Alopecia areata

Summary

Alopecia areata (MONDO:0005340) is a disease with 75 cohort genes (54 GWAS associations across 11 studies) and 200 clinical trials. The dominant Reactome pathway is RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs) (4 cohort genes). Top therapeutic interventions include tofacitinib, ritlecitinib, and triamcinolone acetonide.

At a glance

• Cohort genes: 75
• GWAS associations: 54
• ClinVar variants: 3
• Clinical trials: 200

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	alopecia areata
Mondo ID	MONDO:0005340
EFO	EFO:0004192
MeSH	D000506
DOID	DOID:986
ICD-10-CM	L63
ICD-11	65720611
SNOMED CT	68225006
UMLS	C0002171
MedGen	213
Is cancer (heuristic)	no

Also known as: alopecia areata · alopecia circumscripta

Data availability: 3 ClinVar variants · 54 GWAS associations (11 studies).

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › disorder of pilosebaceous unit › hair anomaly › alopecia › alopecia areata

Related subtypes (25): alopecia, isolated, telogen effluvium, chemotherapy-induced alopecia, alopecia mucinosa, atrichia with papular lesions, loose anagen syndrome, Satoyoshi syndrome, alopecia-intellectual disability-hypergonadotropic hypogonadism syndrome, hereditary hypotrichosis with recurrent skin vesicles, alopecia antibody deficiency, pseudopelade of Brocq, frontal fibrosing alopecia, Quinquaud’s folliculitis decalvans, Graham Little-Piccardi-Lassueur syndrome, lichen planopilaris, hypotrichosis simplex, alopecia totalis, hypotrichosis simplex of the scalp, endocrine alopecia, alopecia universalis onychodystrophy vitiligo, central centrifugal cicatricial alopecia, ectodermal dysplasia alopecia preaxial polydactyly, Slti-Salem syndrome, microcephaly sparse hair intellectual disability seizures, alopecia universalis

Subtypes (2): diffuse alopecia areata, alopecia areata 1

Genetics & variants

GWAS landscape

54 GWAS associations across 11 studies. Top hits map to 31 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs9275524	2e-60	MTCO3P1 - HLA-DQB3	C	1.92
rs9275572	1e-35	MTCO3P1 - HLA-DQB3	G	2.21
rs12183587	6e-24	RAET1M	T	1.48
rs3118470	8e-21	IL2RA	C	1.41
rs231775	2e-20	CTLA4	G	1.4
rs9479482	4e-19	RAET1M - PHB1P1	A	1.65
rs3104394	2e-17	HLA-DQB1 - MTCO3P1	G	0.62
rs574087	9e-14	PRDX5 - CCDC88B	A	1.32
rs1024161	4e-13	CTLA4	A	1.44
rs545851034	6e-13	GRK1	G	3.03
rs149683857	5e-12	IGBP1P5 - RN7SL101P	G	3.56
rs117762827	1e-11	TUBBP11 - RAP1BP2	C	3.05
rs193080770	1e-11	TMEM248P1 - LINC02379	T	2.74
rs190266188	1e-11	GOLGA6L4 - UBE2Q2P8	C	2.37
rs531707316	2e-11	PDPR2P - NPIPB15	G	2.31
rs28905181	3e-11	RPA2	A	4.19
rs529313147	4e-11	RPL36AP21 - SNORD81	A	3.11
rs192141121	4e-11	CSMD1	A	3.89
rs139534993	3e-10	SLC24A2	?
rs2292239	4e-09	ERBB3	T	1.25
rs7682481	5e-09	IL2 - IL21	C	1.23
rs848	5e-09	IL13, TH2LCRR	A	1.27
rs3789129	2e-08	ACOXL	A	1.31
rs1701704	3e-08	IKZF4	C	1.34
rs7682241	4e-08	IL2 - IL21	A	1.34
rs2155219	4e-08	EMSY - LINC02757	T	1.21
rs4916209	7e-08	TNFSF4	?	1.32
rs2476601	9e-08	AP4B1-AS1, PTPN22	A	1.34
rs3862469	2e-07	CLEC16A	C	1.21
rs653178	2e-07	ATXN2	C	1.19

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST004866	Betz RC	2015	2,332	5,233	Genome-wide meta-analysis in alopecia areata resolves HLA associations and reveals two new susceptibility loci.
GCST000719	Petukhova L	2010	1,054	3,278	Genome-wide association study in alopecia areata implicates both innate and adaptive immunity.
GCST90473957	UK Biobank Whole-Genome Sequencing Consortium	2025	800	457,640	Whole-genome sequencing of 490,640 UK Biobank participants.
GCST005539	Redler S	2015	767	1,475	Immunochip-based analysis: high-density genotyping of immune-related loci sheds further light on the autoimmune genetic architecture of alopecia areata.
GCST001295	Forstbauer LM	2011	729	0	Genome-wide pooling approach identifies SPATA5 as a new susceptibility locus for alopecia areata.
GCST90727043	Kim HI	2026	728	43,298	Exome sequencing and analysis of 44,028 British South Asians enriched for high autozygosity.
GCST90478823	Verma A	2024	627	120,788	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90480473	Verma A	2024	627	120,788	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90478824	Verma A	2024	600	450,317	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90482359	Verma A	2024	371	59,320	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

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

MAF distribution

Bucket	Variants
common (>=0.05)	39
low_freq (0.01-0.05)	0
rare (<0.01)	9
unknown	2

