Hypothyroidism

Summary

Hypothyroidism (MONDO:0005420) is a disease (an umbrella term covering 6 Mondo subtypes) with 75 cohort genes (3,279 GWAS associations across 84 studies) and 138 clinical trials. The dominant Reactome pathway is Translocation of ZAP-70 to Immunological synapse (5 cohort genes). Top therapeutic interventions include levothyroxine, liothyronine, and iopamidol.

At a glance

• Umbrella term: 6 Mondo subtypes
• Cohort genes: 75
• GWAS associations: 3,279
• ClinVar variants: 12
• Clinical trials: 138

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypothyroidism
Mondo ID	MONDO:0005420
EFO	EFO:0004705
MeSH	D007037
DOID	DOID:1459
ICD-11	1722092627
NCIT	C26800
SNOMED CT	40930008
UMLS	C0020676
MedGen	6991
Is cancer (heuristic)	no

Also known as: hypothyroidism · underactive thyroid

Data availability: 12 ClinVar variants · 3,279 GWAS associations (84 studies) · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 6 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › endocrine system disorder › thyroid gland disorder › hypothyroidism

Related subtypes (11): thyrocalcitonin secretion disease, thyroiditis, hyperthyroidism, thyroid malformation, hyperthyroxinemia, goiter, C-cell hyperplasia, atrophy of thyroid, euthyroid sick syndrome, thyroid tumor, inherited thyroid metabolism disease

Subtypes (6): postsurgical hypothyroidism, iodine hypothyroidism, myxedema, congenital hypothyroidism, myxedema coma, myxedema heart disease

Genetics & variants

GWAS landscape

3,279 GWAS associations across 84 studies. Top hits map to 11 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs1794269	7e-309	HLA-DQB1 - MTCO3P1	?
rs17213756	5e-305	HLA-DOB	?
rs17425622	1e-300	HLA-DRB1 - HLA-DQA1	?
rs17209950	1e-300	HLA-DRB9 - HLA-DRB5	?
rs1612904	1e-300	HLA-DQB1 - MTCO3P1	?
rs17219281	1e-300	MTCO3P1 - HLA-DQB3	?
rs1555117	1e-300	TSBP1-AS1, TSBP1	?
rs1555116	1e-300	TSBP1, TSBP1-AS1	?
rs33964890	1e-300	HLA-DRB1 - HLA-DQA1	?
rs17203612	1e-300	HLA-DRB9 - HLA-DRB5	?
rs17203570	1e-300	HLA-DRB9 - HLA-DRB5	?
rs17209887	1e-300	HLA-DRB9 - HLA-DRB5	?
rs17203619	1e-300	HLA-DRB9 - HLA-DRB5	?
rs17203636	1e-300	HLA-DRB9 - HLA-DRB5	?
rs17203626	1e-300	HLA-DRB9 - HLA-DRB5	?
rs17203514	1e-300	HLA-DRB9 - HLA-DRB5	?
rs17209866	1e-300	HLA-DRB9 - HLA-DRB5	?
rs17203563	1e-300	HLA-DRB9 - HLA-DRB5	?
rs33998906	3e-267	HLA-DQB2 - HLA-DOB	?
rs1559876	5e-230	NOTCH4 - TSBP1-AS1	?
rs2476601	3e-198	AP4B1-AS1, PTPN22	A	0.38
rs17212937	1e-196	MTCO3P1 - HLA-DQB3	?
rs1738434	2e-188	WHR1	?
rs1588635	8e-153	PTCSC2	C	1.24
rs3184504	1e-142	ATXN2, SH2B3	?
rs17500510	4e-137	HLA-DQA2	?
rs7850258	2e-136	PTCSC2	A	0.21
rs9271365	5e-123	HLA-DRB1 - HLA-DQA1	G	0.25
rs17208314	1e-121	TSBP1-AS1	?
rs17212223	7e-114	HLA-DQB1 - MTCO3P1	?

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90475647	Verma A	2024	62,814	378,321	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90319320	Figueredo J	2024	58,783	633,203	Uncovering the Shared Genetic Components of Thyroid Disorders and Reproductive Health.
GCST90204167	Mathieu S	2022	51,194	443,383	Genetic association and Mendelian randomization for hypothyroidism highlight immune molecular mechanisms.
GCST90473157	UK Biobank Whole-Genome Sequencing Consortium	2025	37,022	421,418	Whole-genome sequencing of 490,640 UK Biobank participants.
GCST90428826	Yu X	2024	30,155	396,652	Shared genetic architecture between autoimmune disorders and B-cell acute lymphoblastic leukemia: insights from large-scale genome-wide cross-trait analysis.
GCST90018862	Sakaue S	2021	30,155	379,986	A cross-population atlas of genetic associations for 220 human phenotypes.
GCST90446433	Chen Y	2024	27,251	415,931	The performance of AlphaMissense to identify genes influencing disease.
GCST90446434	Chen Y	2024	27,251	415,931	The performance of AlphaMissense to identify genes influencing disease.
GCST90038637	Donertas HM	2021	23,497	461,101	Common genetic associations between age-related diseases.
GCST90428109	Liu R	2024	22,350	518,206	Shared genetic architecture between hypothyroidism and rheumatoid arthritis: A large-scale cross-trait analysis.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	2
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	48

MAF distribution

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

Functional consequences

Consequence	Count
intergenic_variant	26
intron_variant	21
missense_variant	2
non_coding_transcript_exon_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs1794269	6	32706117	C>G,T	0.05	intergenic_variant	HLA-DQB1 - MTCO3P1	7e-309	Tier 4: intronic/intergenic
rs17213756	6	32820219	C>T	0.05	intron_variant	HLA-DOB	5e-305	Tier 4: intronic/intergenic
rs17425622	6	32604184	T>C	0.05	intergenic_variant	HLA-DRB1 - HLA-DQA1	1e-300	Tier 4: intronic/intergenic
rs17209950	6	32478811	G>A	0.05	intron_variant	HLA-DRB9 - HLA-DRB5	1e-300	Tier 4: intronic/intergenic
rs1612904	6	32701241	C>A,G,T	0.05	intergenic_variant	HLA-DQB1 - MTCO3P1	1e-300	Tier 4: intronic/intergenic
rs17219281	6	32707868	G>A	0.05	intergenic_variant	MTCO3P1 - HLA-DQB3	1e-300	Tier 4: intronic/intergenic
rs1555117	6	32343371	C>A,G,T	0.05	intron_variant	TSBP1-AS1, TSBP1	1e-300	Tier 4: intronic/intergenic
rs1555116	6	32344963	C>A,G	0.05	intron_variant	TSBP1, TSBP1-AS1	1e-300	Tier 4: intronic/intergenic
rs33964890	6	32616142	T>C	0.05	intergenic_variant	HLA-DRB1 - HLA-DQA1	1e-300	Tier 4: intronic/intergenic
rs17203612	6	32479076	A>T	0.05	intron_variant	HLA-DRB9 - HLA-DRB5	1e-300	Tier 4: intronic/intergenic
rs17203570	6	32478897	A>T	0.05	intron_variant	HLA-DRB9 - HLA-DRB5	1e-300	Tier 4: intronic/intergenic
rs17209887	6	32478274	A>C	0.05	intron_variant	HLA-DRB9 - HLA-DRB5	1e-300	Tier 4: intronic/intergenic
rs17203619	6	32479145	T>C	0.05	intron_variant	HLA-DRB9 - HLA-DRB5	1e-300	Tier 4: intronic/intergenic
rs17203636	6	32479237	G>A,C,T	0.05	intron_variant	HLA-DRB9 - HLA-DRB5	1e-300	Tier 4: intronic/intergenic
rs17203626	6	32479217	G>A,T	0.05	intron_variant	HLA-DRB9 - HLA-DRB5	1e-300	Tier 4: intronic/intergenic
rs17203514	6	32478294	C>G	0.05	intron_variant	HLA-DRB9 - HLA-DRB5	1e-300	Tier 4: intronic/intergenic
rs17209866	6	32478215	G>A	0.05	intron_variant	HLA-DRB9 - HLA-DRB5	1e-300	Tier 4: intronic/intergenic
rs17203563	6	32478682	G>A	0.05	intron_variant	HLA-DRB9 - HLA-DRB5	1e-300	Tier 4: intronic/intergenic
rs33998906	6	32765851	C>T	0.05	intergenic_variant	HLA-DQB2 - HLA-DOB	3e-267	Tier 4: intronic/intergenic
rs1559876	6	32247992	G>A,C,T	0.05	intergenic_variant	NOTCH4 - TSBP1-AS1	5e-230	Tier 4: intronic/intergenic
rs2476601	1	113834946	A>G,T	0.05	missense_variant	AP4B1-AS1, PTPN22	3e-198	Tier 1: coding
rs17212937	6	32713562	C>G,T	0.05	intergenic_variant	MTCO3P1 - HLA-DQB3	1e-196	Tier 4: intronic/intergenic
rs1738434	6	31976259	G>A,C,T	0.05	intron_variant	WHR1	2e-188	Tier 4: intronic/intergenic
rs1588635	9	97775520	A>C,T	0.05	intron_variant	PTCSC2	8e-153	Tier 4: intronic/intergenic
rs3184504	12	111446804	T>A,C,G	0.05	missense_variant	ATXN2, SH2B3	1e-142	Tier 1: coding
rs17500510	6	32745041	G>A,C	0.05	intron_variant	HLA-DQA2	4e-137	Tier 4: intronic/intergenic
rs7850258	9	97786731	A>G,T	0.05	non_coding_transcript_exon_variant	PTCSC2	2e-136	Tier 4: intronic/intergenic
rs9271365	6	32619017	T>A,C,G	0.05	intergenic_variant	HLA-DRB1 - HLA-DQA1	5e-123	Tier 4: intronic/intergenic
rs17208314	6	32287994	C>T		intron_variant	TSBP1-AS1	1e-121	Tier 4: intronic/intergenic
rs17212223	6	32683763	C>T	0.05	intergenic_variant	HLA-DQB1 - MTCO3P1	7e-114	Tier 4: intronic/intergenic

