0.428	missense_variant	CTLA4	2e-59	Tier 1: coding
rs4947296	6	31090401	T>A,C	0.14	intergenic_variant	RNU6-1133P - C6orf15	4e-51	Tier 4: intronic/intergenic
rs6679677	1	113761186	C>A,T	0.107	intergenic_variant	PHTF1 - RSBN1	9e-50	Tier 4: intronic/intergenic
rs73400009	6	33065862	G>A	0.327	intron_variant	HLA-DPA1	2e-40	Tier 4: intronic/intergenic
rs201212911	6	33065401	G>A,T	0.327	intron_variant	HLA-DPA1	3e-40	Tier 4: intronic/intergenic
rs72870107	6	33067553	G>A,T	0.326	intron_variant	HLA-DPA1	1e-39	Tier 4: intronic/intergenic
rs2300519	14	80992418	T>A,G	0.38	intron_variant	TSHR	1e-38	Tier 4: intronic/intergenic
rs3087243	2	203874196	G>A,T	0.445	intergenic_variant	CTLA4 - ICOS	1e-37	Tier 4: intronic/intergenic
rs76589166	6	33066343	C>T	0.322	intron_variant	HLA-DPA1	8e-37	Tier 4: intronic/intergenic
rs9265475	6	31329245	C>T	0.356	intron_variant	LINC02571 - HLA-B	2e-35	Tier 4: intronic/intergenic
rs7190187	16	79701281	C>T	0.305	intron_variant	MAFTRR, LINC01229	7e-35	Tier 4: intronic/intergenic
rs5912838	X	79241621	A>C,G	0.42	intergenic_variant	CTHRC1P1 - KIF4CP	2e-33	Tier 4: intronic/intergenic
rs13136820	4	40305547	C>A,G,T	0.332	regulatory_region_variant	RHOH - LINC02265	3e-33	Tier 3: regulatory
rs6457617	6	32696074	C>A,T	0.45	intergenic_variant	HLA-DQB1 - MTCO3P1	7e-33	Tier 4: intronic/intergenic
rs35923382	6	32554793	G>A,T	0.373	synonymous_variant	HLA-DRB6, HLA-DRB6	9e-33	Tier 4: intronic/intergenic
rs2395521	6	32633923	C>A,G,T	0.227	intergenic_variant	HLA-DQA1	1e-32	Tier 4: intronic/intergenic
rs67640541	6	33065707	C>G,T	0.15	intron_variant	HLA-DPA1	3e-30	Tier 4: intronic/intergenic
rs76819459	16	79685020	A>C,G,T	0.32	intron_variant	LINC01229, MAFTRR	2e-29	Tier 4: intronic/intergenic
rs312729	17	70310696	G>A,T	0.47	intergenic_variant	CALM2P1 - CASC17	8e-29	Tier 4: intronic/intergenic
rs759916207	6	33279039	G>A	0.024	intergenic_variant	B3GALT4	3e-28	Tier 4: intronic/intergenic
rs4409785	11	95578258	T>C	0.151	intron_variant	LNCRNA-IUR - FAM76B	1e-26	Tier 4: intronic/intergenic
rs231779	2	203869764	C>T	0.05	intron_variant	CTLA4	4e-26	Tier 4: intronic/intergenic
rs9265428	6	31328394	C>T	0.351	intron_variant	LINC02571 - HLA-B	3e-24	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 65 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SOX9	Orphanet:140	Campomelic dysplasia
SOX9	Orphanet:2138	46,XX ovotesticular difference of sex development
SOX9	Orphanet:242	46,XY complete gonadal dysgenesis
SOX9	Orphanet:251510	46,XY partial gonadal dysgenesis
SOX9	Orphanet:393	46,XX testicular difference of sex development
SOX9	Orphanet:718	Isolated Pierre Robin sequence
TG	Orphanet:95716	Familial thyroid dyshormonogenesis
TSHR	Orphanet:424	Familial hyperthyroidism due to mutations in TSH receptor
TSHR	Orphanet:90673	Hypothyroidism due to TSH receptor mutations
TSHR	Orphanet:95713	Athyreosis
TSHR	Orphanet:95720	Thyroid hypoplasia
TSHR	Orphanet:99819	Familial gestational hyperthyroidism
BACH2	Orphanet:714472	Inflammatory bowel disease-autoimmunity-sinopulmonary infections-lymphadenopathy syndrome
MMEL1	Orphanet:186	Primary biliary cholangitis
CCR6	Orphanet:220393	Diffuse cutaneous systemic sclerosis
CCR6	Orphanet:220402	Limited cutaneous systemic sclerosis
CD28	Orphanet:2584	Classic mycosis fungoides
CD28	Orphanet:3162	Sézary syndrome
PRICKLE1	Orphanet:308	Progressive myoclonic epilepsy type 1
RNASET2	Orphanet:85136	Cystic leukoencephalopathy without megalencephaly
COL11A2	Orphanet:1427	Autosomal recessive otospondylomegaepiphyseal dysplasia
COL11A2	Orphanet:166100	Autosomal dominant otospondylomegaepiphyseal dysplasia
COL11A2	Orphanet:2021	Fibrochondrogenesis
COL11A2	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
COL11A2	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
CTLA4	Orphanet:2584	Classic mycosis fungoides
CTLA4	Orphanet:3162	Sézary syndrome
CTLA4	Orphanet:391490	Adult-onset myasthenia gravis
CTLA4	Orphanet:436159	Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency
CTLA4	Orphanet:536	Systemic lupus erythematosus
CTLA4	Orphanet:900	Granulomatosis with polyangiitis
SEPSECS	Orphanet:247198	Progressive cerebello-cerebral atrophy
SEPSECS	Orphanet:2524	Pontocerebellar hypoplasia type 2
HLA-B	Orphanet:117	Behçet disease
HLA-B	Orphanet:275798	Pulmonary arterial hypertension associated with connective tissue disease
HLA-B	Orphanet:29207	Reactive arthritis
HLA-B	Orphanet:3287	Takayasu arteritis
HLA-B	Orphanet:36426	Stevens-Johnson syndrome
HLA-B	Orphanet:397	Giant cell arteritis
HLA-DPB1	Orphanet:133	Chronic beryllium disease
HLA-DPB1	Orphanet:900	Granulomatosis with polyangiitis
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
HLA-DQB1	Orphanet:930	Idiopathic achalasia
IL2RA	Orphanet:169100	Immunodeficiency due to CD25 deficiency
IL2RA	Orphanet:85408	Rheumatoid factor-negative polyarticular juvenile idiopathic arthritis
IL2RA	Orphanet:85410	Oligoarticular juvenile idiopathic arthritis
ITGAM	Orphanet:536	Systemic lupus erythematosus

