Allergic disease

Summary

Allergic disease (MONDO:0005271) is a disease (an umbrella term covering 12 Mondo subtypes) with 75 cohort genes (403 GWAS associations across 21 studies) and 346 clinical trials. The dominant Reactome pathway is Formation of the cornified envelope (27 cohort genes). Top therapeutic interventions include omalizumab, albuterol, and brompheniramine.

At a glance

• Umbrella term: 12 Mondo subtypes
• Cohort genes: 75
• GWAS associations: 403
• ClinVar variants: 4
• Clinical trials: 346

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	allergic disease
Mondo ID	MONDO:0005271
MeSH	D006967
DOID	DOID:1205
NCIT	C114476
SNOMED CT	609328004
UMLS	C0020517
MedGen	9370
Is cancer (heuristic)	no

Also known as: allergic disease or disorder · allergic form of disease or disorder · allergic form of immune system disease · allergic reaction · allergic response · allergy · disorder of type I hypersensitivity · type I hypersensitivity disease

Data availability: 4 ClinVar variants · 403 GWAS associations (21 studies).

Disease family

An umbrella term covering 12 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › immune system disorder › hypersensitivity reaction disease › allergic disease

Related subtypes (9): type IV hypersensitivity disease, hypersensitivity vasculitis, type III hypersensitivity disease, IgE responsiveness, atopic, immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome, progestogen hypersensitivity, type II hypersensitivity reaction disease, pseudoallergy, anaphylaxis

Subtypes (12): allergic respiratory disease, drug allergy, gastrointestinal allergy, latex allergy, atopic eczema, atopic IgE-mediated allergic disorder, eye allergy, vulvovaginitis, allergic seminal, allergic otitis media, alpha-gal syndrome, venom allergy, food allergy

Genetics & variants

GWAS landscape

403 GWAS associations across 21 studies. Top hits map to 21 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs61816761	3e-82	FLG, CCDST	A	0.27
rs7936323	2e-63	EMSY - LINC02757	A	1.09
rs10865050	7e-61	IL1RL1, IL18R1	G	1.13
rs5743618	3e-58	TLR1	C	1.1
rs34004019	4e-52	HLA-DQA1 - HLA-DQB1	A	1.1
rs12123821	3e-48	CCDST	T	0.14
rs115045402	2e-47	S100A11 - SPTLC1P4	A	0.2
rs6594499	5e-46	WDR36 - RPS3AP21	C	1.07
rs55646091	2e-40	EMSY - LINC02757	A	1.18
rs6531663	3e-38	TLR1	T	0.07
rs11644510	6e-38	CLEC16A - HNRNPCP4	C	1.07
rs7717955	9e-36	IL7R	C	1.07
rs144829310	1e-35	GTF3AP1 - IL33	T	1.09
rs9273374	8e-35	HLA-DQA1 - HLA-DQB1	?	1.19
rs4795400	7e-34	GSDMB	C	0.05
rs72823628	2e-33	IL1RL1, IL18R1	G	0.08
rs34290285	4e-33	D2HGDH	G	1.08
rs56375023	8e-32	SMAD3	A	1.07
rs1837253	2e-31	BCLAF1P1 - TSLP	C	1.07
rs10174949	7e-31	LINC00299	G	1.07
rs921650	6e-30	GSDMB	A	1.06
rs6869502	6e-29	SLC25A46 - BCLAF1P1	T	1.08
rs793607	3e-28	CCDC54-AS1, DUBR	?	1.08
rs11236791	4e-28	EMSY - LINC02757	A	0.05
rs184587444	4e-28	SPRR2B - SPRR2E	T	0.19
rs6905282	5e-28	HLA-DQA1 - HLA-DQB1	A	0.05
rs12413578	1e-27	LINC02676 - LINC00709	C	1.09
rs72823641	2e-27	IL18R1, IL1RL1	?	1.12
rs950881	6e-27	IL1RL1, IL18R1	?	1.12
rs4145717	9e-27	ADAD1	T	1.06

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90044359	Jiang L	2021	309,586	145,863	A generalized linear mixed model association tool for biobank-scale data.
GCST007732	Ferreira MA	2018	180,129	180,709	Eleven loci with new reproducible genetic associations with allergic disease risk.
GCST005038	Ferreira MA	2017	180,129	180,709	Shared genetic origin of asthma, hay fever and eczema elucidates allergic disease biology.
GCST90081451	Backman JD	2021	73,382	280,642	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90085437	Backman JD	2021	73,382	280,642	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST003990	Pickrell JK	2016	66,973	113,768	Detection and interpretation of shared genetic influences on 42 human traits.
GCST90038661	Donertas HM	2021	35,890	448,708	Common genetic associations between age-related diseases.
GCST007563	Zhu Z	2018	25,685	76,768	A genome-wide cross-trait analysis from UK Biobank highlights the shared genetic architecture of asthma and allergic diseases.
GCST007564	Zhu Z	2018	14,085	76,768	A genome-wide cross-trait analysis from UK Biobank highlights the shared genetic architecture of asthma and allergic diseases.
GCST90018881	Sakaue S	2021	2,409	350,904	A cross-population atlas of genetic associations for 220 human phenotypes.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	2
Tier 2: splice/UTR	2
Tier 3: regulatory	6
Tier 4: intronic/intergenic	40

MAF distribution

Bucket	Variants
common (>=0.05)	43
low_freq (0.01-0.05)	5
rare (<0.01)	1
unknown	1

Functional consequences

Consequence	Count
intron_variant	22
intergenic_variant	17
regulatory_region_variant	6
3_prime_UTR_variant	2
stop_gained	1
missense_variant	1
unknown	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs61816761	1	152313385	G>A,C,T	0.026	stop_gained	FLG, CCDST	3e-82	Tier 1: coding
rs7936323	11	76582714	G>A	0.46	intergenic_variant	EMSY - LINC02757	2e-63	Tier 4: intronic/intergenic
rs10865050	2	102324851	G>A	0.15	intron_variant	IL1RL1, IL18R1	7e-61	Tier 4: intronic/intergenic
rs5743618	4	38797027	C>A,G	0.3	missense_variant	TLR1	3e-58	Tier 1: coding
rs34004019	6	32658626	A>G	0.3	intergenic_variant	HLA-DQA1 - HLA-DQB1	4e-52	Tier 4: intronic/intergenic
rs12123821	1	152206676	C>T	0.051	intron_variant	CCDST	3e-48	Tier 4: intronic/intergenic
rs115045402	1	152057072	G>A	0.028	intron_variant	S100A11 - SPTLC1P4	2e-47	Tier 4: intronic/intergenic
rs6594499	5	111134439	C>A	0.48	regulatory_region_variant	WDR36 - RPS3AP21	5e-46	Tier 3: regulatory
rs55646091	11	76588387	G>A	0.05	regulatory_region_variant	EMSY - LINC02757	2e-40	Tier 3: regulatory
rs6531663	4	38790719	T>A,C,G	0.192	intergenic_variant	TLR1	3e-38	Tier 4: intronic/intergenic
rs11644510	16	11183501	C>T	0.36	regulatory_region_variant	CLEC16A - HNRNPCP4	6e-38	Tier 3: regulatory
rs7717955	5	35862739	C>T	0.29	intron_variant	IL7R	9e-36	Tier 4: intronic/intergenic
rs144829310	9	6208030	G>T	0.16	intergenic_variant	GTF3AP1 - IL33	1e-35	Tier 4: intronic/intergenic
rs9273374	6	32658837	A>C,G,T	0.05	intergenic_variant	HLA-DQA1 - HLA-DQB1	8e-35	Tier 4: intronic/intergenic
rs4795400	17	39910767	C>T	0.459	intron_variant	GSDMB	7e-34	Tier 4: intronic/intergenic
rs72823628	2	102312157	G>A,T	0.126	intron_variant	IL1RL1, IL18R1	2e-33	Tier 4: intronic/intergenic
rs34290285	2	241759225	G>A	0.27	intron_variant	D2HGDH	4e-33	Tier 4: intronic/intergenic
rs56375023	15	67156025	G>A	0.21	intron_variant	SMAD3	8e-32	Tier 4: intronic/intergenic
rs1837253	5	111066174	T>C	0.22	intron_variant	BCLAF1P1 - TSLP	2e-31	Tier 4: intronic/intergenic
rs10174949	2	8302118	G>A,T	0.32	regulatory_region_variant	LINC00299	7e-31	Tier 3: regulatory
rs921650	17	39912823	G>A	0.48	intron_variant	GSDMB	6e-30	Tier 4: intronic/intergenic
rs6869502	5	110830384	A>G,T	0.18	intergenic_variant	SLC25A46 - BCLAF1P1	6e-29	Tier 4: intronic/intergenic
rs793607	3	107340876			intron_variant	CCDC54-AS1, DUBR	3e-28	Tier 4: intronic/intergenic
rs11236791	11	76584554	G>A,C,T	0.469	intergenic_variant	EMSY - LINC02757	4e-28	Tier 4: intronic/intergenic
rs184587444	1	153079185	C>T	0.02	intron_variant	SPRR2B - SPRR2E	4e-28	Tier 4: intronic/intergenic
rs6905282	6	32658238	C>A,G,T	0.466	intergenic_variant	HLA-DQA1 - HLA-DQB1	5e-28	Tier 4: intronic/intergenic
rs12413578	10	9007290	C>G,T	0.1	intron_variant	LINC02676 - LINC00709	1e-27	Tier 4: intronic/intergenic
rs72823641	2	102319699	T>A,C	0.05	intron_variant	IL18R1, IL1RL1	2e-27	Tier 4: intronic/intergenic
rs950881	2	102316052	G>A,C,T	0.05	intron_variant	IL1RL1, IL18R1	6e-27	Tier 4: intronic/intergenic
rs4145717	4	122394921	G>A,C,T	0.34	intron_variant	ADAD1	9e-27	Tier 4: intronic/intergenic