ClinVar germline variants

12 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 3 pathogenic/likely pathogenic, 3 likely pathogenic, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
279598	NM_001282531.3(ADNP):c.2188C>T (p.Arg730Ter)	ADNP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1120267	NM_018017.4(CCDC186):c.767C>G (p.Ser256Ter)	CCDC186	Pathogenic	criteria provided, single submitter
374090	NM_017780.4(CHD7):c.6892C>T (p.Gln2298Ter)	CHD7	Pathogenic	criteria provided, single submitter
208722	NM_002074.5(GNB1):c.239T>C (p.Ile80Thr)	GNB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13919	NM_020975.6(RET):c.2753T>C (p.Met918Thr)	RET	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
373957	NM_015100.4(POGZ):c.402_409dup (p.His137fs)	POGZ	Likely pathogenic	no assertion criteria provided
812763	NM_004733.4(SLC33A1):c.963+1G>A	SLC33A1	Likely pathogenic	no assertion criteria provided
689597	NM_003235.5(TG):c.5804del (p.Asn1935fs)	TG	Likely pathogenic	no assertion criteria provided
523303	GRCh37/hg19 6q25.3(chr6:156772218-157870875)x3	ARID1B	Uncertain significance	criteria provided, single submitter
812547	NM_000651.6(CR1):c.6283C>A (p.His2095Asn)	CR1	Uncertain significance	criteria provided, single submitter
523539	NM_031407.7(HUWE1):c.6485G>C (p.Arg2162Pro)	HUWE1	Uncertain significance	criteria provided, single submitter
4081838	NM_030625.3(TET1):c.4936C>T (p.Arg1646Ter)	TET1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 1 · Orphanet: 75 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 1

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

Gene	HGNC	Evidence routes
TG	TG	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
TRPC4AP	Limited	Autosomal dominant	hypothyroidism

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TG	Orphanet:95716	Familial thyroid dyshormonogenesis
RPS26	Orphanet:124	Diamond-Blackfan anemia
SACS	Orphanet:98	Autosomal recessive spastic ataxia of Charlevoix-Saguenay
ATXN2	Orphanet:803	Amyotrophic lateral sclerosis
ATXN2	Orphanet:98756	Spinocerebellar ataxia type 2
TPO	Orphanet:95716	Familial thyroid dyshormonogenesis
XPA	Orphanet:910	Xeroderma pigmentosum
BACH2	Orphanet:714472	Inflammatory bowel disease-autoimmunity-sinopulmonary infections-lymphadenopathy syndrome
ADNP	Orphanet:404448	Helsmoortel-Van der Aa syndrome
ARID1B	Orphanet:1465	Coffin-Siris syndrome
ARID1B	Orphanet:251056	6q25.2q25.3 microdeletion syndrome
ZNF365	Orphanet:2073	Narcolepsy type 1
ZNF365	Orphanet:83465	Narcolepsy type 2
POGZ	Orphanet:468678	White-Sutton syndrome
SASH1	Orphanet:231040	Familial generalized lentiginosis
SASH1	Orphanet:447961	Pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome
CHD7	Orphanet:138	CHARGE syndrome
CHD7	Orphanet:39041	Omenn syndrome
CHD7	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
CHD7	Orphanet:478	Kallmann syndrome
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
SH2B3	Orphanet:3318	Essential thrombocythemia
SH2B3	Orphanet:391366	Growth retardation-mild developmental delay-chronic hepatitis syndrome
HUWE1	Orphanet:528084	Non-specific syndromic intellectual disability
ERBB3	Orphanet:137776	Lethal congenital contracture syndrome type 2
ERBB3	Orphanet:388	Hirschsprung disease
FOXE1	Orphanet:1226	Bamforth-Lazarus syndrome
FOXE1	Orphanet:146	Differentiated thyroid carcinoma
FOXE1	Orphanet:319487	Familial papillary or follicular thyroid carcinoma
FOXE1	Orphanet:95713	Athyreosis
GNB1	Orphanet:488613	Global developmental delay-neuro-ophthalmological abnormalities-seizures-intellectual disability syndrome
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-C	Orphanet:585909	B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2)
HLA-DQA1	Orphanet:391490	Adult-onset myasthenia gravis
HLA-DQA1	Orphanet:930	Idiopathic achalasia
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

Cohort genes → proteins

75 cohort genes, 69 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	64
gwas_and_clinvar	1
multi_evidence	10