Functional consequences

Consequence	Count
intron_variant	27
intergenic_variant	16
non_coding_transcript_exon_variant	3
missense_variant	2
3_prime_UTR_variant	1
regulatory_region_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs9275524	6	32707332	T>A,C,G	0.05	intergenic_variant	MTCO3P1 - HLA-DQB3	2e-60	Tier 4: intronic/intergenic
rs9275572	6	32711222	A>G,T	0.41	intergenic_variant	MTCO3P1 - HLA-DQB3	1e-35	Tier 4: intronic/intergenic
rs12183587	6	150033472			non_coding_transcript_exon_variant	RAET1M	6e-24	Tier 4: intronic/intergenic
rs3118470	10	6059750	T>A,C	0.05	intron_variant	IL2RA	8e-21	Tier 4: intronic/intergenic
rs231775	2	203867991	A>G,T	0.05	missense_variant	CTLA4	2e-20	Tier 1: coding
rs9479482	6	150036876	T>C	0.43	intergenic_variant	RAET1M - PHB1P1	4e-19	Tier 4: intronic/intergenic
rs3104394	6	32699743	G>A,C,T	0.102	intergenic_variant	HLA-DQB1 - MTCO3P1	2e-17	Tier 4: intronic/intergenic
rs574087	11	64335476	A>G	0.05	intron_variant	PRDX5 - CCDC88B	9e-14	Tier 4: intronic/intergenic
rs1024161	2	203857029	T>A,C	0.4	intron_variant	CTLA4	4e-13	Tier 4: intronic/intergenic
rs545851034	13	113730589	G>A	0.001	intron_variant	GRK1	6e-13	Tier 4: intronic/intergenic
rs149683857	4	27606021	G>A,C,T	0.001	intergenic_variant	IGBP1P5 - RN7SL101P	5e-12	Tier 4: intronic/intergenic
rs117762827	3	103929060	C>T	0	intron_variant	TUBBP11 - RAP1BP2	1e-11	Tier 4: intronic/intergenic
rs193080770	4	126045378	T>A	0.001	intergenic_variant	TMEM248P1 - LINC02379	1e-11	Tier 4: intronic/intergenic
rs190266188	15	84249744	C>T	0	intron_variant	GOLGA6L4 - UBE2Q2P8	1e-11	Tier 4: intronic/intergenic
rs531707316	16	74368507	G>A	0.001	non_coding_transcript_exon_variant	PDPR2P - NPIPB15	2e-11	Tier 4: intronic/intergenic
rs28905181	1	27895485	A>T	0.001	intron_variant	RPA2	3e-11	Tier 4: intronic/intergenic
rs529313147	5	18096274	A>G	0	intergenic_variant	RPL36AP21 - SNORD81	4e-11	Tier 4: intronic/intergenic
rs192141121	8	3207580	A>G	0	intron_variant	CSMD1	4e-11	Tier 4: intronic/intergenic
rs139534993	9	19764186	A>G		intron_variant	SLC24A2	3e-10	Tier 4: intronic/intergenic
rs2292239	12	56088396	T>A,C,G	0.05	intron_variant	ERBB3	4e-09	Tier 4: intronic/intergenic
rs7682481	4	122602871	G>A,C,T	0.05	intron_variant	IL2 - IL21	5e-09	Tier 4: intronic/intergenic
rs848	5	132660808	A>C,G,T	0.05	3_prime_UTR_variant	IL13, TH2LCRR	5e-09	Tier 2: splice/UTR
rs3789129	2	110940463	A>C	0.05	intron_variant	ACOXL	2e-08	Tier 4: intronic/intergenic
rs1701704	12	56018703	T>A,C,G	0.33	intron_variant	IKZF4	3e-08	Tier 4: intronic/intergenic
rs7682241	4	122602720	G>A,T	0.33	non_coding_transcript_exon_variant	IL2 - IL21	4e-08	Tier 4: intronic/intergenic
rs2155219	11	76588150	G>T	0.05	intergenic_variant	EMSY - LINC02757	4e-08	Tier 4: intronic/intergenic
rs4916209	1	173164350	G>A,T	0.05	intergenic_variant	TNFSF4	7e-08	Tier 4: intronic/intergenic
rs2476601	1	113834946	A>G,T	0.05	missense_variant	AP4B1-AS1, PTPN22	9e-08	Tier 1: coding
rs3862469	16	11100223	C>T	0.05	intron_variant	CLEC16A	2e-07	Tier 4: intronic/intergenic
rs653178	12	111569952	C>A,G,T	0.05	intron_variant	ATXN2	2e-07	Tier 4: intronic/intergenic

ClinVar germline variants

3 retrieved; paginated sample, class counts are floors:

1 likely pathogenic, 1 pathogenic/likely pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
374202	NM_014112.5(TRPS1):c.2794G>A (p.Ala932Thr)	TRPS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
267825	46;XY;t(1;9;5)(compleX)dn		Likely pathogenic	criteria provided, single submitter
523239	GRCh37/hg19 18p11.32-11.31(chr18:1345040-3479168)	SMCHD1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 64 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATXN2	Orphanet:803	Amyotrophic lateral sclerosis
ATXN2	Orphanet:98756	Spinocerebellar ataxia type 2
SCNN1A	Orphanet:130	Brugada syndrome
SCNN1A	Orphanet:171876	Generalized pseudohypoaldosteronism type 1
SCNN1A	Orphanet:526	Liddle syndrome
SCNN1A	Orphanet:60033	Idiopathic bronchiectasis
TNFRSF1A	Orphanet:32960	Tumor necrosis factor receptor 1 associated periodic syndrome
TNFRSF1A	Orphanet:329967	Intermittent hydrarthrosis
TNFSF4	Orphanet:2073	Narcolepsy type 1
TNFSF4	Orphanet:536	Systemic lupus erythematosus
TRPS1	Orphanet:502	Trichorhinophalangeal syndrome type 2
TRPS1	Orphanet:77258	Trichorhinophalangeal syndrome type 1
CD28	Orphanet:2584	Classic mycosis fungoides
CD28	Orphanet:3162	Sézary syndrome
ZNF365	Orphanet:2073	Narcolepsy type 1
ZNF365	Orphanet:83465	Narcolepsy type 2
HHAT	Orphanet:1422	Chondrodysplasia-difference of sex development syndrome
CCDC6	Orphanet:146	Differentiated thyroid carcinoma
NANS	Orphanet:168454	Spondyloepimetaphyseal dysplasia, Geneviève type
SYT14	Orphanet:284271	Autosomal recessive cerebellar ataxia-psychomotor delay 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
BLTP1	Orphanet:610569	KIAA1109-related early lethal congenital brain malformations-arthrogryposis syndrome
SMCHD1	Orphanet:2250	Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome
SMCHD1	Orphanet:269	Facioscapulohumeral dystrophy
SH2B3	Orphanet:3318	Essential thrombocythemia
SH2B3	Orphanet:391366	Growth retardation-mild developmental delay-chronic hepatitis syndrome
EGR2	Orphanet:101084	Charcot-Marie-Tooth disease type 1D
EGR2	Orphanet:64748	Dejerine-Sottas syndrome
EGR2	Orphanet:99951	Charcot-Marie-Tooth disease type 4E
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
FPR1	Orphanet:447740	Aggressive periodontitis
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
HSD11B1	Orphanet:168588	Hyperandrogenism due to cortisone reductase deficiency
ICOS	Orphanet:695183	Late-onset combined immunodeficiency due to ICOS deficiency
IFNG	Orphanet:699618	Severe mendelian susceptibility to mycobacterial diseases due to complete IFNG deficiency
IFNG	Orphanet:805	Tuberous sclerosis complex