ClinVar germline variants

4 retrieved; paginated sample, class counts are floors:

2 likely pathogenic, 2 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
267892	46;XX;t(4;14)(p15.2;q13)dn		Likely pathogenic	criteria provided, single submitter
4686670	NM_003238.6(TGFB2):c.593G>A (p.Trp198Ter)	TGFB2	Likely pathogenic	criteria provided, single submitter
523282	GRCh37/hg19 6p24.1-23(chr6:12536624-13968949)	RNF182	Uncertain significance	criteria provided, single submitter
523398	NM_001379110.1(SLC9A6):c.1190C>A (p.Ala397Glu)	SLC9A6	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 54 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BCL6	Orphanet:480541	High grade B-cell lymphoma with MYC and/ or BCL2 and/or BCL6 rearrangement
BCL6	Orphanet:545	Follicular lymphoma
BCL6	Orphanet:98838	Primary mediastinal large B-cell lymphoma
BCL6	Orphanet:98839	Intravascular large B-cell lymphoma
RORA	Orphanet:528084	Non-specific syndromic intellectual disability
RORC	Orphanet:477857	Mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency
RPL5	Orphanet:124	Diamond-Blackfan anemia
RPS26	Orphanet:124	Diamond-Blackfan anemia
RUNX1	Orphanet:102724	Acute myeloid leukemia with t(8;21)(q22;q22) translocation
RUNX1	Orphanet:521	Chronic myeloid leukemia
RUNX1	Orphanet:71290	Familial platelet disorder with associated myeloid malignancy
RUNX1	Orphanet:98850	Aggressive systemic mastocytosis
ATXN2	Orphanet:803	Amyotrophic lateral sclerosis
ATXN2	Orphanet:98756	Spinocerebellar ataxia type 2
SFPQ	Orphanet:319308	MiT family translocation renal cell carcinoma
SLC22A5	Orphanet:158	Systemic primary carnitine deficiency
SLC9A6	Orphanet:85278	Christianson syndrome
SMARCE1	Orphanet:1465	Coffin-Siris syndrome
SMARCE1	Orphanet:2495	Meningioma
SMARCE1	Orphanet:263662	Familial multiple meningioma
SIK1	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
SIK1	Orphanet:697160	Infantile epileptic spasms syndrome
STAT5B	Orphanet:220465	Laron syndrome with immunodeficiency
STAT5B	Orphanet:520	Acute promyelocytic leukemia
STAT6	Orphanet:2126	Solitary fibrous tumor
SUOX	Orphanet:99731	Isolated sulfite oxidase deficiency
TAC3	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
TCAP	Orphanet:154	Familial isolated dilated cardiomyopathy
TCAP	Orphanet:34514	Telethonin-related limb-girdle muscular dystrophy R7
TGFB2	Orphanet:60030	Loeys-Dietz syndrome
TGFB2	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
TNFAIP3	Orphanet:536	Systemic lupus erythematosus
TNFAIP3	Orphanet:674762	Early-onset autoinflammatory syndrome due to A20 haploinsufficiency
TNFRSF11A	Orphanet:1782	Dysosteosclerosis
TNFRSF11A	Orphanet:178389	Osteopetrosis-hypogammaglobulinemia syndrome
TNFRSF11A	Orphanet:2801	Juvenile Paget disease
TNFRSF11A	Orphanet:391490	Adult-onset myasthenia gravis
TNFRSF11A	Orphanet:85195	Familial expansile osteolysis
TNFSF11	Orphanet:667	Autosomal recessive malignant osteopetrosis
TNFSF4	Orphanet:2073	Narcolepsy type 1
TNFSF4	Orphanet:536	Systemic lupus erythematosus
FASLG	Orphanet:3261	Autoimmune lymphoproliferative syndrome
TRAF3	Orphanet:1930	Herpes simplex virus encephalitis
IKZF1	Orphanet:317473	Common variable immunodeficiency phenotype due to IKAROS functional haploinsufficiency
IKZF1	Orphanet:36426	Stevens-Johnson syndrome
IKZF1	Orphanet:585909	B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2)
IKZF1	Orphanet:695172	Combined immunodeficiency due to dimerization defective IKAROS mutation
IKZF1	Orphanet:697414	Early-onset combined immunodeficiency with low Ig due to dominant negative IKAROS mutation
IKZF3	Orphanet:67038	B-cell chronic lymphocytic leukemia
IKZF3	Orphanet:699590	Immune dysregulation with immunodeficiency due to AIOLOS haploinsufficiency