Cohort genes → proteins

41 cohort genes, 41 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	41

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SOX9	HGNC:11204	ENSG00000125398	P48436	Transcription factor SOX-9	gwas
TG	HGNC:11764	ENSG00000042832	P01266	Thyroglobulin	gwas
TSHR	HGNC:12373	ENSG00000165409	P16473	Thyrotropin receptor	gwas
VAV3	HGNC:12659	ENSG00000134215	Q9UKW4	Guanine nucleotide exchange factor VAV3	gwas
CCN4	HGNC:12769	ENSG00000104415	O95388	CCN family member 4	gwas
C6orf15	HGNC:13927	ENSG00000204542	Q6UXA7	Uncharacterized protein C6orf15	gwas
BACH2	HGNC:14078	ENSG00000112182	Q9BYV9	Transcription regulator protein BACH2	gwas
CHRNA9	HGNC:14079	ENSG00000174343	Q9UGM1	Neuronal acetylcholine receptor subunit alpha-9	gwas
C1QTNF6	HGNC:14343	ENSG00000133466	Q9BXI9	Complement C1q tumor necrosis factor-related protein 6	gwas
MMEL1	HGNC:14668	ENSG00000142606	Q495T6	Membrane metallo-endopeptidase-like 1	gwas
CCR6	HGNC:1607	ENSG00000112486	P51684	C-C chemokine receptor type 6	gwas
CD28	HGNC:1653	ENSG00000178562	P10747	T-cell-specific surface glycoprotein CD28	gwas
CEP43	HGNC:17012	ENSG00000213066	O95684	Centrosomal protein 43	gwas
PRICKLE1	HGNC:17019	ENSG00000139174	Q96MT3	Prickle-like protein 1	gwas
FCRL3	HGNC:18506	ENSG00000160856	Q96P31	Fc receptor-like protein 3	gwas
SLC25A27	HGNC:21065	ENSG00000153291	O95847	Mitochondrial uncoupling protein 4	gwas
SLAMF6	HGNC:21392	ENSG00000162739	Q96DU3	SLAM family member 6	gwas
MUC21	HGNC:21661	ENSG00000204544	Q5SSG8	Mucin-21	gwas
RNASET2	HGNC:21686	ENSG00000026297	O00584	Ribonuclease T2	gwas
COL11A2	HGNC:2187	ENSG00000204248	P13942	Collagen alpha-2(XI) chain	gwas
DCHS2	HGNC:23111	ENSG00000197410	Q6V1P9	Protocadherin-23	gwas
RBM45	HGNC:24468	ENSG00000155636	Q8IUH3	RNA-binding protein 45	gwas
CTLA4	HGNC:2505	ENSG00000163599	P16410	Cytotoxic T-lymphocyte protein 4	gwas
AAMDC	HGNC:30205	ENSG00000087884	Q9H7C9	Mth938 domain-containing protein	gwas
GPR174	HGNC:30245	ENSG00000147138	Q9BXC1	Probable G-protein coupled receptor 174	gwas
SEPSECS	HGNC:30605	ENSG00000109618	Q9HD40	O-phosphoseryl-tRNA(Sec) selenium transferase	gwas
TRIB2	HGNC:30809	ENSG00000071575	Q92519	Tribbles homolog 2	gwas
HLA-B	HGNC:4932	ENSG00000234745	P01889	HLA class I histocompatibility antigen, B alpha chain	gwas
HLA-DPB1	HGNC:4940	ENSG00000223865	P04440	HLA class II histocompatibility antigen, DP beta 1 chain	gwas
HLA-DQA2	HGNC:4943	ENSG00000237541	P01906	HLA class II histocompatibility antigen, DQ alpha 2 chain	gwas
HLA-DQB1	HGNC:4944	ENSG00000179344	P01920	HLA class II histocompatibility antigen, DQ beta 1 chain	gwas
IL2RA	HGNC:6008	ENSG00000134460	P01589	Interleukin-2 receptor subunit alpha	gwas
ITGAM	HGNC:6149	ENSG00000169896	P11215	Integrin alpha-M	gwas
ITM2A	HGNC:6173	ENSG00000078596	O43736	Integral membrane protein 2A	gwas
KCNJ2	HGNC:6263	ENSG00000123700	P63252	Inward rectifier potassium channel 2	gwas
LPP	HGNC:6679	ENSG00000145012	Q93052	Lipoma-preferred partner	gwas
MAP3K7	HGNC:6859	ENSG00000135341	O43318	Mitogen-activated protein kinase kinase kinase 7	gwas
RHOH	HGNC:686	ENSG00000168421	Q15669	Rho-related GTP-binding protein RhoH	gwas
ABO	HGNC:79	ENSG00000175164	P16442	Histo-blood group ABO system transferase	gwas
PTPN22	HGNC:9652	ENSG00000134242	Q9Y2R2	Tyrosine-protein phosphatase non-receptor type 22	gwas
RAC2	HGNC:9802	ENSG00000128340	P15153	Ras-related C3 botulinum toxin substrate 2	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SOX9	Transcription factor SOX-9	Transcription factor that plays a key role in chondrocytes differentiation and skeletal development.
TG	Thyroglobulin	Acts as a substrate for the production of iodinated thyroid hormones thyroxine (T4) and triiodothyronine (T3).
TSHR	Thyrotropin receptor	Receptor for the thyroid-stimulating hormone (TSH) or thyrotropin.
VAV3	Guanine nucleotide exchange factor VAV3	Exchange factor for GTP-binding proteins RhoA, RhoG and, to a lesser extent, Rac1.
CCN4	CCN family member 4	Downstream regulator in the Wnt/Frizzled-signaling pathway.