Cohort genes → proteins

75 cohort genes, 74 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	73
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ATXN2	HGNC:10555	ENSG00000204842	Q99700	Ataxin-2	gwas
SCNN1A	HGNC:10599	ENSG00000111319	P37088	Epithelial sodium channel subunit alpha	gwas
STX17	HGNC:11432	ENSG00000136874	P56962	Syntaxin-17	gwas
TNFRSF1A	HGNC:11916	ENSG00000067182	P19438	Tumor necrosis factor receptor superfamily member 1A	gwas
TNFSF18	HGNC:11932	ENSG00000120337	Q9UNG2	Tumor necrosis factor ligand superfamily member 18	gwas
TNFSF4	HGNC:11934	ENSG00000117586	P23510	Tumor necrosis factor ligand superfamily member 4	gwas
TRPS1	HGNC:12340	ENSG00000104447	Q9UHF7	Zinc finger transcription factor Trps1	clinvar
USP15	HGNC:12613	ENSG00000135655	Q9Y4E8	Ubiquitin carboxyl-terminal hydrolase 15	gwas
VDAC1	HGNC:12669	ENSG00000213585	P21796	Non-selective voltage-gated ion channel VDAC1	gwas
IKZF4	HGNC:13179	ENSG00000123411	Q9H2S9	Zinc finger protein Eos	gwas
DEXI	HGNC:13267	ENSG00000182108	O95424	Dexamethasone-induced protein	gwas
ZNF311	HGNC:13847	ENSG00000197935	Q5JNZ3	Zinc finger protein 311	gwas
ULBP3	HGNC:14895	ENSG00000131019	Q9BZM4	UL16-binding protein 3	gwas
IL22	HGNC:14900	ENSG00000127318	Q9GZX6	Interleukin-22	gwas
DUSP22	HGNC:16077	ENSG00000112679	Q9NRW4	Dual specificity protein phosphatase 22	gwas
CD28	HGNC:1653	ENSG00000178562	P10747	T-cell-specific surface glycoprotein CD28	gwas
ANP32B	HGNC:16677	ENSG00000136938	Q92688	Acidic leucine-rich nuclear phosphoprotein 32 family member B	gwas
RAET1L	HGNC:16798	ENSG00000155918	Q5VY80	UL16-binding protein 6	gwas
IL26	HGNC:17119	ENSG00000111536	Q9NPH9	Interleukin-26	gwas
HEMGN	HGNC:17509	ENSG00000136929	Q9BXL5	Hemogen	gwas
DCLRE1B	HGNC:17641	ENSG00000118655	Q9H816	5’ exonuclease Apollo	gwas
ZNF365	HGNC:18194	ENSG00000138311	Q70YC4	Talanin	gwas
HHAT	HGNC:18270	ENSG00000054392	Q5VTY9	Protein-cysteine N-palmitoyltransferase HHAT	gwas
CCDC6	HGNC:18782	ENSG00000108091	Q16204	Coiled-coil domain-containing protein 6	gwas
HIPK1	HGNC:19006	ENSG00000163349	Q86Z02	Homeodomain-interacting protein kinase 1	gwas
THADA	HGNC:19217	ENSG00000115970	Q6YHU6	tRNA (32-2’-O)-methyltransferase regulator THADA	gwas
NANS	HGNC:19237	ENSG00000095380	Q9NR45	N-acetylneuraminate-9-phosphate synthase	gwas
C5orf15	HGNC:20656	ENSG00000113583	Q8NC54	Keratinocyte-associated transmembrane protein 2	gwas
TAFA2	HGNC:21589	ENSG00000198673	Q8N3H0	Chemokine-like protein TAFA-2	gwas
SYT14	HGNC:23143	ENSG00000143469	Q8NB59	Synaptotagmin-14	gwas
ADO	HGNC:23506	ENSG00000181915	Q96SZ5	2-aminoethanethiol dioxygenase	gwas
SLC16A9	HGNC:23520	ENSG00000165449	Q7RTY1	Monocarboxylate transporter 9	gwas
LINC01553	HGNC:23524	ENSG00000235931	A4QN01	Putative uncharacterized protein encoded by LINC01553	gwas
PSMG2	HGNC:24929	ENSG00000128789	Q969U7	Proteasome assembly chaperone 2	gwas
OLFML3	HGNC:24956	ENSG00000116774	Q9NRN5	Olfactomedin-like protein 3	gwas
EXOC2	HGNC:24968	ENSG00000112685	Q96KP1	Exocyst complex component 2	gwas
CTLA4	HGNC:2505	ENSG00000163599	P16410	Cytotoxic T-lymphocyte protein 4	gwas
SERTAD4	HGNC:25236	ENSG00000082497	Q9NUC0	SERTA domain-containing protein 4	gwas
PLEKHG6	HGNC:25562	ENSG00000008323	Q3KR16	Pleckstrin homology domain-containing family G member 6	gwas
ACOXL	HGNC:25621	ENSG00000153093	Q9NUZ1	Acyl-coenzyme A oxidase-like protein	gwas
RSBN1	HGNC:25642	ENSG00000081019	Q5VWQ0	Lysine-specific demethylase 9	gwas
C1orf74	HGNC:26319	ENSG00000162757	Q96LT6	UPF0739 protein C1orf74	gwas
HNF1A-AS1	HGNC:26785	ENSG00000241388		HNF1A antisense RNA 1	gwas
BLTP1	HGNC:26953	ENSG00000138688	Q2LD37	Bridge-like lipid transfer protein family member 1	gwas
UTP25	HGNC:28440	ENSG00000117597	Q68CQ4	U3 small nucleolar RNA-associated protein 25 homolog	gwas
ZNF577	HGNC:28673	ENSG00000161551	Q9BSK1	Zinc finger protein 577	gwas
CLEC16A	HGNC:29013	ENSG00000038532	Q2KHT3	Protein CLEC16A	gwas
SMCHD1	HGNC:29090	ENSG00000101596	A6NHR9	Structural maintenance of chromosomes flexible hinge domain-containing protein 1	clinvar
SH2B3	HGNC:29605	ENSG00000111252	Q9UQQ2	SH2B adapter protein 3	gwas
MAGI3	HGNC:29647	ENSG00000081026	Q5TCQ9	Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 3	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATXN2	Ataxin-2	Involved in EGFR trafficking, acting as negative regulator of endocytic EGFR internalization at the plasma membrane.
SCNN1A	Epithelial sodium channel subunit alpha	This is one of the three pore-forming subunits of the heterotrimeric epithelial sodium channel (ENaC), a critical regulator of sodium balance and fluid homeostasis.
STX17	Syntaxin-17	SNAREs, soluble N-ethylmaleimide-sensitive factor-attachment protein receptors, are essential proteins for fusion of cellular membranes.
TNFRSF1A	Tumor necrosis factor receptor superfamily member 1A	Receptor for TNFSF2/TNF and homotrimeric TNFSF1/lymphotoxin-alpha.
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.
TRPS1	Zinc finger transcription factor Trps1	Transcriptional repressor.
USP15	Ubiquitin carboxyl-terminal hydrolase 15	Hydrolase that removes conjugated ubiquitin from target proteins and regulates various pathways such as the TGF-beta receptor signaling, NF-kappa-B and RNF41/NRDP1-PRKN pathways.
VDAC1	Non-selective voltage-gated ion channel VDAC1	Non-selective voltage-gated ion channel that mediates the transport of anions and cations through the mitochondrion outer membrane and plasma membrane.
IKZF4	Zinc finger protein Eos	DNA-binding protein that binds to the 5’GGGAATRCC-3’ Ikaros-binding sequence.
ZNF311	Zinc finger protein 311	May be involved in transcriptional regulation.