Cohort genes → proteins

75 cohort genes, 73 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	73
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BCL6	HGNC:1001	ENSG00000113916	P41182	B-cell lymphoma 6 protein	gwas
SNORD21	HGNC:10144	ENSG00000206680		small nucleolar RNA, C/D box 21	gwas
SNORA66	HGNC:10223	ENSG00000207523		small nucleolar RNA, H/ACA box 66	gwas
RORA	HGNC:10258	ENSG00000069667	P35398	Nuclear receptor ROR-alpha	gwas
RORC	HGNC:10260	ENSG00000143365	P51449	Nuclear receptor ROR-gamma	gwas
RPL41	HGNC:10354	ENSG00000229117	P62945	Small ribosomal subunit protein eS32	gwas
RPL5	HGNC:10360	ENSG00000122406	P46777	Large ribosomal subunit protein uL18	gwas
RPS26	HGNC:10414	ENSG00000197728	P62854	Small ribosomal subunit protein eS26	gwas
RUNX1	HGNC:10471	ENSG00000159216	Q01196	Runt-related transcription factor 1	gwas
RUNX3	HGNC:10473	ENSG00000020633	Q13761	Runt-related transcription factor 3	gwas
RYBP	HGNC:10480	ENSG00000163602	Q8N488	RING1 and YY1-binding protein	gwas
S100A11	HGNC:10488	ENSG00000163191	P31949	Protein S100-A11	gwas
ATXN2	HGNC:10555	ENSG00000204842	Q99700	Ataxin-2	gwas
CXCR5	HGNC:1060	ENSG00000160683	P32302	C-X-C chemokine receptor type 5	gwas
CCL20	HGNC:10619	ENSG00000115009	P78556	C-C motif chemokine 20	gwas
SFPQ	HGNC:10774	ENSG00000116560	P23246	Splicing factor, proline- and glutamine-rich	gwas
SLC15A2	HGNC:10921	ENSG00000163406	Q16348	Solute carrier family 15 member 2	gwas
SLC22A4	HGNC:10968	ENSG00000197208	Q9H015	Solute carrier family 22 member 4	gwas
SLC22A5	HGNC:10969	ENSG00000197375	O76082	Organic cation/carnitine transporter 2	gwas
SLC7A10	HGNC:11058	ENSG00000130876	Q9NS82	Asc-type amino acid transporter 1	gwas
SLC9A2	HGNC:11072	ENSG00000115616	Q9UBY0	Sodium/hydrogen exchanger 2	gwas
SLC9A4	HGNC:11077	ENSG00000180251	Q6AI14	Sodium/hydrogen exchanger 4	gwas
SLC9A6	HGNC:11079	ENSG00000198689	Q92581	Sodium/hydrogen exchanger 6	clinvar
SMARCE1	HGNC:11109	ENSG00000073584	Q969G3	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1	gwas
SIK1	HGNC:11142	ENSG00000142178	P57059	Serine/threonine-protein kinase SIK1	gwas
SPRR1A	HGNC:11259	ENSG00000169474	P35321	Cornifin-A	gwas
SPRR1B	HGNC:11260	ENSG00000169469	P22528	Cornifin-B	gwas
SPRR2A	HGNC:11261	ENSG00000241794	P35326	Small proline-rich protein 2A	gwas
SPRR2B	HGNC:11262	ENSG00000196805	P35325	Small proline-rich protein 2B	gwas
SPRR2D	HGNC:11264	ENSG00000163216	P22532	Small proline-rich protein 2D	gwas
SPRR2E	HGNC:11265	ENSG00000203785	P22531	Small proline-rich protein 2E	gwas
SPRR2F	HGNC:11266	ENSG00000244094	Q96RM1	Small proline-rich protein 2F	gwas
SPRR3	HGNC:11268	ENSG00000163209	Q9UBC9	Small proline-rich protein 3	gwas
STAT5B	HGNC:11367	ENSG00000173757	P51692	Signal transducer and activator of transcription 5B	gwas
STAT6	HGNC:11368	ENSG00000166888	P42226	Signal transducer and activator of transcription 6	gwas
SULT1A1	HGNC:11453	ENSG00000196502	P50225	Sulfotransferase 1A1	gwas
SUOX	HGNC:11460	ENSG00000139531	P51687	Sulfite oxidase, mitochondrial	gwas
SURF6	HGNC:11478	ENSG00000148296	O75683	Surfeit locus protein 6	gwas
TAC3	HGNC:11521	ENSG00000166863	Q9UHF0	Tachykinin-3	gwas
TCAP	HGNC:11610	ENSG00000173991	O15273	Telethonin	gwas
CFAP68	HGNC:1163	ENSG00000137720	Q9H5F2	Cilia- and flagella-associated protein 68	gwas
TGFB2	HGNC:11768	ENSG00000092969	P61812	Transforming growth factor beta-2 proprotein	clinvar
TCHH	HGNC:11791	ENSG00000159450	Q07283	Trichohyalin	gwas
TLR1	HGNC:11847	ENSG00000174125	Q15399	Toll-like receptor 1	gwas
TNFAIP3	HGNC:11896	ENSG00000118503	P21580	Tumor necrosis factor alpha-induced protein 3	gwas
TNFRSF11A	HGNC:11908	ENSG00000141655	Q9Y6Q6	Tumor necrosis factor receptor superfamily member 11A	gwas
TNFRSF14	HGNC:11912	ENSG00000157873	Q92956	Tumor necrosis factor receptor superfamily member 14	gwas
TNFRSF6B	HGNC:11921	ENSG00000243509	O95407	Tumor necrosis factor receptor superfamily member 6B	gwas
TNFSF11	HGNC:11926	ENSG00000120659	O14788	Tumor necrosis factor ligand superfamily member 11	gwas
TNFSF18	HGNC:11932	ENSG00000120337	Q9UNG2	Tumor necrosis factor ligand superfamily member 18	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BCL6	B-cell lymphoma 6 protein	Transcriptional repressor mainly required for germinal center (GC) formation and antibody affinity maturation which has different mechanisms of action specific to the lineage and biological functions.
RORA	Nuclear receptor ROR-alpha	Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5’-AGGTCA-3’ preceded by a short A-T-rich sequence.
RORC	Nuclear receptor ROR-gamma	Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5’-AGGTCA-3’ preceded by a short A-T-rich sequence.
RPL41	Small ribosomal subunit protein eS32	Component of the small ribosomal subunit (Ref.8).
RPL5	Large ribosomal subunit protein uL18	Component of the ribosome, a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell.
RPS26	Small ribosomal subunit protein eS26	Component of the small ribosomal subunit.
RUNX1	Runt-related transcription factor 1	Forms the heterodimeric complex core-binding factor (CBF) with CBFB.
RUNX3	Runt-related transcription factor 3	Forms the heterodimeric complex core-binding factor (CBF) with CBFB.
RYBP	RING1 and YY1-binding protein	Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development.
S100A11	Protein S100-A11	Facilitates the differentiation and the cornification of keratinocytes.
ATXN2	Ataxin-2	Involved in EGFR trafficking, acting as negative regulator of endocytic EGFR internalization at the plasma membrane.
CXCR5	C-X-C chemokine receptor type 5	Cytokine receptor that binds to B-lymphocyte chemoattractant (BLC).
CCL20	C-C motif chemokine 20	Acts as a ligand for C-C chemokine receptor CCR6.
SFPQ	Splicing factor, proline- and glutamine-rich	DNA- and RNA binding protein, involved in several nuclear processes.
SLC15A2	Solute carrier family 15 member 2	Proton-coupled amino-acid transporter that transports oligopeptides of 2 to 4 amino acids with a preference for dipeptides.
SLC22A4	Solute carrier family 22 member 4	Transporter that mediates the transport of endogenous and microbial zwitterions and organic cations.
SLC22A5	Organic cation/carnitine transporter 2	Sodium-ion dependent, high affinity carnitine transporter.
SLC7A10	Asc-type amino acid transporter 1	Associates with SLC3A2/4F2hc to form a functional heterodimeric complex that translocates small neutral L- and D-amino acids across the plasma membrane.
SLC9A2	Sodium/hydrogen exchanger 2	Plasma membrane Na(+)/H(+) antiporter.
SLC9A4	Sodium/hydrogen exchanger 4	Electroneutral antiporter that exchanges sodium for protons or ammonium ions at the basolateral membrane of epithelia to regulate cell volume and intracellular pH upon hypertonic conditions.
SLC9A6	Sodium/hydrogen exchanger 6	Endosomal Na(+), K(+)/H(+) antiporter.
SMARCE1	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1	Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
SIK1	Serine/threonine-protein kinase SIK1	Serine/threonine-protein kinase involved in various processes such as cell cycle regulation, gluconeogenesis and lipogenesis regulation, muscle growth and differentiation and tumor suppression.
SPRR1A	Cornifin-A	Cross-linked envelope protein of keratinocytes.
SPRR1B	Cornifin-B	Cross-linked envelope protein of keratinocytes.
SPRR2A	Small proline-rich protein 2A	Gut bactericidal protein that selectively kills Gram-positive bacteria by binding to negatively charged lipids on bacterial membranes, leading to bacterial membrane permeabilization and disruption.
SPRR2B	Small proline-rich protein 2B	Cross-linked envelope protein of keratinocytes.
SPRR2D	Small proline-rich protein 2D	Cross-linked envelope protein of keratinocytes.
SPRR2E	Small proline-rich protein 2E	Cross-linked envelope protein of keratinocytes.
SPRR2F	Small proline-rich protein 2F	Cross-linked envelope protein of keratinocytes.
SPRR3	Small proline-rich protein 3	Cross-linked envelope protein of keratinocytes.
STAT5B	Signal transducer and activator of transcription 5B	Carries out a dual function: signal transduction and activation of transcription.
STAT6	Signal transducer and activator of transcription 6	Carries out a dual function: signal transduction and activation of transcription.
SULT1A1	Sulfotransferase 1A1	Sulfotransferase that utilizes 3’-phospho-5’-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the sulfate conjugation of a wide variety of acceptor molecules bearing a hydroxyl or an amine group.
SUOX	Sulfite oxidase, mitochondrial	Catalyzes the oxidation of sulfite to sulfate, the terminal reaction in the oxidative degradation of sulfur-containing amino acids.
SURF6	Surfeit locus protein 6	Binds to both DNA and RNA in vitro, with a stronger binding capacity for RNA.
TAC3	Tachykinin-3	Tachykinins are active peptides which excite neurons, evoke behavioral responses, are potent vasodilators and secretagogues, and contract (directly or indirectly) many smooth muscles.
TCAP	Telethonin	Muscle assembly regulating factor.
CFAP68	Cilia- and flagella-associated protein 68	Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating.
TGFB2	Transforming growth factor beta-2 proprotein	Precursor of the Latency-associated peptide (LAP) and Transforming growth factor beta-2 (TGF-beta-2) chains, which constitute the regulatory and active subunit of TGF-beta-2, respectively.
TCHH	Trichohyalin	Intermediate filament-associated protein that associates in regular arrays with keratin intermediate filaments (KIF) of the inner root sheath cells of the hair follicle and the granular layer of the epidermis.
TLR1	Toll-like receptor 1	Participates in the innate immune response to microbial agents.
TNFAIP3	Tumor necrosis factor alpha-induced protein 3	Ubiquitin-editing enzyme that contains both ubiquitin ligase and deubiquitinase activities.
TNFRSF11A	Tumor necrosis factor receptor superfamily member 11A	Receptor for TNFSF11/RANKL/TRANCE/OPGL; essential for RANKL-mediated osteoclastogenesis.
TNFRSF14	Tumor necrosis factor receptor superfamily member 14	Receptor for four distinct ligands: The TNF superfamily members TNFSF14/LIGHT and homotrimeric LTA/lymphotoxin-alpha and the immunoglobulin superfamily members BTLA and CD160, altogether defining a complex stimulatory and inhibitory signal…
TNFRSF6B	Tumor necrosis factor receptor superfamily member 6B	Decoy receptor that can neutralize the cytotoxic ligands TNFS14/LIGHT, TNFSF15 and TNFSF6/FASL.
TNFSF11	Tumor necrosis factor ligand superfamily member 11	Cytokine that binds to TNFRSF11B/OPG and to TNFRSF11A/RANK.
TNFSF18	Tumor necrosis factor ligand superfamily member 18	Cytokine that binds to TNFRSF18/AITR/GITR.
TNFSF4	Tumor necrosis factor ligand superfamily member 4	Cytokine that binds to TNFRSF4.
FASLG	Tumor necrosis factor ligand superfamily member 6	Cytokine that binds to TNFRSF6/FAS, a receptor that transduces the apoptotic signal into cells.