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TG	HGNC:11764	ENSG00000042832	P01266	Thyroglobulin	gwas,clinvar
TRPC4AP	HGNC:16181	ENSG00000100991	Q8TEL6	Short transient receptor potential channel 4-associated protein	gencc
RPS26	HGNC:10414	ENSG00000197728	P62854	Small ribosomal subunit protein eS26	gwas
SACS	HGNC:10519	ENSG00000151835	Q9NZJ4	Sacsin	gwas
ATXN2	HGNC:10555	ENSG00000204842	Q99700	Ataxin-2	gwas
CCL2	HGNC:10618	ENSG00000108691	P13500	C-C motif chemokine 2	gwas
BRAP	HGNC:1099	ENSG00000089234	Q7Z569	BRCA1-associated protein	gwas
SSTR4	HGNC:11333	ENSG00000132671	P31391	Somatostatin receptor type 4	gwas
TNFRSF19	HGNC:11915	ENSG00000127863	Q9NS68	Tumor necrosis factor receptor superfamily member 19	gwas
TNP1	HGNC:11951	ENSG00000118245	P09430	Spermatid nuclear transition protein 1	gwas
TPO	HGNC:12015	ENSG00000115705	P07202	Thyroid peroxidase	gwas
FMNL1	HGNC:1212	ENSG00000184922	O95466	Formin-like protein 1	gwas
VAV3	HGNC:12659	ENSG00000134215	Q9UKW4	Guanine nucleotide exchange factor VAV3	gwas
VEGFA	HGNC:12680	ENSG00000112715	P15692	Vascular endothelial growth factor A, long form	gwas
XPA	HGNC:12814	ENSG00000136936	P23025	DNA repair protein complementing XP-A cells	gwas
SNTG2	HGNC:13741	ENSG00000172554	Q9NY99	Gamma-2-syntrophin	gwas
C6orf15	HGNC:13927	ENSG00000204542	Q6UXA7	Uncharacterized protein C6orf15	gwas
BACH2	HGNC:14078	ENSG00000112182	Q9BYV9	Transcription regulator protein BACH2	gwas
C1QTNF6	HGNC:14343	ENSG00000133466	Q9BXI9	Complement C1q tumor necrosis factor-related protein 6	gwas
CAPZB	HGNC:1491	ENSG00000077549	P47756	F-actin-capping protein subunit beta	gwas
ADNP	HGNC:15766	ENSG00000101126	Q9H2P0	Activity-dependent neuroprotector homeobox protein	clinvar
CDH13	HGNC:1753	ENSG00000140945	P55290	Cadherin-13	gwas
ARID1B	HGNC:18040	ENSG00000049618	Q8NFD5	AT-rich interactive domain-containing protein 1B	clinvar
ZNF365	HGNC:18194	ENSG00000138311	Q70YC4	Talanin	gwas
POGZ	HGNC:18801	ENSG00000143442	Q7Z3K3	Pogo transposable element with ZNF domain	clinvar
SASH1	HGNC:19182	ENSG00000111961	O94885	SAM and SH3 domain-containing protein 1	gwas
RTKN2	HGNC:19364	ENSG00000182010	Q8IZC4	Rhotekin-2	gwas
CHD7	HGNC:20626	ENSG00000171316	Q9P2D1	ATP-dependent chromatin remodeler CHD7	clinvar
ZDHHC21	HGNC:20750	ENSG00000175893	Q8IVQ6	Palmitoyltransferase ZDHHC21	gwas
SAMD5	HGNC:21180	ENSG00000203727	Q5TGI4	Sterile alpha motif domain-containing protein 5	gwas
ZNF804B	HGNC:21958	ENSG00000182348	A4D1E1	Zinc finger protein 804B	gwas
TEX47	HGNC:22402	ENSG00000164645	Q8TBZ9	Testis-expressed protein 47	gwas
SPATA13	HGNC:23222	ENSG00000182957	Q96N96	Spermatogenesis-associated protein 13	gwas
CR1	HGNC:2334	ENSG00000203710	P17927	Complement receptor type 1	clinvar
CCDC186	HGNC:24349	ENSG00000165813	Q7Z3E2	Coiled-coil domain-containing protein 186	clinvar
CYCSP5	HGNC:24416	ENSG00000227735		CYCS pseudogene 5	gwas
CTLA4	HGNC:2505	ENSG00000163599	P16410	Cytotoxic T-lymphocyte protein 4	gwas
RSBN1	HGNC:25642	ENSG00000081019	Q5VWQ0	Lysine-specific demethylase 9	gwas
NAA25	HGNC:25783	ENSG00000111300	Q14CX7	N-alpha-acetyltransferase 25, NatB auxiliary subunit	gwas
HECTD4	HGNC:26611	ENSG00000173064	Q9Y4D8	Probable E3 ubiquitin-protein ligase HECTD4	gwas
HCG22	HGNC:27780	ENSG00000228789	E2RYF7	Protein PBMUCL2	gwas
DHFRP2	HGNC:2863	ENSG00000228432		dihydrofolate reductase pseudogene 2	gwas
LINC03040	HGNC:28692	ENSG00000181577	Q8N319	Uncharacterized protein LINC03040	gwas
TET1	HGNC:29484	ENSG00000138336	Q8NFU7	Methylcytosine dioxygenase TET1	clinvar
SH2B3	HGNC:29605	ENSG00000111252	Q9UQQ2	SH2B adapter protein 3	gwas
HUWE1	HGNC:30892	ENSG00000086758	Q7Z6Z7	E3 ubiquitin-protein ligase HUWE1	clinvar
ZBTB10	HGNC:30953	ENSG00000205189	Q96DT7	Zinc finger and BTB domain-containing protein 10	gwas
TRMO	HGNC:30967	ENSG00000136932	Q9BU70	tRNA (adenine(37)-N6)-methyltransferase	gwas
MICOS10	HGNC:32068	ENSG00000173436	Q5TGZ0	MICOS complex subunit MIC10	gwas
ERBB3	HGNC:3431	ENSG00000065361	P21860	Receptor tyrosine-protein kinase erbB-3	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TG	Thyroglobulin	Acts as a substrate for the production of iodinated thyroid hormones thyroxine (T4) and triiodothyronine (T3).
TRPC4AP	Short transient receptor potential channel 4-associated protein	Substrate-recognition component of a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex required for cell cycle control.
RPS26	Small ribosomal subunit protein eS26	Component of the small ribosomal subunit.
SACS	Sacsin	Co-chaperone which acts as a regulator of the Hsp70 chaperone machinery and may be involved in the processing of other ataxia-linked proteins.
ATXN2	Ataxin-2	Involved in EGFR trafficking, acting as negative regulator of endocytic EGFR internalization at the plasma membrane.
CCL2	C-C motif chemokine 2	Acts as a ligand for C-C chemokine receptor CCR2.
BRAP	BRCA1-associated protein	Negatively regulates MAP kinase activation by limiting the formation of Raf/MEK complexes probably by inactivation of the KSR1 scaffold protein.
SSTR4	Somatostatin receptor type 4	Receptor for somatostatin-14.
TNFRSF19	Tumor necrosis factor receptor superfamily member 19	Can mediate activation of JNK and NF-kappa-B.
TNP1	Spermatid nuclear transition protein 1	Plays a key role in the replacement of histones to protamine in the elongating spermatids of mammals.
TPO	Thyroid peroxidase	Iodination and coupling of the hormonogenic tyrosines in thyroglobulin to yield the thyroid hormones T(3) and T(4).
FMNL1	Formin-like protein 1	May play a role in the control of cell motility and survival of macrophages.
VAV3	Guanine nucleotide exchange factor VAV3	Exchange factor for GTP-binding proteins RhoA, RhoG and, to a lesser extent, Rac1.
VEGFA	Vascular endothelial growth factor A, long form	Participates in the induction of key genes involved in the response to hypoxia and in the induction of angiogenesis such as HIF1A.
XPA	DNA repair protein complementing XP-A cells	Involved in DNA nucleotide excision repair (NER).
SNTG2	Gamma-2-syntrophin	Adapter protein that binds to and probably organizes the subcellular localization of a variety of proteins.
BACH2	Transcription regulator protein BACH2	Transcriptional regulator that acts as a repressor or activator.
CAPZB	F-actin-capping protein subunit beta	F-actin-capping proteins bind in a Ca(2+)-independent manner to the fast growing ends of actin filaments (barbed end) thereby blocking the exchange of subunits at these ends.
ADNP	Activity-dependent neuroprotector homeobox protein	May be involved in transcriptional regulation.
CDH13	Cadherin-13	Cadherins are calcium-dependent cell adhesion proteins.
ARID1B	AT-rich interactive domain-containing protein 1B	Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
ZNF365	Talanin	May play a role in uric acid excretion.
POGZ	Pogo transposable element with ZNF domain	Plays a role in mitotic cell cycle progression and is involved in kinetochore assembly and mitotic sister chromatid cohesion.
SASH1	SAM and SH3 domain-containing protein 1	Is a positive regulator of NF-kappa-B signaling downstream of TLR4 activation.
RTKN2	Rhotekin-2	May play an important role in lymphopoiesis.
CHD7	ATP-dependent chromatin remodeler CHD7	ATP-dependent chromatin-remodeling factor, slides nucleosomes along DNA; nucleosome sliding requires ATP.
ZDHHC21	Palmitoyltransferase ZDHHC21	Palmitoyltransferase that catalyzes the addition of palmitate onto various protein substrates.
SPATA13	Spermatogenesis-associated protein 13	Acts as a guanine nucleotide exchange factor (GEF) for RHOA, RAC1 and CDC42 GTPases.
CR1	Complement receptor type 1	Membrane immune adherence receptor that plays a critical role in the capture and clearance of complement-opsonized pathogens by erythrocytes and monocytes/macrophages.
CTLA4	Cytotoxic T-lymphocyte protein 4	Inhibitory receptor acting as a major negative regulator of T-cell responses.
RSBN1	Lysine-specific demethylase 9	Histone demethylase that specifically demethylates dimethylated ‘Lys-20’ of histone H4 (H4K20me2) and trimethylated ‘Lys-20’ of histone H4 (H4K20me3) into monomethyl H4K20 (H4K20me1) thereby modulating chromosome architecture.
NAA25	N-alpha-acetyltransferase 25, NatB auxiliary subunit	Non-catalytic subunit of the NatB complex which catalyzes acetylation of the N-terminal methionine residues of peptides beginning with Met-Asp, Met-Glu, Met-Asn and Met-Gln.
HECTD4	Probable E3 ubiquitin-protein ligase HECTD4	E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates.
TET1	Methylcytosine dioxygenase TET1	Dioxygenase that plays a key role in active DNA demethylation, by catalyzing the sequential oxidation of the modified genomic base 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (…
SH2B3	SH2B adapter protein 3	Links T-cell receptor activation signal to phospholipase C-gamma-1, GRB2 and phosphatidylinositol 3-kinase.
HUWE1	E3 ubiquitin-protein ligase HUWE1	E3 ubiquitin-protein ligase which mediates ubiquitination and subsequent proteasomal degradation of target proteins.
ZBTB10	Zinc finger and BTB domain-containing protein 10	May be involved in transcriptional regulation.
TRMO	tRNA (adenine(37)-N6)-methyltransferase	S-adenosyl-L-methionine-dependent methyltransferase responsible for the addition of the methyl group in the formation of N6-methyl-N6-threonylcarbamoyladenosine at position 37 (m(6)t(6)A37) of the tRNA anticodon loop of tRNA(Ser)(GCU).
MICOS10	MICOS complex subunit MIC10	Component of the MICOS complex, a large protein complex of the mitochondrial inner membrane that plays crucial roles in the maintenance of crista junctions, inner membrane architecture, and formation of contact sites to the outer membrane.
ERBB3	Receptor tyrosine-protein kinase erbB-3	Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins.
FOXE1	Forkhead box protein E1	Transcription factor that binds consensus sites on a variety of gene promoters and activate their transcription.
GNB1	Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1	Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems.
GOT1	Aspartate aminotransferase, cytoplasmic	Biosynthesis of L-glutamate from L-aspartate or L-cysteine.
HLA-B	HLA class I histocompatibility antigen, B alpha chain	Antigen-presenting major histocompatibility complex class I (MHCI) molecule.
HLA-C	HLA class I histocompatibility antigen, C alpha chain	Antigen-presenting major histocompatibility complex class I (MHCI) molecule with an important role in reproduction and antiviral immunity.
HLA-DQA1	HLA class II histocompatibility antigen, DQ alpha 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.
HLA-DRB1	HLA class II histocompatibility antigen, DRB1 beta chain	A beta chain of antigen-presenting major histocompatibility complex class II (MHCII) molecule.
HLA-DRB5	HLA class II histocompatibility antigen, DR beta 5 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.