ULBP3	UL16-binding protein 3	Binds and activates the KLRK1/NKG2D receptor, mediating natural killer cell cytotoxicity.
IL22	Interleukin-22	Cytokine that plays a critical role in modulating tissue responses during inflammation.
DUSP22	Dual specificity protein phosphatase 22	Dual specificity phosphatase; can dephosphorylate both phosphotyrosine and phosphoserine or phosphothreonine residues.
CD28	T-cell-specific surface glycoprotein CD28	Receptor that plays a role in T-cell activation, proliferation, survival and the maintenance of immune homeostasis.
ANP32B	Acidic leucine-rich nuclear phosphoprotein 32 family member B	Multifunctional protein that is involved in the regulation of many processes including cell proliferation, apoptosis, cell cycle progression or transcription.
RAET1L	UL16-binding protein 6	Binds and activates the KLRK1/NKG2D receptor, mediating natural killer cell cytotoxicity.
IL26	Interleukin-26	May play a role in local mechanisms of mucosal immunity and seems to have a pro-inflammatory function.
HEMGN	Hemogen	Regulates the proliferation and differentiation of hematopoietic cells.
DCLRE1B	5’ exonuclease Apollo	5’-3’ exonuclease that plays a central role in telomere maintenance and protection during S-phase.
ZNF365	Talanin	May play a role in uric acid excretion.
HHAT	Protein-cysteine N-palmitoyltransferase HHAT	Palmitoyl acyltransferase that catalyzes N-terminal palmitoylation of SHH; which is required for SHH signaling.
HIPK1	Homeodomain-interacting protein kinase 1	Serine/threonine-protein kinase involved in transcription regulation and TNF-mediated cellular apoptosis.
THADA	tRNA (32-2’-O)-methyltransferase regulator THADA	Together with methyltransferase FTSJ1, methylates the 2’-O-ribose of nucleotides at position 32 of the anticodon loop of substrate tRNAs.
NANS	N-acetylneuraminate-9-phosphate synthase	Catalyzes the condensation of phosphoenolpyruvate (PEP) and N-acetylmannosamine 6-phosphate (ManNAc-6-P) to synthesize N-acetylneuraminate-9-phosphate (Neu5Ac-9-P).
TAFA2	Chemokine-like protein TAFA-2	Has a role as neurotrophic factor involved in neuronal survival and neurobiological functions.
SYT14	Synaptotagmin-14	May be involved in the trafficking and exocytosis of secretory vesicles in non-neuronal tissues.
ADO	2-aminoethanethiol dioxygenase	Plays a vital role in regulating thiol metabolism and preserving oxygen homeostasis by oxidizing the sulfur of cysteamine and N-terminal cysteine-containing proteins to their corresponding sulfinic acids using O2 as a cosubstrate.
SLC16A9	Monocarboxylate transporter 9	Extracellular pH-and Na(+)-sensitive low-affinity creatine transporter.
PSMG2	Proteasome assembly chaperone 2	Chaperone protein which promotes assembly of the 20S proteasome as part of a heterodimer with PSMG1.
OLFML3	Olfactomedin-like protein 3	Secreted scaffold protein that plays an essential role in dorsoventral patterning during early development.
EXOC2	Exocyst complex component 2	Component of the exocyst complex involved in the docking of exocytic vesicles with fusion sites on the plasma membrane.
CTLA4	Cytotoxic T-lymphocyte protein 4	Inhibitory receptor acting as a major negative regulator of T-cell responses.
PLEKHG6	Pleckstrin homology domain-containing family G member 6	Guanine nucleotide exchange factor activating the small GTPase RHOA, which, in turn, induces myosin filament formation.
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.
BLTP1	Bridge-like lipid transfer protein family member 1	Bridge-like lipid transfer protein that functions as molecular bridges between endoplasmic reticulum and the membranes targeted for lipid delivery.
UTP25	U3 small nucleolar RNA-associated protein 25 homolog	Component of the ribosomal small subunit processome for the biogenesis of ribosomes, functions in pre-ribosomal RNA (pre-rRNA) processing.
ZNF577	Zinc finger protein 577	May be involved in transcriptional regulation.
CLEC16A	Protein CLEC16A	Regulator of mitophagy through the upstream regulation of the RNF41/NRDP1-PRKN pathway.
SMCHD1	Structural maintenance of chromosomes flexible hinge domain-containing protein 1	Non-canonical member of the structural maintenance of chromosomes (SMC) protein family that plays a key role in epigenetic silencing by regulating chromatin architecture.
SH2B3	SH2B adapter protein 3	Links T-cell receptor activation signal to phospholipase C-gamma-1, GRB2 and phosphatidylinositol 3-kinase.
MAGI3	Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 3	Acts as a scaffolding protein at cell-cell junctions, thereby regulating various cellular and signaling processes.
ADAD1	Adenosine deaminase domain-containing protein 1	Required for male fertility and normal male germ cell differentiation.
TRAF3IP3	TRAF3-interacting JNK-activating modulator	Adapter protein that plays essential roles in both innate and adaptive immunity.
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).
EGR2	E3 SUMO-protein ligase EGR2	Sequence-specific DNA-binding transcription factor.
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.
FPR1	N-formyl peptide receptor 1	Pattern recognition G-protein coupled receptor (PRR/GPCR) involved in innate recognition of N-formyl-methionyl peptides derived from invading microbes and host mitochondria as pathogen- and damage-associated molecular patterns (PAMPs and D…
FPR2	N-formyl peptide receptor 2	Pattern recognition G protein-coupled receptor (GPCR) that recognizes peptides with N-terminal formyl methionine, which are derived from invading pathogens or host mitochondria as pathogen or damage-associated molecular patterns (PAMPs and…