Protein-family classification

Druggable: 13 · Difficult: 15 · Unknown: 47 · Druggable fraction: 0.17

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
Nuclear receptor	2	10.3×	0.065
Transporter	4	4.2×	0.065
Transcription factor	15	1.6×	0.090
Other/Unknown	47	1.1×	0.280
GPCR	2	0.6×	0.955
Protease	1	0.5×	0.955
Enzyme (other)	3	0.5×	0.955
Kinase	1	0.4×	0.955

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BCL6	Transcription factor	no		BTB/POZ_dom, SKP1/BTB/POZ_sf, Znf_C2H2_type
SNORD21	Other/Unknown	no
SNORA66	Other/Unknown	no
RORA	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
RORC	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
RPL41	Other/Unknown	no		Ribosomal_eS32
RPL5	Other/Unknown	no		Rbsml_uL18_euk_arc, Ribosomal_uL18_C_euk, Ribosomal_L18
RPS26	Other/Unknown	no		Ribosomal_eS26, Ribosomal_eS26_sf, Ribosomal_eS26_CS
RUNX1	Transcription factor	no		AML1_Runt, p53-like_TF_DNA-bd_sf, p53/RUNT-type_TF_DNA-bd_sf
RUNX3	Transcription factor	no		AML1_Runt, p53-like_TF_DNA-bd_sf, p53/RUNT-type_TF_DNA-bd_sf
RYBP	Transcription factor	no		Znf_RanBP2, YAF2_RYBP, Znf_RanBP2_sf
S100A11	Other/Unknown	no		S100/CaBP7/8-like_CS, EF_hand_dom, EF-hand-dom_pair
ATXN2	Other/Unknown	no		LsmAD_domain, PAM2_motif, LSM_dom_sf
CXCR5	GPCR	yes		GPCR_Rhodpsn, Chemokine_CXCR5, GPCR_Rhodpsn_7TM
CCL20	Other/Unknown	no		Chemokine_CC_CS, Chemokine_IL8-like_dom, Chemokine_CC_DCCL
SFPQ	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, NOPS
SLC15A2	Transporter	yes		POT_fam, Oligopep_transport, PTR2_symporter_CS
SLC22A4	Transporter	yes		Orgcat_transp/SVOP, MFS_sugar_transport-like, Sugar_transporter_CS
SLC22A5	Transporter	yes		Orgcat_transp/SVOP, MFS_sugar_transport-like, Sugar_transporter_CS
SLC7A10	Transporter	yes		AA/rel_permease1, AminoAcid_Transporter
SLC9A2	Other/Unknown	no		NHE-2/4, NaH_exchanger, Cation/H_exchanger_TM
SLC9A4	Other/Unknown	no		NHE-2/4, NaH_exchanger, Cation/H_exchanger_TM
SLC9A6	Other/Unknown	no		NHE-6/7/9, NaH_exchanger, Cation/H_exchanger_TM
SMARCE1	Other/Unknown	no		HMG_box_dom, HMG_box_dom_sf
SIK1	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
SPRR1A	Other/Unknown	no
SPRR1B	Other/Unknown	no
SPRR2A	Other/Unknown	no		SPRR2
SPRR2B	Other/Unknown	no		SPRR2
SPRR2D	Other/Unknown	no		SPRR2
SPRR2E	Other/Unknown	no		SPRR2
SPRR2F	Other/Unknown	no		SPRR2
SPRR3	Other/Unknown	no
STAT5B	Transcription factor	no		SH2, STAT, p53-like_TF_DNA-bd_sf
STAT6	Transcription factor	no		SH2, STAT, p53-like_TF_DNA-bd_sf
SULT1A1	Enzyme (other)	yes	2.8.2.1	Sulfotransferase_dom, P-loop_NTPase
SUOX	Enzyme (other)	yes	1.8.3.1	OxRdtase_Mopterin-bd_dom, Cyt_B5-like_heme/steroid-bd, MoCF_OxRdtse_dimer
SURF6	Other/Unknown	no		SURF6, Rrp14/SURF6_C
TAC3	Other/Unknown	no		Neurokinin-B/TAC3, Tachy_Neuro_lke_CS
TCAP	Other/Unknown	no		Telethonin, Titin-like_dom_sf
CFAP68	Other/Unknown	no		CFAP68, CFAP68/107
TGFB2	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGFb2
TCHH	Other/Unknown	no		S100/CaBP7/8-like_CS, EF_hand_dom, EF-hand-dom_pair
TLR1	Other/Unknown	no		TIR_dom, Cys-rich_flank_reg_C, Leu-rich_rpt
TNFAIP3	Transcription factor	no		Znf_A20, OTU_dom, OTU_Deubiquitinase
TNFRSF11A	Other/Unknown	no		TNFR/NGFR_Cys_rich_reg, TNFR_11, TNFR_11A
TNFRSF14	Other/Unknown	no		TNFR/NGFR_Cys_rich_reg, TNFR_14, TNFRSF14/UL144_N
TNFRSF6B	Other/Unknown	no		TNFR/NGFR_Cys_rich_reg, TNFRSF6B_N, TNFRSF_decoy_receptor
TNFSF11	Other/Unknown	no		TNF_dom, Tumour_necrosis_fac-like_dom, TNF_ligand_10/11
TNFSF18	Other/Unknown	no		TNF_dom, Tumour_necrosis_fac-like_dom, TNFSF18