Protein-family classification

Druggable: 19 · Difficult: 23 · Unknown: 33 · Druggable fraction: 0.25

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	10	3.9×	0.002
Transcription factor	16	1.8×	0.073
Complement	2	7.2×	0.096
Nuclear receptor	1	5.2×	0.319
Scaffold/PPI	7	1.6×	0.319
Other/Unknown	33	0.8×	0.985
Kinase	2	0.7×	0.985
Enzyme (other)	3	0.5×	0.985
GPCR	1	0.3×	0.985

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TG	Other/Unknown	no		Thyroglobulin_1, CarbesteraseB, Tyr-kin_ephrin_A/B_rcpt-like
TRPC4AP	Other/Unknown	no		ARM-type_fold, TRPC4AP
RPS26	Other/Unknown	no		Ribosomal_eS26, Ribosomal_eS26_sf, Ribosomal_eS26_CS
SACS	Other/Unknown	no		Ubiquitin-like_dom, DnaJ_domain, HEPN_dom
ATXN2	Other/Unknown	no		LsmAD_domain, PAM2_motif, LSM_dom_sf
CCL2	Other/Unknown	no		Chemokine_CC_CS, Chemokine_IL8-like_dom, Interleukin_8-like_sf
BRAP	Transcription factor	no		Znf_UBP, Znf_RING, BRAP2/ETP1_RRM
SSTR4	GPCR	yes		GPCR_Rhodpsn, Somatstn_rcpt, Somatstn_rcpt_4
TNFRSF19	Other/Unknown	no		TNFR/NGFR_Cys_rich_reg, TNFR_19, TNFRSF19_N
TNP1	Other/Unknown	no		Nuclear_transition_prot1, Nuclear_transition_prot1_CS
TPO	Complement	yes	1.11.1.8	EGF-type_Asp/Asn_hydroxyl_site, Sushi_SCR_CCP_dom, EGF
FMNL1	Other/Unknown	no		FH3_dom, GTPase-bd, ARM-like
VAV3	Scaffold/PPI	no		DH_dom, SH2, GDS_CDC24_CS
VEGFA	Other/Unknown	no		PDGF/VEGF_dom, PD_growth_factor_CS, VEGF_C
XPA	Transcription factor	no		XPA/RAD14, DNA-bd_dom_put_sf, Znf_XPA_CS
SNTG2	Scaffold/PPI	no		PDZ, Syntrophin, PDZ_sf
C6orf15	Other/Unknown	no		C6orf15
BACH2	Transcription factor	no		BTB/POZ_dom, bZIP_Maf, bZIP
C1QTNF6	Other/Unknown	no		C1q_dom, Collagen, Tumour_necrosis_fac-like_dom
CAPZB	Other/Unknown	no		CAPZB, F-actin_capping_bsu_CS, CapZ_alpha/beta
ADNP	Transcription factor	no		HD, Homeodomain-like_sf, Znf_C2H2_type
CDH13	Other/Unknown	no		Cadherin-like_dom, Cadherin_pro_dom, Cadherin-like_sf
ARID1B	Other/Unknown	no		ARID_dom, BAF250/Osa, BAF250_C
ZNF365	Transcription factor	no		GenomicStab_NeuMorph_Reg, FBX41/ZN365_Znf-C2H2
POGZ	Transcription factor	no		DDE_SF_endonuclease_dom, HTH_CenpB_DNA-bd_dom, Homeodomain-like_sf
SASH1	Transcription factor	no		SH3_domain, SAM, SAM/pointed_sf
RTKN2	Scaffold/PPI	no		PH_domain, HR1_rho-bd, PH-like_dom_sf
CHD7	Other/Unknown	no		SNF2_N, Chromo/chromo_shadow_dom, Helicase_C-like
ZDHHC21	Other/Unknown	no		Palmitoyltrfase_DHHC, PFA4/ZDH16/20/ERF2-like
SAMD5	Scaffold/PPI	no		SAM, SAM/pointed_sf, SAM-SH3_domain_protein
ZNF804B	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, ZNF804A-like/GPATCH8
TEX47	Other/Unknown	no		TEX47-like
SPATA13	Scaffold/PPI	no		DH_dom, SH3_domain, PH_domain
CR1	Complement	yes		Sushi_SCR_CCP_dom, Sushi/SCR/CCP_sf, SEZ6_CSMD_C4BPB_Regulators
CCDC186	Other/Unknown	no		CCDC186
CYCSP5	Other/Unknown	no
CTLA4	Antibody/Immunoglobulin	yes		Ig_sub, CTLA4, Ig_V-set
RSBN1	Other/Unknown	no		RSBN1/Dpy-2/CEP530
NAA25	Enzyme (other)	yes	2.3.1.254	TPR-like_helical_dom_sf, NAA25_NatB_aux_su
HECTD4	Other/Unknown	no		HECT_dom, SPRY_HECTD4, Hect_E3_ubiquitin_ligase
HCG22	Other/Unknown	no		EZH_Inhibitor
DHFRP2	Other/Unknown	no
LINC03040	Other/Unknown	no		DUF5550
TET1	Transcription factor	no		Znf_CXXC, 2OGFeDO_JBP1/TET_oxygenase_dom, TET1/2/3
SH2B3	Scaffold/PPI	no		SH2, PH_domain, PH-like_dom_sf
HUWE1	Enzyme (other)	yes	2.3.2.26	HECT_dom, WWE_dom, UBA-like_sf
ZBTB10	Transcription factor	no		BTB/POZ_dom, SKP1/BTB/POZ_sf, Znf_C2H2_type
TRMO	Other/Unknown	no		UPF0066_cons_site, TrmO-like_N, YaeB-like_sf
MICOS10	Other/Unknown	no		Mic10
ERBB3	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom

Expression context

Cohort genes with no expression data: 0.

63 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)	1
broad (>20)	74
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left lobe of thyroid gland	8
granulocyte	8
right lobe of thyroid gland	7
thyroid gland	7
male germ line stem cell (sensu Vertebrata) in testis	6
primordial germ cell in gonad	6
monocyte	5
sural nerve	5
ganglionic eminence	5
ventricular zone	5
vermiform appendix	5
Brodmann (1909) area 23	4
buccal mucosa cell	4
calcaneal tendon	4
cerebellar hemisphere	4
right lung	4
endothelial cell	4
cerebellar cortex	4
spleen	4
sperm	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TG	169	tissue_specific	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
TRPC4AP	290	ubiquitous	marker	granulocyte, right adrenal gland cortex, adenohypophysis
RPS26	140	ubiquitous	marker	granulocyte, left adrenal gland cortex, mucosa of transverse colon
SACS	286	ubiquitous	marker	Brodmann (1909) area 23, middle frontal gyrus, frontal pole
ATXN2	286	ubiquitous	marker	buccal mucosa cell, colonic epithelium, olfactory bulb
CCL2	252	ubiquitous	marker	vena cava, gall bladder, islet of Langerhans
BRAP	286	ubiquitous	marker	left testis, right testis, testis
SSTR4	35		yes	endometrium epithelium, metanephric glomerulus, prefrontal cortex
TNFRSF19	224	ubiquitous	marker	upper arm skin, upper leg skin, bronchial epithelial cell
TNP1	150	tissue_specific	marker	sperm, male germ cell, adult organism
TPO	132	tissue_specific	marker	left lobe of thyroid gland, thyroid gland, right lobe of thyroid gland
FMNL1	236	ubiquitous	marker	granulocyte, monocyte, leukocyte
VAV3	258	ubiquitous	marker	tongue squamous epithelium, renal medulla, esophagus squamous epithelium
VEGFA	297	ubiquitous	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
XPA	289	ubiquitous	marker	calcaneal tendon, Brodmann (1909) area 23, left lobe of thyroid gland
SNTG2	166	broad	marker	sural nerve, male germ line stem cell (sensu Vertebrata) in testis, right testis
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
C1QTNF6	170	ubiquitous	marker	decidua, right uterine tube, stromal cell of endometrium
CAPZB	303	ubiquitous	marker	muscle layer of sigmoid colon, monocyte, smooth muscle tissue
ADNP	295	ubiquitous	marker	ganglionic eminence, cortical plate, ventricular zone
CDH13	152	ubiquitous	marker	descending thoracic aorta, right coronary artery, thoracic aorta
ARID1B	256	ubiquitous	marker	bone marrow cell, colonic epithelium, sural nerve
ZNF365	206	broad	yes	middle temporal gyrus, lateral nuclear group of thalamus, Brodmann (1909) area 23
POGZ	298	ubiquitous	marker	right uterine tube, right hemisphere of cerebellum, cerebellar hemisphere
SASH1	293	ubiquitous	marker	synovial joint, lateral globus pallidus, skin of hip
RTKN2	152	ubiquitous	marker	right lung, ventricular zone, primordial germ cell in gonad
CHD7	269	ubiquitous	marker	secondary oocyte, cerebellar vermis, sural nerve
ZDHHC21	245	ubiquitous	marker	epithelial cell of pancreas, endothelial cell, Brodmann (1909) area 23
SAMD5	201	broad	marker	kidney epithelium, esophagus squamous epithelium, mammary duct

Protein interactions among cohort

Intra-cohort edges: 35.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HUWE1	5,793
CCL2	5,749
CAPZB	5,209
CHD7	4,819
ERBB3	4,511
INSR	4,446
CTLA4	3,863
HLA-DRB1	3,448
ATXN2	3,360
HLA-B	3,209

Intra-cohort edges

A	B	Sources
ADNP	ARID1B	string_interaction
ATXN2	SH2B3	string_interaction
BACH2	C1QTNF6	string_interaction
BACH2	SH2B3	string_interaction
C1QTNF6	ERBB3	string_interaction
C1QTNF6	NAA25	string_interaction
C1QTNF6	SH2B3	string_interaction
C6orf15	TG	string_interaction
CAPZB	PDE8B	string_interaction
CAPZB	RTKN2	intact
CTLA4	ICOS	string_interaction
CTLA4	TPO	string_interaction
ERBB3	HLA-B	biogrid_interaction
ERBB3	NRG1	intact
ERBB3	SH2B3	intact
ERBB3	VAV3	intact
FOXE1	PDE8B	string_interaction
FOXE1	TG	string_interaction
FOXE1	TPO	intact, string_interaction
FOXE1	TRMO	string_interaction
HECTD4	NAA25	string_interaction
HLA-B	HLA-C	biogrid_interaction, intact
HLA-B	HLA-DQA2	string_interaction
HLA-C	HLA-DQB1	intact
HLA-C	HLA-DRB5	biogrid_interaction
HLA-DQA1	HLA-DQA2	intact
HLA-DQA1	HLA-DQB1	biogrid_interaction, intact
HLA-DQA1	HLA-DRB5	intact
HLA-DQA2	HLA-DRB1	string_interaction
HLA-DRB1	HLA-DRB5	biogrid_interaction, intact
NAA25	SH2B3	string_interaction
PHTF1	RSBN1	string_interaction
SAMD5	SASH1	string_interaction
TEX47	ZNF804B	string_interaction
TG	TPO	string_interaction