Protein-family classification

Druggable: 20 · Difficult: 9 · Unknown: 46 · Druggable fraction: 0.27

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
Complement	2	7.2×	0.239
Antibody/Immunoglobulin	6	2.3×	0.239
Other/Unknown	46	1.1×	0.729
Phosphatase	1	1.1×	0.955
Kinase	3	1.1×	0.955
Transporter	1	1.0×	0.955
GPCR	3	1.0×	0.955
Transcription factor	7	0.8×	0.955
Protease	1	0.5×	0.955
Enzyme (other)	3	0.5×	0.955
Scaffold/PPI	2	0.5×	0.955

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATXN2	Other/Unknown	no		LsmAD_domain, PAM2_motif, LSM_dom_sf
SCNN1A	Other/Unknown	no		ENaC, ENaC_chordates, ENaC_CS
STX17	Other/Unknown	no		T_SNARE_dom, Syntaxin/epimorphin_CS, SNARE
TNFRSF1A	Other/Unknown	no		Death_dom, TNFR/NGFR_Cys_rich_reg, DEATH-like_dom_sf
TNFSF18	Other/Unknown	no		TNF_dom, Tumour_necrosis_fac-like_dom, TNFSF18
TNFSF4	Other/Unknown	no		TNF_dom, Tumour_necrosis_fac-like_dom, TNF_CS
TRPS1	Transcription factor	no		Znf_GATA, Znf_C2H2_type, Znf_NHR/GATA
USP15	Protease	yes		Peptidase_C19_UCH, Pept_C19_DUSP, RNA3’P_cycl/enolpyr_Trfase_a/b
VDAC1	Other/Unknown	no		Porin_Euk, Porin_dom_sf, Porin_Euk/Tom40
IKZF4	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Ikaros_C2H2-ZF
DEXI	Other/Unknown	no		Dexamethasone-induced
ZNF311	Transcription factor	no		KRAB, Znf_C2H2_type, KRAB_dom_sf
ULBP3	Other/Unknown	no		MHC_I-like_Ag-recog, MHC_I/II-like_Ag-recog, MHC_I-like_Ag-recog_sf
IL22	Other/Unknown	no		4_helix_cytokine-like_core, IL-10_CS, IL-22
DUSP22	Phosphatase	yes		Dual-sp_phosphatase_cat-dom, Tyr_Pase_dom, TYR_PHOSPHATASE_DUAL_dom
CD28	Antibody/Immunoglobulin	yes		CD28, Ig_V-set, Ig-like_fold
ANP32B	Other/Unknown	no		Leu-rich_rpt, U2A’_phosphoprotein32A_C, LRR_dom_sf
RAET1L	Other/Unknown	no		MHC_I-like_Ag-recog, MHC_I/II-like_Ag-recog, MHC_I-like_Ag-recog_sf
IL26	Other/Unknown	no		4_helix_cytokine-like_core, IL-10_CS, IL-10/19/20/24/26
HEMGN	Other/Unknown	no		Hemogen
DCLRE1B	Other/Unknown	no		DRMBL, RibonucZ/Hydroxyglut_hydro
ZNF365	Transcription factor	no		GenomicStab_NeuMorph_Reg, FBX41/ZN365_Znf-C2H2
HHAT	Other/Unknown	no		MBOAT_fam, MB_O-acyltransferase
CCDC6	Other/Unknown	no		DUF2046
HIPK1	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
THADA	Other/Unknown	no		ARM-type_fold, THADA/TRM732_DUF2428, tRNA_methyltransferase_THADA
NANS	Enzyme (other)	yes	2.5.1.132	Antifreeze_III, SAF_AFP_Neu5Ac, PseI/NeuA/B-like_N
C5orf15	Other/Unknown	no		KCT2
TAFA2	Other/Unknown	no		Chemokine-like_TAFA, TAFA_chemokine-like
SYT14	Other/Unknown	no		C2_dom, C2_domain_sf, SYT14/14L/16
ADO	Enzyme (other)	yes	1.13.11.19	RmlC_Cupin_sf, PCO/ADO, RmlC-like_jellyroll
SLC16A9	Transporter	yes		MFS, MFS_dom, MCT9
LINC01553	Other/Unknown	no
PSMG2	Other/Unknown	no		Proteasome_assmbl_chp_2_euk, Proteasome_assmbl_chaperone_2, PSMG2_sf
OLFML3	Other/Unknown	no		Olfac-like_dom, Olfactomedin-like_domain
EXOC2	Antibody/Immunoglobulin	yes		IPT_dom, Ig-like_fold, Ig_E-set
CTLA4	Antibody/Immunoglobulin	yes		Ig_sub, CTLA4, Ig_V-set
SERTAD4	Other/Unknown	no		SERTA_dom, SERTAD4
PLEKHG6	Scaffold/PPI	no		DH_dom, PH_domain, PH-like_dom_sf
ACOXL	Other/Unknown	no		Acyl-CoA_oxidase_C, AcylCoA_DH/ox_M, AcylCoA_DH/oxidase_NM_dom_sf
RSBN1	Other/Unknown	no		RSBN1/Dpy-2/CEP530
C1orf74	Other/Unknown	no		DUF4504
HNF1A-AS1	Other/Unknown	no
BLTP1	Other/Unknown	no		BLTP1, BLTP1_N, BLTP1_M
UTP25	Other/Unknown	no		UTP25, P-loop_NTPase, UTP25_C
ZNF577	Transcription factor	no		KRAB, Znf_C2H2_type, KRAB_dom_sf
CLEC16A	Other/Unknown	no		CLEC16A/TT9_N, CLEC16A/TT9, CLEC16A/TT9_C
SMCHD1	Other/Unknown	no		SMC_hinge, SMC_hinge_sf, HATPase_C_sf
SH2B3	Scaffold/PPI	no		SH2, PH_domain, PH-like_dom_sf
MAGI3	Kinase	yes		WW_dom, PDZ, Guanylate_kin-like_dom

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
male germ line stem cell (sensu Vertebrata) in testis	12
primordial germ cell in gonad	9
buccal mucosa cell	8
secondary oocyte	8
calcaneal tendon	7
vermiform appendix	7
monocyte	6
lymph node	6
granulocyte	6
gall bladder	5
leukocyte	5
blood	4
sperm	4
mucosa of transverse colon	4
left testis	4
colonic epithelium	3
mononuclear cell	3
cortical plate	3
olfactory segment of nasal mucosa	3
rectum	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATXN2	286	ubiquitous	marker	buccal mucosa cell, colonic epithelium, olfactory bulb
SCNN1A	283	broad	marker	nasal cavity epithelium, metanephros cortex, right uterine tube
STX17	274	ubiquitous	marker	nipple, secondary oocyte, calcaneal tendon
TNFRSF1A	292	ubiquitous	marker	tendon of biceps brachii, gall bladder, left uterine tube
TNFSF18	98	broad	yes	male germ line stem cell (sensu Vertebrata) in testis, gall bladder, stromal cell of endometrium
TNFSF4	181	broad	marker	primordial germ cell in gonad, monocyte, mononuclear cell
TRPS1	284	ubiquitous	marker	mammary duct, epithelium of mammary gland, calcaneal tendon
USP15	294	broad	marker	monocyte, mononuclear cell, leukocyte
VDAC1	295	ubiquitous	marker	biceps brachii, skeletal muscle tissue of biceps brachii, gastrocnemius
IKZF4	242	ubiquitous	marker	buccal mucosa cell, left adrenal gland, adrenal cortex
DEXI	282	ubiquitous	yes	apex of heart, hindlimb stylopod muscle, left adrenal gland cortex
ZNF311	127	broad	yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, cortical plate
ULBP3	180	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, kidney epithelium, epithelial cell of pancreas
IL22	57		marker	buccal mucosa cell, diaphragm, pancreatic ductal cell
DUSP22	286	ubiquitous	marker	secondary oocyte, cervix squamous epithelium, gingival epithelium
CD28	154	broad	marker	lymph node, vermiform appendix, blood
ANP32B	295	ubiquitous	marker	tendon of biceps brachii, trabecular bone tissue, cranial nerve II
RAET1L	63	tissue_specific	yes	lower esophagus mucosa, esophagus mucosa, vagina
IL26	44	tissue_specific	yes	vermiform appendix, decidua, lower lobe of lung
HEMGN	106	broad	marker	trabecular bone tissue, sperm, bone marrow
DCLRE1B	224	ubiquitous	yes	secondary oocyte, primordial germ cell in gonad, oocyte
ZNF365	206	broad	yes	middle temporal gyrus, lateral nuclear group of thalamus, Brodmann (1909) area 23
HHAT	137	ubiquitous	yes	male germ line stem cell (sensu Vertebrata) in testis, olfactory segment of nasal mucosa, primordial germ cell in gonad
CCDC6	283	ubiquitous	marker	secondary oocyte, oocyte, esophagus squamous epithelium
HIPK1	294	ubiquitous	marker	bronchial epithelial cell, cerebellar vermis, epithelium of bronchus
THADA	276	ubiquitous	marker	calcaneal tendon, right uterine tube, right lobe of thyroid gland
NANS	285	ubiquitous	marker	mucosa of sigmoid colon, mucosa of transverse colon, rectum
C5orf15	303	ubiquitous	marker	tibia, bronchial epithelial cell, germinal epithelium of ovary
TAFA2	201	broad	marker	secondary oocyte, buccal mucosa cell, primary visual cortex
SYT14	89	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, cortical plate, islet of Langerhans