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

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

Top tissues across cohort

Tissue	Cohort genes
lower esophagus mucosa	10
granulocyte	8
male germ line stem cell (sensu Vertebrata) in testis	6
sural nerve	5
mucosa of transverse colon	5
lymph node	5
gastrocnemius	4
mucosa of stomach	4
lateral nuclear group of thalamus	4
primordial germ cell in gonad	4
buccal mucosa cell	4
cartilage tissue	4
spleen	4
monocyte	4
mononuclear cell	4
blood	3
hindlimb stylopod muscle	3
left ovary	3
epithelium of bronchus	3
olfactory segment of nasal mucosa	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BCL6	300	ubiquitous	marker	gastrocnemius, mucosa of stomach, blood
SNORD21	59		yes	sural nerve, liver, adrenal tissue
SNORA66	121		yes	sural nerve, lower esophagus mucosa, adrenal tissue
RORA	284	ubiquitous	marker	upper leg skin, lateral nuclear group of thalamus, skin of hip
RORC	209	broad	marker	gastrocnemius, male germ line stem cell (sensu Vertebrata) in testis, hindlimb stylopod muscle
RPL41	134	ubiquitous	marker	ovary, right ovary, left ovary
RPL5	292	ubiquitous	marker	germinal epithelium of ovary, primordial germ cell in gonad, parietal pleura
RPS26	140	ubiquitous	marker	granulocyte, left adrenal gland cortex, mucosa of transverse colon
RUNX1	253	ubiquitous	marker	olfactory segment of nasal mucosa, epithelium of bronchus, mucosa of paranasal sinus
RUNX3	220	broad	marker	granulocyte, buccal mucosa cell, lymph node
RYBP	292	tissue_specific	marker	lower lobe of lung, cartilage tissue, endothelial cell
S100A11	292	ubiquitous	marker	lower esophagus mucosa, esophagus mucosa, olfactory segment of nasal mucosa
ATXN2	286	ubiquitous	marker	buccal mucosa cell, colonic epithelium, olfactory bulb
CXCR5	172	tissue_specific	marker	granulocyte, spleen, lymph node
CCL20	202	broad	marker	epithelium of nasopharynx, cartilage tissue, gall bladder
SFPQ	295	ubiquitous	marker	ventricular zone, tendon of biceps brachii, ganglionic eminence
SLC15A2	245	broad	marker	nasal cavity epithelium, bronchial epithelial cell, epithelium of bronchus
SLC22A4	201	ubiquitous	marker	bronchial epithelial cell, epithelium of bronchus, bronchus
SLC22A5	235	ubiquitous	marker	gastrocnemius, mucosa of transverse colon, muscle of leg
SLC7A10	138	broad	yes	omental fat pad, peritoneum, adipose tissue of abdominal region
SLC9A2	144	broad	marker	rectum, male germ line stem cell (sensu Vertebrata) in testis, mucosa of transverse colon
SLC9A4	67	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, stomach, body of stomach
SLC9A6	286	ubiquitous	yes	lateral nuclear group of thalamus, middle temporal gyrus, pons
SMARCE1	197	ubiquitous	marker	calcaneal tendon, embryo, ganglionic eminence
SIK1	138	not_expressed	marker	mucosa of stomach, skin of abdomen, zone of skin
SPRR1A	191	tissue_specific	marker	cervix squamous epithelium, lower esophagus mucosa, gingiva
SPRR1B	175	broad	marker	amniotic fluid, gingiva, cervix squamous epithelium
SPRR2A	155	tissue_specific	marker	buccal mucosa cell, lower esophagus mucosa, esophagus squamous epithelium
SPRR2B	77	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, lower esophagus mucosa, esophagus mucosa
SPRR2D	127	tissue_specific	marker	lower esophagus mucosa, esophagus mucosa, endometrium epithelium

Protein interactions among cohort

Intra-cohort edges: 54.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RPL5	6,028
RUNX1	4,994
FASLG	4,373
IKZF1	4,096
STAT5B	3,986
BCL6	3,984
TNFAIP3	3,716
TRAF1	3,557
TRAF3	3,493
SUOX	3,449

Intra-cohort edges

A	B	Sources
BCL6	CXCR5	string_interaction
BCL6	HDAC7	string_interaction
BCL6	TRAF1	biogrid_interaction, intact
CRNN	SPRR3	string_interaction
FASLG	TNFRSF6B	biogrid_interaction, intact, string_interaction
GSDMA	RUNX3	string_interaction
GSDMA	SPRR2E	biogrid_interaction
HDAC7	IKZF4	biogrid_interaction
IKZF1	IKZF4	biogrid_interaction, intact
IKZF1	RUNX1	string_interaction
IKZF1	RUNX3	string_interaction
IKZF3	IKZF4	intact
IKZF3	RUNX1	string_interaction
IKZF3	RUNX3	string_interaction
IKZF4	RUNX1	string_interaction
IKZF4	SUOX	string_interaction
RPL5	RPS26	biogrid_interaction
RUNX1	RUNX3	string_interaction
RUNX1	SLC22A4	string_interaction
SLC15A2	SLC22A4	string_interaction
SLC15A2	SLC22A5	string_interaction
SLC22A4	SLC22A5	intact
SPRR1A	SPRR2A	string_interaction
SPRR1A	SPRR2D	string_interaction
SPRR1A	SPRR2E	string_interaction
SPRR1A	SPRR2F	string_interaction
SPRR1A	TCHH	string_interaction
SPRR1B	SPRR2A	string_interaction
SPRR1B	SPRR2D	string_interaction
SPRR1B	SPRR2E	string_interaction
SPRR1B	SPRR2F	string_interaction
SPRR1B	TCHH	string_interaction
SPRR2A	SPRR2D	string_interaction
SPRR2A	SPRR2E	string_interaction
SPRR2A	SPRR2F	string_interaction
SPRR2A	SPRR3	string_interaction
SPRR2D	SPRR2E	string_interaction
SPRR2D	SPRR2F	string_interaction
SPRR2D	SPRR3	string_interaction
SPRR2E	SPRR2F	string_interaction
SPRR2E	SPRR3	string_interaction
SPRR2F	SPRR3	string_interaction
SPRR3	TCHH	string_interaction
STAT5B	SUOX	intact
TNFAIP3	TRAF1	string_interaction
TNFAIP3	TRAF3	string_interaction
TNFRSF11A	TNFSF11	intact, string_interaction
TNFRSF11A	TRAF1	biogrid_interaction
TNFRSF11A	TRAF3	biogrid_interaction
TNFRSF14	TNFRSF6B	string_interaction

Structural data

PDB: 45 · AlphaFold-only: 28 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BCL6	P41182	246
RPS26	P62854	190
RPL41	P62945	185
RPL5	P46777	184
RORC	P51449	161
MRPS21	P82921	71
TNFAIP3	P21580	17
SFPQ	P23246	13
SULT1A1	P50225	11
TGFB2	P61812	11
TRAF3	Q13114	10
IKZF1	Q13422	10
UHRF2	Q96PU4	9
SMARCE1	Q969G3	8
TNFRSF14	Q92956	8
TNFRSF6B	O95407	8
STAT6	P42226	7
TNFSF18	Q9UNG2	7
CCL20	P78556	6
TLR1	Q15399	6
HDAC7	Q8WUI4	6
RUNX1	Q01196	5
RYBP	Q8N488	5
SLC7A10	Q9NS82	4
SURF6	O75683	4
ZNF217	O75362	4
RORA	P35398	3
S100A11	P31949	3
SLC15A2	Q16348	3
SLC22A5	O76082	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
WNT11	O96014	90.35
SERPINB7	O75635	89.91
SLC22A4	Q9H015	85.07
CXCR5	P32302	80.85
GSDMA	Q96QA5	80.60
ACKR5	O15218	79.73
BTG4	Q9NY30	79.62
SPRR2B	P35325	78.45
SPRR2E	P22531	77.66
SPRR2D	P22532	77.37
SPRR2A	P35326	77.32
SPRR2F	Q96RM1	75.55
ADAMTS10	Q9H324	73.88
SLC9A6	Q92581	70.61
SPRR1B	P22528	70.02
DEXI	O95424	69.88
SPRR1A	P35321	69.36
TPD52	P55327	69.11
TCHH	Q07283	67.96
SLC9A4	Q6AI14	66.73
SLC9A2	Q9UBY0	66.40
TOB2	Q14106	66.37
SIK1	P57059	61.31
ZMYM4	Q5VZL5	59.70
SPRR3	Q9UBC9	52.87
CRNN	Q9UBG3	49.45
IKZF3	Q9UKT9	48.06
TSBP1	Q5SRN2	45.58