Structural data

PDB: 41 · AlphaFold-only: 28 · No structure: 6

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GNB1	P62873	1,262
PDE10A	Q9Y233	359
HLA-B	P01889	237
RPS26	P62854	190
HLA-DRB1	P01911	108
INSR	P06213	88
VEGFA	P15692	56
NR3C2	P08235	30
HLA-DQA1	P01909	28
ERBB3	P21860	23
CTLA4	P16410	22
HUWE1	Q7Z6Z7	19
XPA	P23025	18
CCL2	P13500	14
HLA-C	P10321	13
NRG1	Q02297	11
HLA-DQB1	P01920	10
CAPZB	P47756	8
SACS	Q9NZJ4	7
CR1	P17927	7
GOT1	P17174	7
HLA-DRB5	Q30154	4
TG	P01266	3
POGZ	Q7Z3K3	3
CHD7	Q9P2D1	3
NAA25	Q14CX7	3
FOXA2	Q9Y261	3
IGFBP5	P24593	3
SSTR4	P31391	2
BACH2	Q9BYV9	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HLA-DQA2	P01906	89.29
ZDHHC21	Q8IVQ6	87.81
TPO	P07202	84.00
TRPC4AP	Q8TEL6	82.81
TEX47	Q8TBZ9	80.47
C1QTNF6	Q9BXI9	77.42
BRAP	Q7Z569	76.92
PDE8B	O95263	74.88
CCDC186	Q7Z3E2	74.62
SPATA13	Q96N96	72.49
MICOS10	Q5TGZ0	72.13
SAMD5	Q5TGI4	71.96
RTKN2	Q8IZC4	70.33
HCG22	E2RYF7	69.41
TRMO	Q9BU70	67.98
SH2B3	Q9UQQ2	63.45
RSBN1	Q5VWQ0	62.96
FOXE1	O00358	62.02
PHTF1	Q9UMS5	62.01
TNP1	P09430	61.97
NKX2-3	Q8TAU0	60.75
TNFRSF19	Q9NS68	60.50
ADNP	Q9H2P0	57.07
LINC03040	Q8N319	49.90
C6orf15	Q6UXA7	43.65
ZNF804B	A4D1E1	43.04
ZNF365	Q70YC4	30.21
HECTD4	Q9Y4D8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 321. Enrichment computed across 79 evidence-associated genes (47 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 47 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	5	67.5×	3e-06	HLA-DQA1, HLA-DQA2, HLA-DRB1, HLA-DRB5, PTPN22
Phosphorylation of CD3 and TCR zeta chains	5	57.9×	3e-06	HLA-DQA1, HLA-DQA2, HLA-DRB1, HLA-DRB5, PTPN22
Co-inhibition by PD-1	5	55.2×	3e-06	HLA-DQA1, HLA-DQA2, HLA-DRB1, HLA-DRB5, PTPN11
Interferon gamma signaling	7	18.7×	6e-06	HLA-B, HLA-C, HLA-DQA1, HLA-DQA2, HLA-DQB1, HLA-DRB1, HLA-DRB5
Generation of second messenger molecules	4	29.4×	6e-04	HLA-DQA1, HLA-DQA2, HLA-DRB1, HLA-DRB5
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	5	10.3×	0.006	ERBB3, ICOS, INSR, NRG1, PTPN11
MHC class II antigen presentation	5	9.5×	0.008	CAPZB, HLA-DQA1, HLA-DQA2, HLA-DRB1, HLA-DRB5
GRB7 events in ERBB2 signaling	2	81.0×	0.010	ERBB3, NRG1
Downstream TCR signaling	4	10.9×	0.016	HLA-DQA1, HLA-DQA2, HLA-DRB1, HLA-DRB5
Constitutive Signaling by Aberrant PI3K in Cancer	4	10.8×	0.016	ERBB3, ICOS, NRG1, PTPN11
PIP3 activates AKT signaling	5	7.1×	0.019	ERBB3, ICOS, INSR, NRG1, PTPN11
RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs)	2	48.6×	0.020	CR1, CTLA4
Endosomal/Vacuolar pathway	2	44.2×	0.022	HLA-B, HLA-C
Downregulation of ERBB2:ERBB3 signaling	2	34.7×	0.031	ERBB3, NRG1
ERBB2 Activates PTK6 Signaling	2	34.7×	0.031	ERBB3, NRG1
ERBB2 Regulates Cell Motility	2	30.4×	0.038	ERBB3, NRG1
PI3K events in ERBB2 signaling	2	28.6×	0.041	ERBB3, NRG1
Defective SLC33A1 causes spastic paraplegia 42 (SPG42)	1	243.0×	0.060	SLC33A1
Co-inhibition by CTLA4	2	22.1×	0.060	CTLA4, PTPN11
SHC1 events in ERBB2 signaling	2	20.2×	0.060	ERBB3, NRG1
DAP12 interactions	2	20.2×	0.060	HLA-B, HLA-C
Signaling by ERBB2 TMD/JMD mutants	2	20.2×	0.060	ERBB3, NRG1
Interferon alpha/beta signaling	3	9.7×	0.060	HLA-B, HLA-C, PTPN11
Signaling by ERBB2 KD Mutants	2	18.0×	0.073	ERBB3, NRG1
Antigen Presentation: Folding, assembly and peptide loading of class I MHC	2	16.8×	0.081	HLA-B, HLA-C
Downregulation of ERBB2 signaling	2	16.2×	0.083	ERBB3, NRG1
RAF/MAP kinase cascade	4	5.2×	0.085	BRAP, ERBB3, NRG1, RET
Signaling by ERBB2	2	14.7×	0.089	ERBB3, NRG1
FLT3 Signaling	2	14.7×	0.089	SH2B3, PTPN11
GPVI-mediated activation cascade	2	13.1×	0.108	VAV3, PTPN11

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 67 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
peptide antigen assembly with MHC class II protein complex	5	78.6×	3e-06	HLA-DQA1, HLA-DQA2, HLA-DQB1, HLA-DRB1, HLA-DRB5
positive regulation of T cell activation	6	39.7×	3e-06	CCL2, HLA-DQA1, HLA-DQA2, HLA-DQB1, HLA-DRB1, HLA-DRB5
antigen processing and presentation of exogenous peptide antigen via MHC class II	5	40.6×	3e-05	HLA-DQA1, HLA-DQA2, HLA-DQB1, HLA-DRB1, HLA-DRB5
positive regulation of immune response	5	35.9×	5e-05	HLA-DQA1, HLA-DQA2, HLA-DQB1, HLA-DRB1, HLA-DRB5
lamellipodium assembly	4	26.5×	0.002	VAV3, CAPZB, CDH13, SPATA13
adaptive immune response	7	8.8×	0.002	CTLA4, HLA-B, HLA-C, HLA-DQA1, HLA-DQA2, HLA-DQB1, HLA-DRB5
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	7	8.2×	0.002	VAV3, VEGFA, ERBB3, IGFBP5, INSR, PTPN11, RET
thyroid hormone generation	3	44.4×	0.004	TG, TPO, FOXE1
cranial nerve development	2	167.7×	0.004	CHD7, ERBB3
negative regulation of T cell proliferation	4	19.7×	0.004	CR1, CTLA4, HLA-DRB1, PTPN11
immune response	8	5.6×	0.005	CTLA4, HLA-B, HLA-C, HLA-DQA1, HLA-DQA2, HLA-DQB1, HLA-DRB1, ICOS
ERBB signaling pathway	2	100.6×	0.009	NRG1, PTPN11
negative regulation of secretion	2	100.6×	0.009	ERBB3, NRG1
negative regulation of T cell activation	3	23.6×	0.014	CTLA4, PTPN11, PTPN22
positive regulation of T cell mediated cytotoxicity	3	22.9×	0.014	HLA-B, HLA-C, HLA-DRB1
macrophage differentiation	3	21.0×	0.018	VEGFA, HLA-DRB1, NKX2-3
cAMP catabolic process	2	55.9×	0.023	PDE10A, PDE8B
response to carbohydrate	2	50.3×	0.025	ADNP, GOT1
ERBB2-ERBB3 signaling pathway	2	50.3×	0.025	ERBB3, NRG1
genitalia development	2	50.3×	0.025	CHD7, PTPN11
positive regulation of lipopolysaccharide-mediated signaling pathway	2	45.7×	0.025	SASH1, PTPN11
atrioventricular canal development	2	45.7×	0.025	CHD7, PTPN11
heart morphogenesis	3	16.8×	0.025	VEGFA, CHD7, INSR
negative regulation of T cell receptor signaling pathway	3	16.4×	0.025	CTLA4, PTPN11, PTPN22
detection of bacterium	2	41.9×	0.026	HLA-B, HLA-DRB1
hormone biosynthetic process	2	41.9×	0.026	TG, TPO
positive regulation of positive chemotaxis	2	41.9×	0.026	VEGFA, CDH13
T cell receptor signaling pathway	4	9.1×	0.026	CTLA4, HLA-DQB1, HLA-DRB1, PTPN22
antigen processing and presentation of endogenous peptide antigen via MHC class Ib	2	38.7×	0.027	HLA-B, HLA-C
antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway, TAP-independent	2	38.7×	0.027	HLA-B, HLA-C