Protein interactions among cohort

Intra-cohort edges: 50.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IFNG	7,383
VDAC1	5,780
TNFRSF1A	4,523
ERBB3	4,511
HSD11B1	3,931
CTLA4	3,863
MAGI3	3,725
IRF4	3,450
IL13	3,427
USP15	3,366

Intra-cohort edges

A	B	Sources
ACOXL	LRRC32	string_interaction
ADAD1	BLTP1	string_interaction
ADAD1	SH2B3	string_interaction
ADO	EGR2	string_interaction
AP4B1	BCL2L15	string_interaction
AP4B1	RSBN1	string_interaction
ATXN2	SH2B3	string_interaction
BCL2L15	MAGI3	string_interaction
BCL2L15	RSBN1	string_interaction
BLTP1	SH2B3	string_interaction
C1orf74	TRAF3IP3	string_interaction
C1orf74	UTP25	string_interaction
CD28	CTLA4	intact, string_interaction
CD28	ICOS	string_interaction
CD28	TNFSF18	string_interaction
CD28	TNFSF4	string_interaction
CLEC16A	DEXI	string_interaction
CLEC16A	SH2B3	string_interaction
CTLA4	ICOS	string_interaction
CTLA4	IKZF4	string_interaction
CTLA4	LRRC32	string_interaction
CTLA4	TNFSF18	string_interaction
CTLA4	ULBP3	biogrid_interaction
DCLRE1B	RSBN1	string_interaction
DUSP22	EXOC2	string_interaction
DUSP22	IRF4	string_interaction
ERBB3	SH2B3	intact
FOXE1	HEMGN	string_interaction
FOXE1	IRF6	string_interaction
FOXE1	TRMO	string_interaction
HEMGN	TRMO	string_interaction
HLA-DQA2	IFNG	string_interaction
ICOS	IL21	string_interaction
ICOS	TNFSF4	string_interaction
IFNG	IL13	string_interaction
IFNG	IL21	string_interaction
IFNG	IL22	string_interaction
IKZF4	IL2RA	string_interaction
IKZF4	IRF4	string_interaction
IKZF4	LRRC32	string_interaction
IL15RA	IL2RA	string_interaction
IL2	IL2RA	intact
IL22	IL26	string_interaction
IL2RA	ULBP3	biogrid_interaction
IRF6	UTP25	string_interaction
MAGI3	SMCHD1	intact
OLFML3	RSBN1	string_interaction
SERTAD4	SYT14	string_interaction
STX17	ULBP3	string_interaction
TNFSF18	TNFSF4	string_interaction

Structural data

PDB: 41 · AlphaFold-only: 33 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HSD11B1	P28845	42
IL2	P60568	37
ERBB3	P21860	23
CTLA4	P16410	22
IRF4	Q15306	19
USP15	Q9Y4E8	15
TNFRSF1A	P19438	13
PSMG2	Q969U7	13
FPR2	P25090	13
IL13	P35225	13
VDAC1	P21796	12
CD28	P10747	10
HHAT	Q5VTY9	10
HLA-DQB1	P01920	10
IL2RA	P01589	10
ADO	Q96SZ5	9
DUSP22	Q9NRW4	8
IFNG	P01579	8
TNFSF18	Q9UNG2	7
IL22	Q9GZX6	6
LRRC32	Q14392	6
DCLRE1B	Q9H816	5
FPR1	P21462	5
AP4B1	Q9Y6B7	5
ANP32B	Q92688	4
IL15RA	Q13261	4
SCNN1A	P37088	3
STX17	P56962	3
IL21	Q9HBE4	3
RAET1L	Q5VY80	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACOXL	Q9NUZ1	92.00
C1orf74	Q96LT6	90.75
HLA-DQA2	P01906	89.29
TAFA2	Q8N3H0	87.99
OLFML3	Q9NRN5	87.21
IL26	Q9NPH9	85.81
FPR3	P25089	83.62
EXOC2	Q96KP1	80.82
UTP25	Q68CQ4	78.78
ADAD1	Q96M93	78.19
SLC16A9	Q7RTY1	76.70
TRAF3IP3	Q9Y228	74.77
IRF6	O14896	74.19
CLEC16A	Q2KHT3	72.17
DEXI	O95424	69.88
PLEKHG6	Q3KR16	68.36
TRMO	Q9BU70	67.98
SYT14	Q8NB59	65.50
ZNF311	Q5JNZ3	65.02
ZNF577	Q9BSK1	64.28
SH2B3	Q9UQQ2	63.45
RSBN1	Q5VWQ0	62.96
FOXE1	O00358	62.02
C5orf15	Q8NC54	57.94
HEMGN	Q9BXL5	54.29
HIPK1	Q86Z02	52.62
SERTAD4	Q9NUC0	52.58
LINC01553	A4QN01	52.48
SERTAD4-AS1	Q5TG53	51.60
TRPS1	Q9UHF7	49.12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 180. Enrichment computed across 88 evidence-associated genes (56 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 56 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs)	4	81.6×	2e-05	CTLA4, IFNG, IL2, IL2RA
Formyl peptide receptors bind formyl peptides and many other ligands	3	76.5×	4e-04	FPR1, FPR2, FPR3
Interferon gamma signaling	6	13.4×	4e-04	HLA-DQA2, HLA-DQB1, IFNG, IRF4, IRF6, CIITA
TNFs bind their physiological receptors	3	21.1×	0.017	TNFRSF1A, TNFSF18, TNFSF4
Interleukin-2 signaling	2	34.0×	0.054	IL2, IL2RA
Regulation of IFNG signaling	2	29.1×	0.062	IFNG, PTPN2
Translocation of ZAP-70 to Immunological synapse	2	22.7×	0.088	HLA-DQA2, PTPN22
Phosphorylation of CD3 and TCR zeta chains	2	19.4×	0.105	HLA-DQA2, PTPN22
Nef mediated downregulation of CD28 cell surface expression	1	102.0×	0.133	CD28
Interleukin-20 family signaling	2	15.1×	0.133	IL22, IL26
Interleukin receptor SHC signaling	2	14.6×	0.133	IL2, IL2RA
Co-stimulation by CD28	2	13.6×	0.133	CD28, CTLA4
FLT3 Signaling	2	12.4×	0.133	SH2B3, BCL2L11
Constitutive Signaling by Aberrant PI3K in Cancer	3	6.8×	0.133	CD28, ERBB3, ICOS
Interferon Signaling	3	6.4×	0.133	IRF4, IRF6, CIITA
Cytokine Signaling in Immune system	5	3.6×	0.133	SH2B3, IRF4, IRF6, CIITA, BCL2L11
Nuclear events stimulated by ALK signaling in cancer	2	11.7×	0.134	ICOS, IRF4
Activation of BIM and translocation to mitochondria	1	51.0×	0.190	BCL2L11
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	3	5.2×	0.190	CD28, ERBB3, ICOS
HHAT G278V doesn’t palmitoylate Hh-Np	1	40.8×	0.199	HHAT
RUNX3 regulates BCL2L11 (BIM) transcription	1	40.8×	0.199	BCL2L11
Interleukin-10 signaling	2	8.3×	0.199	TNFRSF1A, FPR1
GRB7 events in ERBB2 signaling	1	34.0×	0.209	ERBB3
TNFR1-mediated ceramide production	1	34.0×	0.209	TNFRSF1A
Sensory perception of salty taste	1	34.0×	0.209	SCNN1A
Suppression of apoptosis	1	29.1×	0.234	TRIM27
Interleukin-18 signaling	1	25.5×	0.248	IL13
IFNG signaling activates MAPKs	1	25.5×	0.248	IFNG
BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members	1	22.7×	0.252	BCL2L11
Prednisone ADME	1	22.7×	0.252	HSD11B1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 78 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
immune response	12	7.2×	5e-05	TNFSF4, ULBP3, RAET1L, IL26, CTLA4, HLA-DQA2, HLA-DQB1, ICOS (+4 more)
positive regulation of interleukin-10 production	5	25.7×	3e-04	TNFSF4, CD28, IL13, IL21, IRF4
negative regulation of inflammatory response	7	12.3×	3e-04	TNFRSF1A, IL22, FPR2, IL13, IL2, IL2RA, PTPN2
positive regulation of cytokine production	5	17.4×	0.002	TNFSF4, CD28, IL26, IFNG, IL21
regulation of CD4-positive, alpha-beta T cell proliferation	2	216.1×	0.002	IL2, IL2RA
positive regulation of immunoglobulin production	4	24.7×	0.002	TNFSF4, IL13, IL2, IL21
positive regulation of inflammatory response	6	11.2×	0.002	TNFRSF1A, TNFSF18, TNFSF4, IFNG, IL2, IL21
complement receptor mediated signaling pathway	3	43.2×	0.003	FPR1, FPR2, FPR3
regulation of T cell homeostatic proliferation	2	144.0×	0.004	IL2, IL2RA
negative regulation of T cell receptor signaling pathway	4	18.8×	0.004	DUSP22, CTLA4, PTPN2, PTPN22
positive regulation of tyrosine phosphorylation of STAT protein	3	28.2×	0.009	TNFSF18, IFNG, IL21
negative regulation of regulatory T cell differentiation	2	86.4×	0.010	TNFSF4, CTLA4
inflammatory response	9	4.3×	0.010	TNFRSF1A, TNFSF4, IL22, FPR1, FPR2, FPR3, IL13, IL2RA (+1 more)
microglial cell activation	3	24.0×	0.011	FPR2, IFNG, IL13
positive regulation of tissue remodeling	2	72.0×	0.013	IL2, IL21
adaptive immune response	6	6.5×	0.013	TNFSF18, CTLA4, HLA-DQA2, HLA-DQB1, IFNG, IL2
positive regulation of interleukin-4 production	3	21.6×	0.013	TNFSF4, CD28, IRF4
Schwann cell differentiation	2	61.7×	0.014	EGR2, ERBB3
negative regulation of T cell activation	3	20.2×	0.014	DUSP22, CTLA4, PTPN22
positive regulation of type II interferon production	4	11.5×	0.014	TNFSF4, IL2, IL21, PTPN22
interleukin-2-mediated signaling pathway	2	54.0×	0.017	IL2, IL2RA
extrinsic apoptotic signaling pathway in absence of ligand	3	18.0×	0.017	ERBB3, IL2, BCL2L11
activated T cell proliferation	2	48.0×	0.020	IL2, IL2RA
positive regulation of natural killer cell differentiation	2	43.2×	0.024	IL15RA, IL21
positive regulation of isotype switching to IgG isotypes	2	39.3×	0.025	CD28, IL2
positive regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway	2	39.3×	0.025	PTPN2, BCL2L11
immune system process	3	15.1×	0.025	DUSP22, IRF4, IRF6
T cell differentiation	3	14.7×	0.025	IL2, PTPN2, PTPN22
T follicular helper cell differentiation	2	36.0×	0.029	ICOS, IL21
antigen processing and presentation of endogenous peptide antigen via MHC class Ib	2	33.2×	0.031	ULBP3, RAET1L