BACH2	Transcription regulator protein BACH2	Transcriptional regulator that acts as a repressor or activator.
CHRNA9	Neuronal acetylcholine receptor subunit alpha-9	Component of neuronal acetylcholine receptors (nAChRs) that function as pentameric, ligand-gated cation channels with high calcium permeability among other activities. nAChRs are excitatory neurotrasnmitter receptors formed by a collection…
MMEL1	Membrane metallo-endopeptidase-like 1	Metalloprotease involved in sperm function, possibly by modulating the processes of fertilization and early embryonic development.
CCR6	C-C chemokine receptor type 6	Receptor for the C-C type chemokine CCL20.
CD28	T-cell-specific surface glycoprotein CD28	Receptor that plays a role in T-cell activation, proliferation, survival and the maintenance of immune homeostasis.
CEP43	Centrosomal protein 43	Required for anchoring microtubules to the centrosomes.
PRICKLE1	Prickle-like protein 1	Involved in the planar cell polarity pathway that controls convergent extension during gastrulation and neural tube closure.
FCRL3	Fc receptor-like protein 3	Promotes TLR9-induced B-cell proliferation, activation and survival but inhibits antibody production and suppresses plasma cell differentiation.
SLC25A27	Mitochondrial uncoupling protein 4	Facilitates proton transport across the inner mitochondrial membrane and may dissipate excessive proton gradient associated with oxidative and metabolic stress at neuronal synapses.
SLAMF6	SLAM family member 6	Self-ligand receptor of the signaling lymphocytic activation molecule (SLAM) family.
RNASET2	Ribonuclease T2	Ribonuclease that plays an essential role in innate immune response by recognizing and degrading RNAs from microbial pathogens that are subsequently sensed by TLR8.
COL11A2	Collagen alpha-2(XI) chain	May play an important role in fibrillogenesis by controlling lateral growth of collagen II fibrils.
DCHS2	Protocadherin-23	Calcium-dependent cell-adhesion protein.
RBM45	RNA-binding protein 45	RNA-binding protein with binding specificity for poly(C).
CTLA4	Cytotoxic T-lymphocyte protein 4	Inhibitory receptor acting as a major negative regulator of T-cell responses.
AAMDC	Mth938 domain-containing protein	May play a role in preadipocyte differentiation and adipogenesis.
GPR174	Probable G-protein coupled receptor 174	G-protein-coupled receptor of lysophosphatidylserine (LysoPS) that plays different roles in immune response.
SEPSECS	O-phosphoseryl-tRNA(Sec) selenium transferase	Converts O-phosphoseryl-tRNA(Sec) to selenocysteinyl-tRNA(Sec) required for selenoprotein biosynthesis.
TRIB2	Tribbles homolog 2	Interacts with MAPK kinases and regulates activation of MAP kinases.
HLA-B	HLA class I histocompatibility antigen, B alpha chain	Antigen-presenting major histocompatibility complex class I (MHCI) molecule.
HLA-DPB1	HLA class II histocompatibility antigen, DP 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-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.
IL2RA	Interleukin-2 receptor subunit alpha	Receptor for interleukin-2.
ITGAM	Integrin alpha-M	Integrin ITGAM/ITGB2 is implicated in various adhesive interactions of monocytes, macrophages and granulocytes as well as in mediating the uptake of complement-coated particles and pathogens.
KCNJ2	Inward rectifier potassium channel 2	Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it.
LPP	Lipoma-preferred partner	May play a structural role at sites of cell adhesion in maintaining cell shape and motility.
MAP3K7	Mitogen-activated protein kinase kinase kinase 7	Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway.
RHOH	Rho-related GTP-binding protein RhoH	Negative regulator of hematopoietic progenitor cell proliferation, survival and migration.
ABO	Histo-blood group ABO system transferase	This protein is the basis of the ABO blood group system.
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.
RAC2	Ras-related C3 botulinum toxin substrate 2	Plasma membrane-associated small GTPase which cycles between an active GTP-bound and inactive GDP-bound state.