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 659. Enrichment computed across 250 evidence-associated genes (146 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 146 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of the cornified envelope	27	16.2×	8e-23	SPRR1A, SPRR1B, SPRR2A, SPRR2B, SPRR2D, SPRR2E, SPRR2F, SPRR3 (+19 more)
Keratinization	26	9.9×	2e-16	SPRR1A, SPRR1B, SPRR2A, SPRR2B, SPRR2D, SPRR2E, SPRR2F, SPRR3 (+18 more)
Developmental Biology	34	3.4×	5e-08	RPL41, RPS26, RUNX1, SMARCE1, SPRR1A, SPRR1B, SPRR2A, SPRR2B (+26 more)
TNFs bind their physiological receptors	6	16.2×	2e-04	TNFRSF14, TNFRSF6B, TNFSF11, TNFSF18, TNFSF4, FASLG
Sodium/Proton exchangers	3	26.1×	0.021	SLC9A2, SLC9A4, SLC9A6
RUNX3 regulates RUNX1-mediated transcription	2	52.1×	0.053	RUNX1, RUNX3
SLC-mediated transport of organic cations	3	15.6×	0.069	RUNX1, SLC22A4, SLC22A5
R-HSA-549132	3	15.6×	0.069	RUNX1, SLC22A4, SLC22A5
ERBB2 Regulates Cell Motility	3	14.7×	0.074	DIAPH1, ERBB2, ERBB3
TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway	3	13.8×	0.080	TNFRSF11A, TNFSF11, TRAF3
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	4	8.2×	0.081	RUNX1, RYBP, SMARCE1, ARID1B
GRB7 events in ERBB2 signaling	2	26.1×	0.119	ERBB2, ERBB3
RUNX3 Regulates Immune Response and Cell Migration	2	26.1×	0.119	RORC, RUNX3
Interleukin-4 and Interleukin-13 signaling	6	4.2×	0.140	BCL6, RORA, RORC, STAT6, FASLG, SOCS1
Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes	3	9.8×	0.140	RORA, RORC, SIK1
SLC-mediated transmembrane transport	8	3.2×	0.140	RUNX1, SLC22A4, SLC22A5, SLC7A10, SLC9A2, SLC9A4, SLC9A6, SLC39A8
Regulation of PD-L1(CD274) translation	2	17.4×	0.202	MIR34B, MIR34C
RNA Polymerase II Transcription	14	2.2×	0.202	BCL6, RORA, RORC, RUNX1, RUNX3, RYBP, SMARCE1, CAMK4 (+6 more)
RUNX3 regulates p14-ARF	2	15.6×	0.237	RUNX1, RUNX3
R-HSA-425366	4	5.0×	0.255	RUNX1, SLC22A4, SLC22A5, SLC39A8
TNFR2 non-canonical NF-kB pathway	4	5.0×	0.255	TNFRSF11A, TNFSF11, FASLG, TRAF3
Signaling by Interleukins	7	3.1×	0.255	BCL6, RORA, RORC, CCL20, STAT5B, STAT6, SOCS1
Defective ALG9 causes CDG-1l	1	78.2×	0.293	ALG9
Defective SLC9A6 causes X-linked, syndromic mental retardation,, Christianson type (MRXSCH)	1	78.2×	0.293	SLC9A6
Differentiation of naive CD4+ T cells to T helper 1 cells (Th1 cells)	2	12.0×	0.293	RUNX1, RUNX3
Downregulation of ERBB2:ERBB3 signaling	2	11.2×	0.293	ERBB2, ERBB3
ERBB2 Activates PTK6 Signaling	2	11.2×	0.293	ERBB2, ERBB3
Interleukin-7 signaling	3	6.5×	0.293	STAT5B, SOCS1, TSLP
Homology Directed Repair	3	6.3×	0.293	RTEL1, CDK2, RMI2
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	3	6.3×	0.293	RTEL1, CDK2, RMI2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 218 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
keratinization	24	25.8×	8e-25	SPRR1B, SPRR2B, SPRR2D, SPRR2F, SPRR3, TCHH, LCE2D, LCE2B (+16 more)
epidermis development	9	8.7×	6e-04	SPRR1A, SPRR1B, SPRR2B, SPRR2D, SPRR2E, SPRR2F, SPRR3, LCE2B (+1 more)
negative regulation of transcription by RNA polymerase II	30	2.4×	0.002	BCL6, RORC, RUNX1, RUNX3, RYBP, SFPQ, SIK1, STAT6 (+22 more)
regulation of steroid metabolic process	3	33.1×	0.024	RORA, RORC, STAT5B
positive regulation of inflammatory response	8	5.3×	0.035	STAT5B, TNFSF18, TNFSF4, IL33, TLR6, CEBPA, TSLP, ETS1
positive regulation of fever generation by positive regulation of prostaglandin secretion	2	77.3×	0.036	TNFRSF11A, TNFSF11
inflammatory response	16	2.8×	0.045	BCL6, CCL20, TLR1, TNFAIP3, TNFSF4, CAMK4, TLR10, CCR7 (+8 more)
regulation of lymphocyte differentiation	2	51.5×	0.047	IKZF3, NDFIP1
isotype switching to IgE isotypes	2	51.5×	0.047	BCL6, STAT6
negative regulation of isotype switching to IgE isotypes	2	51.5×	0.047	BCL6, NDFIP1
TRIF-dependent toll-like receptor signaling pathway	3	21.1×	0.047	TRAF3, TLR6, TICAM2
toll-like receptor signaling pathway	4	11.0×	0.047	TLR1, TRAF3, TLR10, TLR6
tumor necrosis factor-mediated signaling pathway	5	7.6×	0.047	TNFRSF11A, TNFSF11, TNFSF18, TRAF1, TRAF3
positive regulation of interleukin-6 production	7	5.4×	0.047	TLR1, TNFSF4, IL33, TLR6, TSLP, AIF1, FCER1G
tolerance induction in gut-associated lymphoid tissue	2	38.6×	0.068	RORC, ZBTB46
carnitine transport	2	38.6×	0.068	SLC22A4, SLC22A5
negative regulation of CD4-positive, alpha-beta T cell differentiation	2	38.6×	0.068	RUNX1, RUNX3
positive regulation of interleukin-13 production	3	15.5×	0.068	TNFSF4, IL33, TSLP
immune response	13	2.8×	0.068	CXCR5, CCL20, TLR1, TNFRSF14, TNFSF11, TNFSF4, TLR10, CCR7 (+5 more)
macrophage differentiation	4	8.6×	0.076	IL33, ZBTB46, CEBPA, SOCS1
hemopoiesis	5	6.1×	0.082	RUNX1, RUNX3, TGFB2, KLF3, KIRREL3
quaternary ammonium group transport	2	30.9×	0.085	SLC22A4, SLC22A5
cellular response to sterol	2	30.9×	0.085	RORA, RORC
positive regulation of CD8-positive, alpha-beta T cell differentiation	2	30.9×	0.085	RUNX1, RUNX3
regulation of cell differentiation	4	7.9×	0.085	BCL6, RUNX1, RUNX3, SIK1
regulation of cytokine production	5	5.7×	0.089	BCL6, TRAF3, LITAF, SOCS1, ZBTB39
keratinocyte differentiation	5	5.7×	0.089	SPRR1A, SPRR1B, SPRR2B, SPRR2F, SPRR3
defense response to Gram-negative bacterium	6	4.6×	0.089	TNFRSF14, LCE3C, GSDMB, LCE3A, LCE3B, TSLP
regulation of germinal center formation	2	25.8×	0.090	BCL6, TNFAIP3
negative regulation of type 2 immune response	2	25.8×	0.090	STAT6, NDFIP1