Therapeutics

Drugs indicated for this disease

0 approved, 8 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Baricitinib	Phase 3 (in late-stage trials)
Clobetasol Propionate	Phase 3 (in late-stage trials)
Diphtheria Toxoid	Phase 3 (in late-stage trials)
Garlic	Phase 3 (in late-stage trials)
Hydrocortisone	Phase 3 (in late-stage trials)
Methotrexate	Phase 3 (in late-stage trials)
Ritlecitinib	Phase 3 (in late-stage trials)
Upadacitinib	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Abatacept, Amlitelimab, Bexarotene, Brepocitinib, Crisaborole, Delgocitinib, Dupilumab, Etrasimod, Hyaluronic Acid (Non-Animal Stabilized), Ruxolitinib, Secukinumab, Tofacitinib, Tralokinumab, Triamcinolone, Triamcinolone Acetonide.

Drug target analysis

Approved (phase 4): 8 · Phase ≥3: 8 · Phased (≥1): 12 · Undrugged: 63

Druggability breadth: 39 of 88 evidence-associated genes (44%) 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
SCNN1A	AMILORIDE
CCDC6	PONATINIB
HIPK1	FEDRATINIB
ERBB3	MOBOCERTINIB
FPR1	PHENYLBUTAZONE
FPR2	LOPERAMIDE HYDROCHLORIDE
FPR3	NEFAZODONE HYDROCHLORIDE
HSD11B1	FUROSEMIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ERBB3	23	4
HIPK1	21	4
HSD11B1	13	4
FPR1	11	4
FPR3	10	4
CCDC6	6	4
FPR2	4	4
SCNN1A	2	4
IL2	2	2
TNFRSF1A	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AMILORIDE	4	SCNN1A
PONATINIB	4	CCDC6
LENVATINIB	4	CCDC6
CABOZANTINIB	4	CCDC6
VANDETANIB	4	CCDC6, ERBB3
PRALSETINIB	4	CCDC6
FEDRATINIB	4	HIPK1
SORAFENIB	4	HIPK1
RUXOLITINIB	4	HIPK1
BOSUTINIB	4	ERBB3, HIPK1
NINTEDANIB	4	HIPK1
SUNITINIB	4	HIPK1
MOBOCERTINIB	4	ERBB3
AFATINIB	4	ERBB3
NERATINIB	4	ERBB3
OSIMERTINIB	4	ERBB3
DASATINIB	4	ERBB3
ERLOTINIB	4	ERBB3
LAPATINIB	4	ERBB3
GEFITINIB	4	ERBB3
PHENYLBUTAZONE	4	FPR1
MONTELUKAST SODIUM	4	FPR1
CINACALCET HYDROCHLORIDE	4	FPR1, FPR3
PENICILLIN G POTASSIUM	4	FPR1
APREPITANT	4	FPR1
LOPERAMIDE HYDROCHLORIDE	4	FPR1, FPR2
PERPHENAZINE	4	FPR1, FPR3
SULFINPYRAZONE	4	FPR1
TRIFLUOPERAZINE	4	FPR2
NEFAZODONE HYDROCHLORIDE	4	FPR3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 5.