Protein-family classification

Druggable: 24 · Difficult: 5 · Unknown: 12 · Druggable fraction: 0.59

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	9	6.4×	1e-04
Complement	1	6.5×	0.657
Ion channel	1	2.7×	0.657
Phosphatase	1	2.0×	0.657
Transporter	1	1.9×	0.657
GPCR	3	1.8×	0.657
Enzyme (other)	5	1.5×	0.657
Kinase	2	1.4×	0.657
Protease	1	0.9×	0.898
Transcription factor	4	0.8×	0.898
Scaffold/PPI	1	0.4×	0.996
Other/Unknown	12	0.5×	1.000

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SOX9	Transcription factor	no		HMG_box_dom, Sox_N, HMG_box_dom_sf
TG	Other/Unknown	no		Thyroglobulin_1, CarbesteraseB, Tyr-kin_ephrin_A/B_rcpt-like
TSHR	GPCR	yes		GPCR_Rhodpsn, Gphrmn_rcpt_fam, TSH_rcpt
VAV3	Scaffold/PPI	no		DH_dom, SH2, GDS_CDC24_CS
CCN4	Other/Unknown	no		IGFBP-like, TSP1_rpt, VWF_dom
C6orf15	Other/Unknown	no		C6orf15
BACH2	Transcription factor	no		BTB/POZ_dom, bZIP_Maf, bZIP
CHRNA9	Other/Unknown	no		Nicotinic_acetylcholine_rcpt, Neurotrans-gated_channel_TM, Neur_channel
C1QTNF6	Other/Unknown	no		C1q_dom, Collagen, Tumour_necrosis_fac-like_dom
MMEL1	Protease	yes	3.4.24.B14	Peptidase_M13, Peptidase_M13_N, Peptidase_M13_C
CCR6	GPCR	yes		GPCR_Rhodpsn, Chemokine_rcpt, Chemokine_CCR6
CD28	Antibody/Immunoglobulin	yes		CD28, Ig_V-set, Ig-like_fold
CEP43	Other/Unknown	no		LisH, FOP_dimerisation-dom_N
PRICKLE1	Transcription factor	no		Znf_LIM, PET_domain, PET_prickle
FCRL3	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, Ig-like_dom
SLC25A27	Transporter	yes		MCP_transmembrane, MCP_dom_sf, Mito_Metabolite_Transporter
SLAMF6	Antibody/Immunoglobulin	yes		Ig_sub, Ig-like_dom, Ig_V-set
MUC21	Other/Unknown	no		Tandem-repeating_mucin, Mucin_dom
RNASET2	Enzyme (other)	yes	4.6.1.19	RNase_T2-like, RNase_T2_His_AS_1, RNase_T2_His_AS_2
COL11A2	Other/Unknown	no		Fib_collagen_C, Laminin_G, Collagen
DCHS2	Other/Unknown	no		Cadherin-like_dom, Cadherin-like_sf, Cadherin_CS
RBM45	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, RBM45_RRM1
CTLA4	Antibody/Immunoglobulin	yes		Ig_sub, CTLA4, Ig_V-set
AAMDC	Other/Unknown	no		NDUFAF3/AAMDC, AAMDC, MTH938-like_sf
GPR174	GPCR	yes		GPCR_Rhodpsn, GPCR_Rhodpsn_7TM, GPR174_7tmA
SEPSECS	Enzyme (other)	yes	2.9.1.2	SepSecS/SepCysS, PyrdxlP-dep_Trfase_major, PyrdxlP-dep_Trfase
TRIB2	Kinase	yes		Prot_kinase_dom, Kinase-like_dom_sf, Tribbles/Ser_Thr_kinase_40
HLA-B	Antibody/Immunoglobulin	yes		MHC_I_a_a1/a2, Ig/MHC_CS, Ig_C1-set
HLA-DPB1	Antibody/Immunoglobulin	yes		MHC_II_b_N, Ig/MHC_CS, Ig_C1-set
HLA-DQA2	Antibody/Immunoglobulin	yes		MHC_II_a_N, Ig/MHC_CS, Ig_C1-set
HLA-DQB1	Antibody/Immunoglobulin	yes		MHC_II_b_N, Ig/MHC_CS, Ig_C1-set
IL2RA	Complement	yes		Sushi_SCR_CCP_dom, IL-2_rcpt_alpha, Sushi/SCR/CCP_sf
ITGAM	Antibody/Immunoglobulin	yes		Integrin_alpha, VWF_A, FG-GAP
ITM2A	Other/Unknown	no		BRICHOS_dom, ITM2
KCNJ2	Ion channel	yes		K_chnl_inward-rec_Kir2.1, K_chnl_inward-rec_Kir_cyto, K_chnl_inward-rec_Kir_N
LPP	Transcription factor	no		Znf_LIM
MAP3K7	Kinase	yes		Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ser/Thr_kinase_AS
RHOH	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTPase_Rho, Small_GTP-bd
ABO	Enzyme (other)	yes	2.4.1.37	Glyco_trans_6, Nucleotide-diphossugar_trans
PTPN22	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, Tyr_Pase_cat
RAC2	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTPase_Rho, Small_GTP-bd

Expression context

Cohort genes with no expression data: 0.

36 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)	41
unknown	0

Top tissues across cohort

Tissue	Cohort genes
lymph node	9
vermiform appendix	7
granulocyte	7
male germ line stem cell (sensu Vertebrata) in testis	6
spleen	5
tendon of biceps brachii	5
blood	4
right lobe of thyroid gland	3
primordial germ cell in gonad	3
buccal mucosa cell	3
ileal mucosa	3
left lobe of thyroid gland	2
thyroid gland	2
cartilage tissue	2
right uterine tube	2
adenohypophysis	2
left ovary	2
thymus	2
monocyte	2
vena cava	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SOX9	274	ubiquitous	marker	ventricular zone, cranial nerve II, hair follicle
TG	169	tissue_specific	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
TSHR	169	broad	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
VAV3	258	ubiquitous	marker	tongue squamous epithelium, renal medulla, esophagus squamous epithelium
CCN4	177	broad	yes	cartilage tissue, tibia, mucosa of paranasal sinus
C6orf15	31	tissue_specific	yes	skin of leg, zone of skin, skin of abdomen
BACH2	237	ubiquitous	marker	cortical plate, sural nerve, epithelium of nasopharynx
CHRNA9	82	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, penis
C1QTNF6	170	ubiquitous	marker	decidua, right uterine tube, stromal cell of endometrium
MMEL1	131	broad	yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, left testis
CCR6	103	broad	marker	lymph node, vermiform appendix, spleen
CD28	154	broad	marker	lymph node, vermiform appendix, blood
CEP43	278	ubiquitous	marker	sperm, secondary oocyte, tendon of biceps brachii
PRICKLE1	243	ubiquitous	marker	buccal mucosa cell, tendon of biceps brachii, lateral nuclear group of thalamus
FCRL3	167	tissue_specific	marker	ileal mucosa, granulocyte, lymph node
SLC25A27	243	ubiquitous	marker	mucosa of stomach, adenohypophysis, left ovary
SLAMF6	148	broad	marker	granulocyte, lymph node, spleen
MUC21	103	tissue_specific	marker	lower esophagus mucosa, esophagus mucosa, vagina
RNASET2	291	ubiquitous	marker	right uterine tube, granulocyte, blood
COL11A2	134	broad	yes	pituitary gland, male germ line stem cell (sensu Vertebrata) in testis, adenohypophysis
DCHS2	120	tissue_specific	marker	prefrontal cortex, calcaneal tendon, superior frontal gyrus
RBM45	239	ubiquitous	marker	mucosa of transverse colon, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis
CTLA4	164	tissue_specific	marker	lymph node, vermiform appendix, buccal mucosa cell
AAMDC	287	ubiquitous	marker	tendon of biceps brachii, hindlimb stylopod muscle, apex of heart
GPR174	133	broad	marker	thymus, ileal mucosa, lymph node
SEPSECS	219	ubiquitous	yes	ileal mucosa, male germ line stem cell (sensu Vertebrata) in testis, right lobe of liver
TRIB2	285	ubiquitous	marker	left ovary, ganglionic eminence, right ovary
HLA-B	134	ubiquitous	marker	blood, spleen, granulocyte
HLA-DPB1	135	ubiquitous	marker	granulocyte, lymph node, vermiform appendix
HLA-DQA2	127	broad	marker	granulocyte, vermiform appendix, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 19.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RAC2	6,478
MAP3K7	5,457
SOX9	4,935
ITGAM	4,816
RHOH	4,044
CTLA4	3,863
HLA-B	3,209
RBM45	3,011
CD28	2,958
IL2RA	2,557