Therapeutics

Drugs indicated for this disease

45 approved, 16 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Acrivastine	Approved (phase 4)
Astemizole	Approved (phase 4)
Azatadine	Approved (phase 4)
Azelastine	Approved (phase 4)
Bilastine	Approved (phase 4)
Bromodiphenhydramine	Approved (phase 4)
Brompheniramine	Approved (phase 4)
Buclizine	Approved (phase 4)
Carbinoxamine	Approved (phase 4)
Cetirizine	Approved (phase 4)
Chlorpheniramine	Approved (phase 4)
Chlorphenoxamine	Approved (phase 4)
Clemastine	Approved (phase 4)
Cortisone Acetate	Approved (phase 4)
Cyclizine	Approved (phase 4)
Cyproheptadine	Approved (phase 4)
Desloratadine	Approved (phase 4)
Dexbrompheniramine	Approved (phase 4)
Dimenhydrinate	Approved (phase 4)
Diphenhydramine	Approved (phase 4)
Diphenylpyraline	Approved (phase 4)
Ebastine	Approved (phase 4)
Epinastine	Approved (phase 4)
Epinephrine	Approved (phase 4)
Fexofenadine	Approved (phase 4)
Glycerin	Approved (phase 4)
Ketotifen	Approved (phase 4)
Levocetirizine	Approved (phase 4)
Loratadine	Approved (phase 4)
Meclizine	Approved (phase 4)
Methapyrilene	Approved (phase 4)
Methdilazine	Approved (phase 4)
Methylpromazine	Approved (phase 4)
Mizolastine	Approved (phase 4)
Pheniramine	Approved (phase 4)
Phenol	Approved (phase 4)
Promethazine	Approved (phase 4)
Pyrilamine	Approved (phase 4)
Rupatadine	Approved (phase 4)
Terfenadine	Approved (phase 4)
Thenalidine	Approved (phase 4)
Thiethylperazine	Approved (phase 4)
Tripelennamine	Approved (phase 4)
Triprolidine	Approved (phase 4)
Tritoqualine	Approved (phase 4)
Amoxicillin	Phase 3 (in late-stage trials)
Arginine	Phase 3 (in late-stage trials)
Betamethasone	Phase 3 (in late-stage trials)
Calcium	Phase 3 (in late-stage trials)
Ciclesonide	Phase 3 (in late-stage trials)
Dexamethasone	Phase 3 (in late-stage trials)
Freneslerbart	Phase 3 (in late-stage trials)
Ligelizumab	Phase 3 (in late-stage trials)
Mevonlerbart	Phase 3 (in late-stage trials)
Oxomemazine	Phase 3 (in late-stage trials)
Paclitaxel	Phase 3 (in late-stage trials)
Prednisolone	Phase 3 (in late-stage trials)
Silicon Dioxide	Phase 3 (in late-stage trials)
Sodium Fluoride	Phase 3 (in late-stage trials)
Sodium Lauryl Sulfate	Phase 3 (in late-stage trials)
Triclosan	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Albuterol, Antazoline, Budesonide, Cholecalciferol, Denosumab, Dexchlorpheniramine, Dimethindene, Doxylamine, Dupilumab, Formoterol, Omalizumab, Prednisone, Propolis Wax, Remibrutinib, Sodium Chloride, Sodium Monofluorophosphate, Tozinameran, Trimethobenzamide, Umesolerbart, Zafirlukast.

Drug target analysis

Approved (phase 4): 13 · Phase ≥3: 14 · Phased (≥1): 17 · Undrugged: 58

Druggability breadth: 71 of 250 evidence-associated genes (28%) 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
RORA	TRETINOIN
RORC	DIGOXIN
RPL41	GENTAMICIN SULFATE
RPL5	GENTAMICIN SULFATE
RPS26	GENTAMICIN SULFATE
RUNX1	APOMORPHINE HYDROCHLORIDE
SLC15A2	CYCLACILLIN
SIK1	FEDRATINIB
STAT6	THIORIDAZINE HYDROCHLORIDE
SULT1A1	ESTRADIOL
IKZF1	POMALIDOMIDE
IKZF3	POMALIDOMIDE
HDAC7	CELECOXIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HDAC7	28	4
SIK1	19	4
STAT6	11	4
RORC	9	4
SLC15A2	8	4
IKZF3	5	4
SLC9A2	3	2
SULT1A1	3	4
IKZF1	3	4
BCL6	2	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TRETINOIN	4	RORA, RORC
DIGOXIN	4	RORC
ALITRETINOIN	4	RORC
GENTAMICIN SULFATE	4	RPL41, RPL5, RPS26
APOMORPHINE HYDROCHLORIDE	4	RUNX1
CYCLACILLIN	4	SLC15A2
CEFTIBUTEN	4	SLC15A2
CEFADROXIL	4	SLC15A2
CEPHALEXIN ANHYDROUS	4	SLC15A2
AMPICILLIN	4	SLC15A2
CEFACLOR ANHYDROUS	4	SLC15A2
FEDRATINIB	4	SIK1
AXITINIB	4	SIK1
NERATINIB	4	SIK1
VANDETANIB	4	SIK1
BOSUTINIB	4	SIK1
PAZOPANIB	4	SIK1
NINTEDANIB	4	SIK1
SUNITINIB	4	SIK1
DASATINIB	4	SIK1
MIDOSTAURIN	4	SIK1
THIORIDAZINE HYDROCHLORIDE	4	STAT6
DOXORUBICIN HYDROCHLORIDE	4	STAT6
AMSACRINE	4	STAT6
ADENOSINE	4	STAT6
AMANTADINE	4	STAT6
BISACODYL	4	STAT6
ESTRADIOL	4	SULT1A1
ETHINYL ESTRADIOL	4	SULT1A1
POMALIDOMIDE	4	IKZF1, IKZF3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
HDAC7	1,710	Binding:1695, ADMET:10, Functional:4, Toxicity:1
RORC	758	Binding:707, Functional:50, Unclassified:1
SIK1	210	Binding:205, Toxicity:4, ADMET:1
BCL6	209	Binding:202, Functional:7
RORA	115	Binding:111, Functional:3, Unclassified:1
IKZF1	106	Binding:105, Functional:1
IKZF3	101	Binding:100, Functional:1
SLC22A5	97	Functional:79, ADMET:18
RPL5	90	Binding:90
RPL41	89	Binding:89
RPS26	89	Binding:89
STAT6	81	Binding:77, Functional:4
TLR1	59	Binding:59
STAT5B	55	Binding:55
CXCR5	33	Binding:21, Functional:12
TNFSF11	30	Binding:30
SLC22A4	29	Functional:26, ADMET:3
RUNX1	20	Binding:17, Functional:3
SLC15A2	20	Functional:16, ADMET:4
SULT1A1	19	ADMET:15, Binding:4
SLC9A2	10	Binding:8, Functional:2
SFPQ	7	Binding:7
SMARCE1	7	Binding:7
ATXN2	5	Binding:3, Functional:2
ACKR5	4	Binding:4
TGFB2	3	Binding:3
BACH2	3	Binding:3
FASLG	2	Binding:2
RYBP	1	Binding:1
S100A11	1	Binding:1
SPRR3	1	Binding:1
TAC3	1	Binding:1
TNFAIP3	1	Binding:1
CDK2AP1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SULT1A1	2.8.2.1, 2.8.2.2	aryl sulfotransferase, alcohol sulfotransferase
SUOX	1.8.3.1	sulfite oxidase
HDAC7	3.5.1.98	histone deacetylase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
BCL6	209
RORA	115
RORC	758
SIK1	210
IKZF1	106
IKZF3	101
HDAC7	1,710

Pharmacogenomics

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

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

Chemical tractability of cohort targets

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

Compound	Max phase	Cohort target (bioactivity)
TRETINOIN	4	RORA, RORC
DIGOXIN	4	RORC
ALITRETINOIN	4	RORC
GENTAMICIN SULFATE	4	RPL41, RPL5, RPS26
APOMORPHINE HYDROCHLORIDE	4	RUNX1
CYCLACILLIN	4	SLC15A2
CEFTIBUTEN	4	SLC15A2
CEFADROXIL	4	SLC15A2
CEPHALEXIN ANHYDROUS	4	SLC15A2
AMPICILLIN	4	SLC15A2
CEFACLOR ANHYDROUS	4	SLC15A2
FEDRATINIB	4	SIK1
AXITINIB	4	SIK1
NERATINIB	4	SIK1
VANDETANIB	4	SIK1
BOSUTINIB	4	SIK1
PAZOPANIB	4	SIK1
NINTEDANIB	4	SIK1
SUNITINIB	4	SIK1
DASATINIB	4	SIK1
MIDOSTAURIN	4	SIK1
THIORIDAZINE HYDROCHLORIDE	4	STAT6
DOXORUBICIN HYDROCHLORIDE	4	STAT6
AMSACRINE	4	STAT6
ADENOSINE	4	STAT6
AMANTADINE	4	STAT6
BISACODYL	4	STAT6
ESTRADIOL	4	SULT1A1
ETHINYL ESTRADIOL	4	SULT1A1
POMALIDOMIDE	4	IKZF1, IKZF3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	13	RORA, RORC, RPL41, RPL5, RPS26, RUNX1, SLC15A2, SIK1, STAT6, SULT1A1 (+3 more)
B	Phased (≥1) drug, not yet approved	4	BCL6, SLC9A2, STAT5B, TGFB2
C	Druggable family + PDB, no drug	3	SLC22A5, SLC7A10, SUOX
D	Druggable family + AlphaFold only, no drug	4	CXCR5, SLC22A4, ADAMTS10, ACKR5
E	Difficult family or no structure, no drug	51	SNORD21, SNORA66, RUNX3, RYBP, S100A11, ATXN2, CCL20, SFPQ, SLC9A4, SLC9A6 (+41 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RUNX3	0	IKZF1
SLC22A4	29	RUNX1
IKZF4	0	RUNX1
SNORD21	0	—
SNORA66	0	—
RYBP	1	—
S100A11	1	—
ATXN2	5	—
CXCR5	33	—
CCL20	0	—
SFPQ	7	—
SLC22A5	97	—
SLC7A10	0	—
SLC9A4	0	—
SLC9A6	0	—
SMARCE1	7	—
SPRR1A	0	—
SPRR1B	0	—
SPRR2A	0	—
SPRR2B	0	—
SPRR2D	0	—
SPRR2E	0	—
SPRR2F	0	—
SPRR3	1	—
SUOX	0	—
SURF6	0	—
TAC3	1	—
TCAP	0	—
CFAP68	0	—
TCHH	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 346.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	219
PHASE1	35
PHASE3	32
PHASE2	26
PHASE4	19
PHASE1/PHASE2	6
PHASE2/PHASE3	5
EARLY_PHASE1	4