Therapeutics

Drugs indicated for this disease

4 approved, 2 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Cholestyramine	Approved (phase 4)
Fenofibrate	Approved (phase 4)
Mecasermin	Approved (phase 4)
OMEGA-3-ACID ETHYL ESTERS	Approved (phase 4)
Levothyroxine	Phase 3 (in late-stage trials)
Liothyronine	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Thyroid.

Drug target analysis

Approved (phase 4): 11 · Phase ≥3: 12 · Phased (≥1): 13 · Undrugged: 62

Druggability breadth: 36 of 79 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
RPS26	GENTAMICIN SULFATE
SSTR4	OCTREOTIDE
TPO	PROPYLTHIOURACIL
VEGFA	VADADUSTAT
TET1	VADADUSTAT
ERBB3	MOBOCERTINIB
GOT1	ADAPALENE
INSR	FEDRATINIB
MYT1	DASATINIB ANHYDROUS
NR3C2	PROGESTERONE
PDE10A	VARDENAFIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
INSR	36	4
NR3C2	24	4
ERBB3	23	4
PDE10A	16	4
SSTR4	6	4
VEGFA	5	4
GOT1	4	4
MYT1	4	4
TPO	3	4
CCL2	2	3

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
GENTAMICIN SULFATE	4	RPS26
OCTREOTIDE	4	SSTR4
GALLIUM OXODOTREOTIDE	4	SSTR4
PROPYLTHIOURACIL	4	TPO
VADADUSTAT	4	TET1, VEGFA
BELZUTIFAN	4	VEGFA
PANOBINOSTAT	4	TET1
MOBOCERTINIB	4	ERBB3
AFATINIB	4	ERBB3
NERATINIB	4	ERBB3, INSR
VANDETANIB	4	ERBB3
BOSUTINIB	4	ERBB3
OSIMERTINIB	4	ERBB3, INSR
DASATINIB	4	ERBB3, MYT1
ERLOTINIB	4	ERBB3
LAPATINIB	4	ERBB3, INSR
GEFITINIB	4	ERBB3
ADAPALENE	4	GOT1
HYDRALAZINE	4	GOT1
HYDRALAZINE HYDROCHLORIDE	4	GOT1
ZIPRASIDONE	4	GOT1
FEDRATINIB	4	INSR
SORAFENIB	4	INSR
INFIGRATINIB PHOSPHATE	4	INSR
INFIGRATINIB	4	INSR
ENTRECTINIB	4	INSR
CERITINIB	4	INSR
BRIGATINIB	4	INSR
NINTEDANIB	4	INSR
SUNITINIB	4	INSR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 8.

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

Symbol	Assays	Type breakdown
INSR	954	Binding:900, Functional:49, ADMET:4, Toxicity:1
PDE10A	357	Binding:345, ADMET:9, Functional:3
NR3C2	286	Binding:195, Functional:89, ADMET:2
SSTR4	174	Binding:153, Functional:19, ADMET:2
ERBB3	169	Binding:169
RPS26	89	Binding:89
VEGFA	64	Binding:64
PDE8B	35	Binding:33, ADMET:1, Functional:1
TET1	28	Binding:28
CCL2	24	Binding:24
IGFBP5	24	Binding:24
GOT1	19	Binding:19
HLA-DRB1	17	Binding:17
TPO	12	Binding:12
GNB1	12	Binding:12
CAPZB	9	Binding:9
MYT1	9	Binding:9
FMNL1	7	Binding:7
ICOS	7	Binding:7
XPA	6	Binding:6
ATXN2	5	Binding:3, Functional:2
HUWE1	4	Binding:3, Functional:1
BACH2	3	Binding:3
ZBTB10	3	Binding:3
BRAP	2	Binding:2
HLA-DQA1	2	Binding:2
CTLA4	1	Binding:1
MICOS10	1	Binding:1
HLA-B	1	Binding:1
HLA-C	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TPO	1.11.1.8, 3.6.1.52	iodide peroxidase, diphosphoinositol-polyphosphate diphosphatase
NAA25	2.3.1.254	N-terminal methionine Nalpha-acetyltransferase NatB
HUWE1	2.3.2.26	HECT-type E3 ubiquitin transferase
ERBB3	2.7.10.1	receptor protein-tyrosine kinase
GOT1	2.6.1.1, 2.6.1.64	aspartate transaminase, glutamine-phenylpyruvate transaminase
INSR	2.7.10.1	receptor protein-tyrosine kinase
PDE10A	3.1.4.17	3’,5’-cyclic-nucleotide phosphodiesterase
PDE8B	3.1.4.53	3’,5’-cyclic-AMP phosphodiesterase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SSTR4	174
ERBB3	169
INSR	954
NR3C2	286
PDE10A	357