Intra-cohort edges

A	B	Sources
BACH2	C1QTNF6	string_interaction
C1QTNF6	PTPN22	string_interaction
C6orf15	MUC21	string_interaction
C6orf15	TG	string_interaction
CCR6	CEP43	string_interaction
CCR6	RNASET2	string_interaction
CD28	CTLA4	intact, string_interaction
CEP43	HLA-DQA2	string_interaction
CEP43	RNASET2	string_interaction
CTLA4	FCRL3	string_interaction
CTLA4	PTPN22	string_interaction
CTLA4	TSHR	string_interaction
FCRL3	PTPN22	string_interaction
FCRL3	RNASET2	string_interaction
FCRL3	TSHR	string_interaction
GPR174	ITM2A	string_interaction
HLA-B	HLA-DQA2	string_interaction
HLA-DQA2	RNASET2	string_interaction
TG	TSHR	string_interaction

Structural data

PDB: 27 · AlphaFold-only: 14 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HLA-B	P01889	237
ABO	P16442	151
ITGAM	P11215	31
MAP3K7	O43318	25
CTLA4	P16410	22
PTPN22	Q9Y2R2	14
CD28	P10747	10
HLA-DPB1	P04440	10
HLA-DQB1	P01920	10
IL2RA	P01589	10
TSHR	P16473	9
SEPSECS	Q9HD40	7
GPR174	Q9BXC1	5
CHRNA9	Q9UGM1	4
RBM45	Q8IUH3	4
RAC2	P15153	4
TG	P01266	3
KCNJ2	P63252	3
BACH2	Q9BYV9	2
AAMDC	Q9H7C9	2
SOX9	P48436	1
VAV3	Q9UKW4	1
CCR6	P51684	1
CEP43	O95684	1
SLAMF6	Q96DU3	1
RNASET2	O00584	1
TRIB2	Q92519	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RHOH	Q15669	92.81
MMEL1	Q495T6	90.34
HLA-DQA2	P01906	89.29
SLC25A27	O95847	80.95
ITM2A	O43736	80.66
FCRL3	Q96P31	77.46
C1QTNF6	Q9BXI9	77.42
CCN4	O95388	77.16
MUC21	Q5SSG8	74.30
LPP	Q93052	60.99
PRICKLE1	Q96MT3	55.55
COL11A2	P13942	50.18
C6orf15	Q6UXA7	43.65
DCHS2	Q6V1P9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 214. Enrichment computed across 41 evidence-associated genes (26 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 26 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Translocation of ZAP-70 to Immunological synapse	3	73.2×	0.001	HLA-DPB1, HLA-DQA2, PTPN22
Phosphorylation of CD3 and TCR zeta chains	3	62.8×	0.001	HLA-DPB1, HLA-DQA2, PTPN22
Interferon gamma signaling	4	19.3×	0.004	HLA-B, HLA-DPB1, HLA-DQA2, HLA-DQB1
RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs)	2	87.8×	0.012	CTLA4, IL2RA
Co-inhibition by PD-1	2	39.9×	0.040	HLA-DPB1, HLA-DQA2
Downstream TCR signaling	3	14.8×	0.040	HLA-DPB1, HLA-DQA2, MAP3K7
Co-stimulation by CD28	2	29.3×	0.061	CD28, CTLA4
Generation of second messenger molecules	2	26.6×	0.061	HLA-DPB1, HLA-DQA2
GPVI-mediated activation cascade	2	23.7×	0.061	VAV3, RAC2
Innate Immune System	5	4.9×	0.061	CCR6, MUC21, RNASET2, ITGAM, MAP3K7
Immune System	7	3.5×	0.061	CCR6, CD28, SLAMF6, MUC21, RNASET2, ITGAM, MAP3K7
Nef mediated downregulation of CD28 cell surface expression	1	219.6×	0.075	CD28
Sensory perception of sour taste	1	219.6×	0.075	KCNJ2
C-type lectin receptors (CLRs)	2	18.3×	0.081	MUC21, MAP3K7
Developmental Lineage of Pancreatic Ductal Cells	2	17.6×	0.081	SOX9, COL11A2
Classical Kir channels	1	109.8×	0.121	KCNJ2
The fatty acid cycling model	1	87.8×	0.135	SLC25A27
Acetylcholine inhibits contraction of outer hair cells	1	87.8×	0.135	CHRNA9
G protein gated Potassium channels	1	43.9×	0.160	KCNJ2
FGFR1 mutant receptor activation	1	43.9×	0.160	CEP43
IRAK2 mediated activation of TAK1 complex	1	43.9×	0.160	MAP3K7
Endosomal/Vacuolar pathway	1	39.9×	0.160	HLA-B
Highly calcium permeable postsynaptic nicotinic acetylcholine receptors	1	39.9×	0.160	CHRNA9
TICAM1,TRAF6-dependent induction of TAK1 complex	1	39.9×	0.160	MAP3K7
Alpha-protein kinase 1 signaling pathway	1	39.9×	0.160	MAP3K7
Hormone ligand-binding receptors	1	36.6×	0.160	TSHR
Interleukin-2 signaling	1	36.6×	0.160	IL2RA
CD28 dependent Vav1 pathway	1	33.8×	0.160	CD28
Downstream signaling events of B Cell Receptor (BCR)	1	31.4×	0.160	MAP3K7
Acetylcholine binding and downstream events	1	31.4×	0.160	CHRNA9