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05758532	PHASE4	RECRUITING	Non-specific Effects of a Modified Measles Vaccination Schedule to Prevent Allergy and Unrelated Infection in Children
NCT06834165	PHASE4	RECRUITING	Study Evaluating the Safety and Efficacy of Neffy or Intramuscular Adrenalin in Patients With Allergic Reactions After Oral Food Challenge or Allergen Immunotherapy
NCT06935890	PHASE4	RECRUITING	Jack Jumper Ant Venom Immunotherapy Long-term Effectiveness Investigation
NCT00147940	PHASE4	TERMINATED	Correlation of Nasal Volume, Cross-Sectional Area With Nasalance Scores Measured by Acoustic Rhinometry and Nasometry
NCT00258141	PHASE4	UNKNOWN	Study With Rupatadine in Mosquito-Bite Allergic Adult Subjects
NCT00547768	PHASE4	COMPLETED	Comparative Study Evaluating the Effects of Fexofenadine HCI 180 mg With Orange Juice Versus Placebo With Orange Juice in a Skin Wheal and Flare Challenge Model.
NCT00673218	PHASE4	UNKNOWN	The Effect of Xolair on Inhibiting Leukotriene and Cytokine (IL-4 and IL-13) Release From Blood Basophils
NCT00779116	PHASE4	COMPLETED	Multi-center, Pediatric, Open-label, Preference Study of Desloratadine 2.5 mg Reditab (SCH34117) and Zyrtec 5.0 mg Chewable Tablet Medications (Study P04574)(COMPLETED)
NCT00780403	PHASE4	COMPLETED	Multi-Center, Pediatric, Open-Label, Preference Study of Desloratadine 2.5 mg Reditab (SCH34117) and Zyrtec ® 5.0 mg Chewable Tablet Medications (Study P04573) (Completed)
NCT01159379	PHASE4	UNKNOWN	Safety of Ertapenem in Beta-lactam Allergic Patients.
NCT01367470	PHASE4	COMPLETED	Influence of Probiotic VSL#3 Administration on Metabolic and Immunological Profile of the Milk of Breastfeeding Mothers
NCT01601847	PHASE4	COMPLETED	Wheezing in Black Preterm Infants: Impact of Vitamin D Supplementation Strategy
NCT02168478	PHASE4	COMPLETED	Neo-Synalar Modified 48 Hour Patch Test
NCT02264535	PHASE4	COMPLETED	A Pilot Study for Ginkgolides Meglumine Injection Skin Testing.
NCT02440243	PHASE4	COMPLETED	Grass Pollen Subcutaneous Immunotherapy in Elderly Patients
NCT02953106	PHASE4	TERMINATED	Effects of Intranasal Fluticasone Plus Azelastine on Airway Inflammation in Patients With Asthma & Allergic Rhinitis
NCT06011603	PHASE4	COMPLETED	Prineo Sensitivity Dressing Study
NCT06288334	PHASE4	UNKNOWN	Exploration of the Optimal Dosage of Cetirizine in the Treatment of Allergic Diseases in Chinese Children
NCT07103720	PHASE4	COMPLETED	The Nonirritating Concentrations of Midazolam, Ketamine, and Ondansetron
NCT06560255	PHASE3	RECRUITING	Fish Oil in pREgnancY for Personalized Prevention of Early Childhood Asthma
NCT06570889	PHASE3	RECRUITING	VItamin D in pregnanCy for prevenTion Of eaRlY Childhood Asthma
NCT06771791	PHASE3	RECRUITING	Evaluation of the Efficacy of Oral Immunotherapy With Raw Apple in Patients Allergic to Birch Pollen and Apple: Prospective, Multicenter, Comparative Phase III Study
NCT07003919	PHASE3	RECRUITING	Safety Study of Viaskin® Peanut Patch in Peanut-Allergic Children 1 Through 3 Years of Age (COMFORT Toddlers)
NCT00227279	PHASE3	COMPLETED	A Trial of the ALK Grass Tablet in Subjects With Hayfever
NCT00263926	PHASE3	COMPLETED	Efficacy and Safety of a Purified Standardised Wasp Venom Preparation
NCT00293046	PHASE3	COMPLETED	Assessment of Grazax® Treatment Compliance
NCT00309036	PHASE3	COMPLETED	Safety and Efficacy of Recombinant Grass Pollen Allergen Cocktail in the Treatment of Allergic Rhinoconjunctivitis
NCT00310466	PHASE3	COMPLETED	Efficacy and Safety Trial of SLITone(TM) Birch in Subjects With Hayfever
NCT00367640	PHASE2/PHASE3	COMPLETED	Safety and Efficacy of Sublingual Immunotherapy (SLIT) Tablets in Grass Pollen Rhinoconjunctivitis
NCT00408616	PHASE3	COMPLETED	Efficacy and Safety of Grazax in Children
NCT00409409	PHASE3	COMPLETED	Efficacy and Safety of 300 IR Sublingual Immunotherapy (SLIT) Tablets in Children Suffering From Grass Pollen Rhinoconjunctivitis
NCT00413556	PHASE3	COMPLETED	Changes in the Immune Response and Skin Reactivity of Grass Pollen Allergic Patients Treated With ALK Grass Tablets
NCT00418379	PHASE3	COMPLETED	Phase III Study to Assess the Long Term Efficacy, Carry-over Effect and Safety of 300 IR Sublingual Immunotherapy Tablets
NCT00421655	PHASE3	COMPLETED	A Trial of Grazax in Subjects With Hayfever
NCT00537342	PHASE3	COMPLETED	Immunotherapy With Depigmented and Polymerized Allergen Extract of Olea Europaea (GPIT)
NCT00550550	PHASE3	COMPLETED	Efficacy and Safety of Grass Sublingual Tablet in Children and Adolescents (P05239 AM3)(COMPLETED)
NCT00554983	PHASE3	COMPLETED	Efficacy and Safety From a Recombinant Folding Variant of Bet v 1
NCT00562159	PHASE3	COMPLETED	Efficacy and Safety of Grass Sublingual Tablet in Adults (P05238 AM3)(COMPLETED)
NCT00623701	PHASE3	COMPLETED	Efficacy and Safety From a High-dosed Sublingual Grass Pollen Preparation
NCT00633919	PHASE2/PHASE3	COMPLETED	Efficacy of SLITone in House Dust Mite Allergic Patients

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
OMALIZUMAB	4	8
ALBUTEROL	4	3
BROMPHENIRAMINE	4	3
CETIRIZINE	4	3
CLEMASTINE	4	3
DESLORATADINE	4	3
OLIVE OIL	4	2
OLOPATADINE	4	2
CHLORPHENIRAMINE	4	1
CHOLECALCIFEROL	4	1
CICLESONIDE	4	1
EPINEPHRINE	4	1
ERTAPENEM	4	1
FLUTICASONE PROPIONATE	4	1
LEVOCETIRIZINE	4	1
LOTEPREDNOL ETABONATE	4	1
MANNITOL	4	1
MOMETASONE FUROATE	4	1
RUPATADINE	4	1
SORBITOL	4	1
FLUTICASONE	3	2
MOMETASONE	3	2
LIGELIZUMAB	3	1
MALTODEXTRIN	3	1
GAMMA-TOCOPHEROL	2	1
GOLD	2	1
LESIGERCEPT	2	1
OZUREPRUBART	2	1
MDX-1303	1	1
CHEMBL4283412	0	1