Pharmacogenomics

Cohort genes with a PharmGKB record: 72; 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)
GENTAMICIN SULFATE	4	RPS26
OCTREOTIDE	4	SSTR4
GALLIUM OXODOTREOTIDE	4	SSTR4
PROPYLTHIOURACIL	4	TPO
VADADUSTAT	4	TET1, VEGFA
BELZUTIFAN	4	VEGFA
PANOBINOSTAT	4	TET1
MOBOCERTINIB	4	ERBB3
AFATINIB	4	ERBB3
NERATINIB	4	ERBB3, INSR
VANDETANIB	4	ERBB3
BOSUTINIB	4	ERBB3
OSIMERTINIB	4	ERBB3, INSR
DASATINIB	4	ERBB3, MYT1
ERLOTINIB	4	ERBB3
LAPATINIB	4	ERBB3, INSR
GEFITINIB	4	ERBB3
ADAPALENE	4	GOT1
HYDRALAZINE	4	GOT1
HYDRALAZINE HYDROCHLORIDE	4	GOT1
ZIPRASIDONE	4	GOT1
FEDRATINIB	4	INSR
SORAFENIB	4	INSR
INFIGRATINIB PHOSPHATE	4	INSR
INFIGRATINIB	4	INSR
ENTRECTINIB	4	INSR
CERITINIB	4	INSR
BRIGATINIB	4	INSR
NINTEDANIB	4	INSR
SUNITINIB	4	INSR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	11	RPS26, SSTR4, TPO, VEGFA, TET1, ERBB3, GOT1, INSR, MYT1, NR3C2 (+1 more)
B	Phased (≥1) drug, not yet approved	2	CCL2, GNB1
C	Druggable family + PDB, no drug	12	CR1, CTLA4, NAA25, HUWE1, HLA-B, HLA-C, HLA-DQA1, HLA-DQB1, HLA-DRB1, HLA-DRB5 (+2 more)
D	Druggable family + AlphaFold only, no drug	1	HLA-DQA2
E	Difficult family or no structure, no drug	49	TG, TRPC4AP, SACS, ATXN2, BRAP, TNFRSF19, TNP1, FMNL1, VAV3, XPA (+39 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TG	0	TPO
NRG1	0	ERBB3
TRPC4AP	0	—
SACS	0	—
ATXN2	5	—
BRAP	2	—
TNFRSF19	0	—
TNP1	0	—
FMNL1	7	—
VAV3	0	—
XPA	6	—
SNTG2	0	—
C6orf15	0	—
BACH2	3	—
C1QTNF6	0	—
CAPZB	9	—
ADNP	0	—
CDH13	0	—
ARID1B	0	—
ZNF365	0	—
POGZ	0	—
SASH1	0	—
RTKN2	0	—
CHD7	0	—
ZDHHC21	0	—
SAMD5	0	—
ZNF804B	0	—
TEX47	0	—
SPATA13	0	—
CR1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 138.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	99
PHASE4	23
PHASE2	10
PHASE2/PHASE3	4
PHASE3	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06073665	PHASE4	RECRUITING	Dosing of LT4 in Older Individuals
NCT00001730	PHASE4	COMPLETED	Study of Radioiodine (131-I) Uptake Following Administration of Thyrogen and Hypothyroid States During Thyroid Hormone Withdrawal.
NCT00111735	PHASE4	UNKNOWN	Thyroxine Titration Study
NCT00206375	PHASE4	TERMINATED	Growth Hormone and GnRH Agonist in Adolescents With Acquired Hypothyroidism
NCT00565864	PHASE4	COMPLETED	Neurocognitive and Metabolic Effects of Mild Hypothyroidism
NCT01379170	PHASE4	UNKNOWN	Thyroid Study Type 2 Diabetes Mellitus (T2DM)
NCT01536678	PHASE4	COMPLETED	Bioequivalence of Two Levothyroxine Tablet Formulations in Healthy Indian Volunteers
NCT01647750	PHASE4	COMPLETED	Study of Optimal Replacement of Thyroxine in the Elderly
NCT01769157	PHASE4	COMPLETED	Effects of L-carnitine on Hypothyroidism
NCT01831869	PHASE4	UNKNOWN	Effect of L-Thyroxine on Lipid Profiles and Atherosclerosis in Subclinical Hypothyroidism
NCT01848171	PHASE4	UNKNOWN	Effects of L-thyroxine Replacement on Serum Lipid and Atherosclerosis in Hypothyroidism
NCT01921452	PHASE4	COMPLETED	Study to Verify Clinical Utility of Point-of-Care (POC) Thyroid Stimulating Hormone (TSH) Test Kits as Compared to Third Generation TSH Test Kit
NCT02280330	PHASE4	COMPLETED	Iodine Status of Preschoolers Given Micronutrient Powder for 6 Months
NCT02512978	PHASE4	UNKNOWN	Thyroid Hormone Replacement for Hypothyroidism and Acute Myocardial Infarction(ThyroHeart-AMI)
NCT02577367	PHASE4	WITHDRAWN	Mean Percentage of Levothyroxine Dosage Increase in Patients With Hypothyroidism Started on Enteral Feeding
NCT02917863	PHASE4	UNKNOWN	Randomized Crossover Trial for the Evaluation of the Possible Effects in the Intestine of Two Different Pharmaceutical Forms of L - Thyroxine in Patients With Primary Acquired Hypothyroidism
NCT03342001	PHASE4	COMPLETED	Hypothyroidism Treated With Calcitonin
NCT03631771	PHASE4	WITHDRAWN	Pediatric Risk of Hypothyroidism With Iodinated Contrast Media
NCT03779906	PHASE4	TERMINATED	Thyroid Function of Pediatric Subjects Following Isovue® Administration
NCT04747275	PHASE4	TERMINATED	Use of Liquid Stable Levothyroxine in Trisomy 21 Pediatric Patients
NCT04878614	PHASE4	TERMINATED	Comparison of Levothyroxine Formulation in Hypothyroid Patients With Enteral Feeding
NCT05247476	PHASE4	UNKNOWN	Type 2 Deiodinase Gene Polymorphism and the Treatment of Hypothyroidism Caused by Thyroidectomy in Thyroid Cancer Patients.
NCT06096454	PHASE4	UNKNOWN	Effect of Life Style Modification and Metformin on Hypothyroidism With Insulin Resistance
NCT06345339	PHASE2/PHASE3	RECRUITING	A Study to Assess the Safety and Efficacy of Oral Armour Thyroid Compared to Synthetic T4 for the Treatment of Primary Hypothyroidism in Adult Participants
NCT06731764	PHASE2/PHASE3	RECRUITING	Novel Approaches to the Treatment of Hypothyroidism
NCT01204359	PHASE3	UNKNOWN	The Prospective Study of Standard Treatment of Graves Disease Iodine 131 and Prevention of Adverse Reactions
NCT02548715	PHASE2/PHASE3	WITHDRAWN	Levothyroxine Treatment for Subclinical Hypothyroidism After Head and Neck Surgery
NCT03053115	PHASE2/PHASE3	COMPLETED	Combined Replacement Therapy With Levothyroxine and Liothyronine in Thyroidectomized Patients
NCT01800617	PHASE2	COMPLETED	A Study of T3 Therapy in Patients With Hypothyroidism
NCT01916304	PHASE2	COMPLETED	Study of Dose Adjustment From Levothyroxine to a New Levothyroxine Sodium Test Formulation
NCT03627611	PHASE2	COMPLETED	Identification of Non-responders to Levothyroxine Therapy
NCT04124705	PHASE2	COMPLETED	A Study of Armour® Thyroid Compared to Synthetic T4 (Levothyroxine) in Previously Hypothyroid Participants
NCT04782856	PHASE2	COMPLETED	Energy Metabolism in Thyroidectomized Patients
NCT05412979	PHASE2	COMPLETED	A Study Evaluating the Safety and Efficacy of Hormone Replacement Therapy With ST-1891 Compared to Levothyroxine in Patients With Primary Hypothyroidism
NCT05712421	PHASE2	COMPLETED	A Study Evaluation the Safety and Efficacy of Hormone Replacement Therapy With North Star Compared to Levothyroxine in Patients With Primary Hypothyroidism
NCT05733078	PHASE2	UNKNOWN	Effect of Vitamin C Supplementation in Patients With Primary Hypothyroidism
NCT05804149	PHASE2	COMPLETED	Effect of Acupuncture and Low Caloric Diet on Primary Hypothyroidism and Irregular Menstruation in Infertile Women
NCT05823012	PHASE2	COMPLETED	Study of XP-8121 For the Treatment of Adult Subjects With Hypothyroidism
NCT06826248	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Clinical Efficacy of Darqeen Capsule for the Management of Hypothyroidism Associated with Female Reproductive Hormonal Imbalance
NCT00001159	Not specified	RECRUITING	Natural History of Thyroid Function Disorders

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
LEVOTHYROXINE	4	42
LIOTHYRONINE	4	7
IOPAMIDOL	4	2
CALCITONIN	4	1
IODIXANOL	4	1
IOHEXOL	4	1
IOPROMIDE	4	1
IOVERSOL	4	1
LEVOCARNITINE	4	1
SOMATROPIN	4	1
THYROTROPIN ALFA	4	1
THYROID	3	3
BIFIDOBACTERIUM SPP.	3	1
IODINE	3	1
RATHYRONINE	2	1
CHEMBL4778520	0	4
THYROXINE	0	4
CHEMBL1335195	0	1
CHEMBL1397069	0	1
CHEMBL1434196	0	1