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 40 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
T cell receptor signaling pathway	6	22.8×	5e-05	CD28, CTLA4, HLA-DPB1, HLA-DQB1, MAP3K7, PTPN22
immune response	9	10.6×	5e-05	CCR6, FCRL3, SLAMF6, CTLA4, HLA-B, HLA-DQA2, HLA-DQB1, IL2RA (+1 more)
peptide antigen assembly with MHC class II protein complex	3	79.0×	0.001	HLA-DPB1, HLA-DQA2, HLA-DQB1
antigen processing and presentation of exogenous peptide antigen via MHC class II	3	40.8×	0.006	HLA-DPB1, HLA-DQA2, HLA-DQB1
positive regulation of immune response	3	36.1×	0.007	HLA-DPB1, HLA-DQA2, HLA-DQB1
positive regulation of T cell activation	3	33.3×	0.007	HLA-DPB1, HLA-DQA2, HLA-DQB1
adaptive immune response	5	10.5×	0.007	CTLA4, HLA-B, HLA-DPB1, HLA-DQA2, HLA-DQB1
humoral immune response	3	21.1×	0.023	CCR6, CD28, HLA-DQB1
cell-cell adhesion	4	10.2×	0.033	SOX9, PRICKLE1, ITGAM, LPP
positive regulation of type II interferon production	3	16.9×	0.036	SLAMF6, HLA-DPB1, PTPN22
extracellular matrix assembly	2	46.8×	0.036	SOX9, PRICKLE1
regulation of T cell tolerance induction	1	421.3×	0.045	IL2RA
regulation of skeletal muscle contraction via regulation of action potential	1	421.3×	0.045	KCNJ2
regulation of toll-like receptor 9 signaling pathway	1	421.3×	0.045	FCRL3
phosphoanandamide dephosphorylation	1	421.3×	0.045	PTPN22
thyroid-stimulating hormone signaling pathway	1	421.3×	0.045	TSHR
isotype switching to IgA isotypes	1	421.3×	0.045	CCR6
regulation of mast cell chemotaxis	1	421.3×	0.045	RAC2
primary adaptive immune response involving T cells and B cells	1	421.3×	0.045	BACH2
DN3 thymocyte differentiation	1	421.3×	0.045	CCR6
cellular response to thyrotropin-releasing hormone	1	421.3×	0.045	TSHR
conversion of seryl-tRNAsec to selenocys-tRNAsec	1	210.7×	0.045	SEPSECS
negative regulation of immune system process	1	210.7×	0.045	SOX9
regulation of natural killer cell proliferation	1	210.7×	0.045	PTPN22
epithelial cell proliferation involved in prostatic bud elongation	1	210.7×	0.045	SOX9
regulation of cell proliferation involved in tissue homeostasis	1	210.7×	0.045	SOX9
regulation of branching involved in lung morphogenesis	1	210.7×	0.045	SOX9
cell proliferation involved in heart morphogenesis	1	210.7×	0.045	SOX9
polarized secretion of basement membrane proteins in epithelium	1	210.7×	0.045	PRICKLE1
response to curcumin	1	210.7×	0.045	ITGAM

Therapeutics

Drugs indicated for this disease

0 approved, 4 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Cholestyramine	Phase 3 (in late-stage trials)
Potassium Iodide	Phase 3 (in late-stage trials)
Prednisolone	Phase 3 (in late-stage trials)
Propylthiouracil	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Batoclimab, Levothyroxine, Methimazole, Mycophenolate Mofetil, Thyrotropin Alfa.

Drug target analysis

Approved (phase 4): 4 · Phase ≥3: 4 · Phased (≥1): 6 · Undrugged: 35

Druggability breadth: 19 of 41 evidence-associated genes (46%) 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
TSHR	LEVOSALBUTAMOL
CHRNA9	ACETYLCHOLINE
CCR6	TEGASEROD MALEATE
MAP3K7	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TSHR	354	4
MAP3K7	29	4
CCR6	3	4
CHRNA9	2	4
TRIB2	1	1
RAC2	1	1
SOX9	0	0
TG	0	0
VAV3	0	0
CCN4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LEVOSALBUTAMOL	4	TSHR
PROGESTERONE	4	TSHR
DICLOFENAC SODIUM	4	TSHR
CLOTRIMAZOLE	4	TSHR
DAPSONE	4	TSHR
COLCHICINE	4	TSHR
OXAPROZIN	4	TSHR
BUMETANIDE	4	TSHR
GLIPIZIDE	4	TSHR
CARBAMAZEPINE	4	TSHR
METHYL SALICYLATE	4	TSHR
PHENELZINE	4	TSHR
EDROPHONIUM	4	TSHR
SULFAPHENAZOLE	4	TSHR
AMOXAPINE	4	TSHR
PYRIDOSTIGMINE	4	TSHR
ACETAMINOPHEN	4	TSHR
DICYCLOMINE	4	TSHR
IODIPAMIDE	4	TSHR
TESTOSTERONE PROPIONATE	4	TSHR
TETRABENAZINE	4	TSHR
CELECOXIB	4	TSHR
PROPANTHELINE	4	TSHR
BENOXINATE	4	TSHR
NICARDIPINE HYDROCHLORIDE	4	TSHR
PYRITHIONE ZINC	4	TSHR
GUANABENZ ACETATE	4	TSHR
PROPIOLACTONE	4	TSHR
CHLOROTRIANISENE	4	TSHR
PHENOXYBENZAMINE HYDROCHLORIDE	4	TSHR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 7.

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

Symbol	Assays	Type breakdown
MAP3K7	375	Binding:374, ADMET:1
PTPN22	137	Binding:122, Functional:10, ADMET:5
CHRNA9	105	Binding:102, Functional:2, ADMET:1
CCR6	60	Functional:33, Binding:27
TRIB2	40	Binding:40
GPR174	39	Functional:35, Binding:4
TSHR	33	Functional:24, Binding:9
KCNJ2	31	Binding:23, ADMET:8
ITGAM	14	Binding:12, Functional:2
ABO	6	Binding:6
RAC2	4	Binding:4
SOX9	3	Binding:3
BACH2	3	Binding:3
MMEL1	2	Binding:2
CEP43	2	Binding:2
IL2RA	2	Binding:2
CD28	1	Functional:1
CTLA4	1	Binding:1
HLA-B	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MMEL1	3.4.24.B14
RNASET2	4.6.1.19	ribonuclease T2
SEPSECS	2.9.1.2	O-phospho-L-seryl-tRNASec:L-selenocysteinyl-tRNA synthase
RHOH	3.6.5.2	small monomeric GTPase
ABO	2.4.1.37, 2.4.1.40, 2.4.1.88	fucosylgalactoside 3-alpha-galactosyltransferase, glycoprotein-fucosylgalactoside alpha-N-acetylgalactosaminyltransferase, globoside alpha-N-acetylgalactosaminyltransferase
PTPN22	3.1.3.48	protein-tyrosine-phosphatase
RAC2	3.6.5.2	small monomeric GTPase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CHRNA9	105
MAP3K7	375
PTPN22	137

Pharmacogenomics

Cohort genes with a PharmGKB record: 41; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
HLA-B	1

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)
LEVOSALBUTAMOL	4	TSHR
PROGESTERONE	4	TSHR
DICLOFENAC SODIUM	4	TSHR
CLOTRIMAZOLE	4	TSHR
DAPSONE	4	TSHR
COLCHICINE	4	TSHR
OXAPROZIN	4	TSHR
BUMETANIDE	4	TSHR
GLIPIZIDE	4	TSHR
CARBAMAZEPINE	4	TSHR
METHYL SALICYLATE	4	TSHR
PHENELZINE	4	TSHR
EDROPHONIUM	4	TSHR
SULFAPHENAZOLE	4	TSHR
AMOXAPINE	4	TSHR
PYRIDOSTIGMINE	4	TSHR
ACETAMINOPHEN	4	TSHR
DICYCLOMINE	4	TSHR
IODIPAMIDE	4	TSHR
TESTOSTERONE PROPIONATE	4	TSHR
TETRABENAZINE	4	TSHR
CELECOXIB	4	TSHR
PROPANTHELINE	4	TSHR
BENOXINATE	4	TSHR
NICARDIPINE HYDROCHLORIDE	4	TSHR
PYRITHIONE ZINC	4	TSHR
GUANABENZ ACETATE	4	TSHR
PROPIOLACTONE	4	TSHR
CHLOROTRIANISENE	4	TSHR
PHENOXYBENZAMINE HYDROCHLORIDE	4	TSHR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	4	TSHR, CHRNA9, CCR6, MAP3K7
B	Phased (≥1) drug, not yet approved	2	TRIB2, RAC2
C	Druggable family + PDB, no drug	14	CD28, SLAMF6, RNASET2, CTLA4, GPR174, SEPSECS, HLA-B, HLA-DPB1, HLA-DQB1, IL2RA (+4 more)
D	Druggable family + AlphaFold only, no drug	5	MMEL1, FCRL3, SLC25A27, HLA-DQA2, RHOH
E	Difficult family or no structure, no drug	16	SOX9, TG, VAV3, CCN4, C6orf15, BACH2, C1QTNF6, CEP43, PRICKLE1, MUC21 (+6 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TG	0	TSHR
CEP43	2	CCR6
PTPN22	137	—
SOX9	3	—
VAV3	0	—
CCN4	0	—
C6orf15	0	—
BACH2	3	—
C1QTNF6	0	—
MMEL1	2	—
CD28	1	—
PRICKLE1	0	—
FCRL3	0	—
SLC25A27	0	—
SLAMF6	0	—
MUC21	0	—
RNASET2	0	—
COL11A2	0	—
DCHS2	0	—
RBM45	0	—
CTLA4	1	—
AAMDC	0	—
GPR174	39	—
SEPSECS	0	—
HLA-B	1	—
HLA-DPB1	0	—
HLA-DQA2	0	—
HLA-DQB1	0	—
IL2RA	2	—
ITGAM	14	—

Clinical trials & evidence

Clinical trials

Clinical trials: 86.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	59
PHASE3	8
PHASE4	7
PHASE2	5
PHASE1	4
PHASE2/PHASE3	1
PHASE1/PHASE2	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05435547	PHASE4	RECRUITING	Preoperative Corticosteroids in Autoimmune Thyroid Disease
NCT05461820	PHASE4	RECRUITING	Effects of Different Treatment Schemes on the Regulation and Recurrence of Graves’ Disease
NCT00150137	PHASE4	COMPLETED	Antithyroid Drugs During Radioiodine Therapy
NCT00400465	PHASE4	COMPLETED	Is the Routine Pressure Dressing After Thyroidectomy Necessary?
NCT00946296	PHASE4	COMPLETED	Impact of SSKI Pre-Treatment on Blood Loss in Thyroidectomy for Graves Disease
NCT03667157	PHASE4	COMPLETED	Liver Function After Intravenous Methylprednisolone Administration
NCT03969108	PHASE4	COMPLETED	Diagnostic Accuracy Study of Indocyanine Green for Parathyroid Perfusion Assessment
NCT07570316	PHASE3	NOT_YET_RECRUITING	A Study to Assess Efficacy and Safety of Efgartigimod PH20 SC PFS in Adult Participants With Graves’ Disease
NCT07596849	PHASE3	NOT_YET_RECRUITING	A Study to Assess Efficacy and Safety of Efgartigimod PH20 SC PFS in Adult Participants With Graves’ Disease.
NCT01039818	PHASE3	COMPLETED	Comparison of Different Doses of 131I in Severe Graves’ Hyperthyroidism
NCT01295333	PHASE3	COMPLETED	Assessing the Impact of the Early and Systematic Hormonal Replacement After Radio-isotopic Ablation of Graves’hyperthyroïdism on Quality of Life, Efficiency and Tolerance
NCT01616108	PHASE2/PHASE3	UNKNOWN	Bupivacaine Injection of Eye Muscles to Treat Strabismus
NCT03066076	PHASE3	UNKNOWN	Total Thyroidectomy Versus Thionamides in Patients With Moderate-to-Severe Graves’ Ophthalmopathy
NCT03303053	PHASE3	UNKNOWN	Efficacy and Safety of Cholestyramine and Prednisolone as Adjunctive Therapy in Treatment of Overt Hyperthyroidism
NCT04080505	PHASE3	TERMINATED	Does Potassium Iodide (SSKI) Reduce Vascularity in Graves’ Thyroidectomy?
NCT05118542	PHASE3	COMPLETED	Effect of Hyperthyroidism and Its Treatment in Graves’ Disease to Early Marker of Atherosclerosis
NCT07369063	PHASE2	RECRUITING	Impact of Vitamin D Therapy on Thyroid Function and Antibody Levels in Pediatric Graves’ Disease
NCT01727973	PHASE1/PHASE2	COMPLETED	Efficacy of Subantimicrobial Dose Doxycycline for Moderate to Severe and Active Graves’ Orbitopathy
NCT02203682	PHASE2	UNKNOWN	Doxycycline Treatment in Mild Thyroid-Associated Ophthalmopathy
NCT02993302	PHASE2	COMPLETED	Effects Of Oral Alfacalcidol On Maturation Of Dendritic Cells In Graves’ Disease Patients
NCT05907668	PHASE2	COMPLETED	A Proof-of-Concept Study to Assess Batoclimab in Participants With Graves’ Disease
NCT06240455	PHASE2	SUSPENDED	Phase 2 Study to Assess Efficacy & Safety of WP1302 Prevent Relapse of MMI w/Draw in Subj. w/ Graves’ dz
NCT06980649	PHASE1	RECRUITING	Study of BHV-1300 in Graves’ Disease
NCT07286656	PHASE1	RECRUITING	A Study of GensSci098 in Subjects With Graves’ Disease
NCT07305818	PHASE1	RECRUITING	NEXUS Study: A Study to Test Single and Multiple Doses of MER511 Given to Adults With Graves’ Disease
NCT02973802	PHASE1	COMPLETED	ATX-GD-59 in Patients With Graves Disease Not Treated With Anti-thyroid Therapy
NCT07129642	EARLY_PHASE1	RECRUITING	Allogeneic Anti-CD19 CAR-T for Refractory Graves’ Disease
NCT03517579	Not specified	RECRUITING	Personalized Treatment in Thyroid Disorders
NCT05635266	Not specified	RECRUITING	Tissue Repository Providing Annotated Biospecimens for Approved Investigator-directed Biomedical Research Initiatives
NCT05678374	Not specified	RECRUITING	Exploring Immunological Markers Associated With Mental Fatigue in Graves’ Disease
NCT06081439	Not specified	RECRUITING	Validating Immunological Markers Associated With Mental Fatigue in Graves’ Disease
NCT06134219	Not specified	RECRUITING	Course for Brain Fatigue After Graves’ Disease Controlled Study
NCT06275373	Not specified	RECRUITING	The Effect of Teprotumumab on Thyroid Eye Disease and Thyroid Dysfunction
NCT06309316	Not specified	RECRUITING	The Impact of Person Centred Care (PCC) in Grave’s Disease
NCT06327828	Not specified	NOT_YET_RECRUITING	Methimazole in Graves’ Disease - Comparing the Computer-aided Treatment DigiThy Versus Usual Care
NCT06426758	Not specified	NOT_YET_RECRUITING	Graves’ Disease Induced by Epstein-Barr Virus Lytic Reactivation
NCT06506149	Not specified	RECRUITING	A Prospective Evaluation of Microwave Ablation (MWA) in the Treatment of Relapsed Graves’ Disease
NCT06537141	Not specified	NOT_YET_RECRUITING	Role of Embolization of Thyroid Arteries as a Treatment for Different Thyroid Disorders
NCT06540469	Not specified	NOT_YET_RECRUITING	Iodine Supplementation in Graves’ Hyperthyroidism
NCT06864351	Not specified	RECRUITING	Prospective Evaluation of OptiThyDose

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
METHIMAZOLE	4	8
DOXYCYCLINE ANHYDROUS	4	2
EFGARTIGIMOD ALFA	4	2
INDOCYANINE GREEN ACID FORM	4	2
POTASSIUM IODIDE	4	2
CHOLESTYRAMINE	4	1
PROPYLTHIOURACIL	4	1
SELENIUM	3	1
POTASSIUM ION	0	2
CHEMBL50241	0	1