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

Symbol	Assays	Type breakdown
HSD11B1	311	Binding:308, Functional:3
HIPK1	285	Binding:285
FPR2	194	Binding:110, Functional:84
ERBB3	169	Binding:169
FPR1	138	Functional:85, Binding:53
CCDC6	74	Binding:74
IL2	35	Binding:34, ADMET:1
TNFRSF1A	24	Binding:23, Functional:1
DUSP22	19	Binding:19
HHAT	14	Binding:14
ANP32B	9	Binding:9
FPR3	8	Functional:4, Binding:4
USP15	7	Binding:7
SMCHD1	7	Binding:7
ICOS	7	Binding:7
SCNN1A	6	Binding:4, ADMET:1, Functional:1
VDAC1	6	Binding:6
ATXN2	5	Binding:3, Functional:2
PSMG2	5	Binding:5
MAGI3	4	Binding:4
IL15RA	4	Binding:4
IRF4	3	Binding:3
IL2RA	2	Binding:2
CD28	1	Functional:1
RAET1L	1	Binding:1
DCLRE1B	1	Binding:1
NANS	1	Binding:1
CTLA4	1	Binding:1
IFNG	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NANS	2.5.1.132, 2.5.1.56, 2.5.1.57	3-deoxy-D-glycero-D-galacto-nonulopyranosonate 9-phosphate synthase, N-acetylneuraminate synthase, N-acylneuraminate-9-phosphate synthase
ADO	1.13.11.19	cysteamine dioxygenase
ERBB3	2.7.10.1	receptor protein-tyrosine kinase
FPR1	3.1.4.4	phospholipase D
HSD11B1	1.1.1.146, 1.1.1.B40	11beta-hydroxysteroid dehydrogenase,

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
HIPK1	285
ERBB3	169
FPR1	138
FPR2	194
HSD11B1	311

Pharmacogenomics

Cohort genes with a PharmGKB record: 74; 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)
AMILORIDE	4	SCNN1A
PONATINIB	4	CCDC6
LENVATINIB	4	CCDC6
CABOZANTINIB	4	CCDC6
VANDETANIB	4	CCDC6, ERBB3
PRALSETINIB	4	CCDC6
FEDRATINIB	4	HIPK1
SORAFENIB	4	HIPK1
RUXOLITINIB	4	HIPK1
BOSUTINIB	4	ERBB3, HIPK1
NINTEDANIB	4	HIPK1
SUNITINIB	4	HIPK1
MOBOCERTINIB	4	ERBB3
AFATINIB	4	ERBB3
NERATINIB	4	ERBB3
OSIMERTINIB	4	ERBB3
DASATINIB	4	ERBB3
ERLOTINIB	4	ERBB3
LAPATINIB	4	ERBB3
GEFITINIB	4	ERBB3
PHENYLBUTAZONE	4	FPR1
MONTELUKAST SODIUM	4	FPR1
CINACALCET HYDROCHLORIDE	4	FPR1, FPR3
PENICILLIN G POTASSIUM	4	FPR1
APREPITANT	4	FPR1
LOPERAMIDE HYDROCHLORIDE	4	FPR1, FPR2
PERPHENAZINE	4	FPR1, FPR3
SULFINPYRAZONE	4	FPR1
TRIFLUOPERAZINE	4	FPR2
NEFAZODONE HYDROCHLORIDE	4	FPR3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	8	SCNN1A, CCDC6, HIPK1, ERBB3, FPR1, FPR2, FPR3, HSD11B1
B	Phased (≥1) drug, not yet approved	4	TNFRSF1A, ANP32B, SMCHD1, IL2
C	Druggable family + PDB, no drug	11	USP15, DUSP22, CD28, NANS, ADO, CTLA4, MAGI3, HLA-DQB1, ICOS, IL15RA (+1 more)
D	Druggable family + AlphaFold only, no drug	3	SLC16A9, EXOC2, HLA-DQA2
E	Difficult family or no structure, no drug	49	ATXN2, STX17, TNFSF18, TNFSF4, TRPS1, VDAC1, IKZF4, DEXI, ZNF311, ULBP3 (+39 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ATXN2	5	—
STX17	0	—
TNFSF18	0	—
TNFSF4	0	—
TRPS1	0	—
USP15	7	—
VDAC1	6	—
IKZF4	0	—
DEXI	0	—
ZNF311	0	—
ULBP3	0	—
IL22	0	—
DUSP22	19	—
CD28	1	—
RAET1L	1	—
IL26	0	—
HEMGN	0	—
DCLRE1B	1	—
ZNF365	0	—
HHAT	14	—
THADA	0	—
NANS	1	—
C5orf15	0	—
TAFA2	0	—
SYT14	0	—
ADO	0	—
SLC16A9	0	—
LINC01553	0	—
PSMG2	5	—
OLFML3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 200.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	71
PHASE2	55
PHASE4	23
PHASE3	20
PHASE1	12
PHASE1/PHASE2	8
EARLY_PHASE1	6
PHASE2/PHASE3	5

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06399783	PHASE4	NOT_YET_RECRUITING	Topical Simvastatin Versus Topical Steroid in Treatment of Alopecia Areata
NCT07381556	PHASE4	RECRUITING	Cyclosporine Or Methotrexate for Pediatric Alopecia Areata: Routine Clinical Care Effectiveness Study
NCT07406204	PHASE4	NOT_YET_RECRUITING	Tofacitinib vs Methotrexate for Severe Alopecia Areata (TOFA-MTX-AA)
NCT07453238	PHASE4	NOT_YET_RECRUITING	Comparison of Topical Calcipotriol and Intralesional Steroids in Alopecia Areata
NCT07459933	PHASE4	NOT_YET_RECRUITING	Topical Methotrexate vs Minoxidil for Localized Alopecia Areata
NCT00176943	PHASE4	COMPLETED	Characteristics of T Cells From Alopecia Areata Scalp Skin Before and After Treatment With Aldara 5%
NCT00176969	PHASE4	COMPLETED	Response of Topical Capsaicin in Alopecia Areata
NCT00176982	PHASE4	COMPLETED	Plaquenil for Alopecia Areata, Alopecia Totalis
NCT00177021	PHASE4	COMPLETED	Aldara for the Treatment of Extensive Alopecia Areata
NCT01023841	PHASE4	COMPLETED	Safety and Efficacy of Bimatoprost Solution in Treating Eyelash Loss or Hypotrichosis in Children
NCT01898806	PHASE4	TERMINATED	Intralesional Steroids in the Treatment of Alopecia Areata
NCT02350023	PHASE4	COMPLETED	Comparison of Topical Latanoprost vs Topical Corticosteroid in Treatment of Localized Alopecia Areata
NCT03473600	PHASE4	UNKNOWN	Cryotherapy Versus Steroids In Alopecia Areata:Trichoscopic Evaluation
NCT03535233	PHASE4	COMPLETED	Topical 5% Minoxidil and Potent Topical Corticosteroid Versus Intralesional Corticosteroid in the Treatment of Alopecia Areata
NCT03630198	PHASE4	COMPLETED	Pain Outcomes Following Intralesional Corticosteroid Injections
NCT03800979	PHASE4	COMPLETED	Effectiveness and Safety of Tofacitinib in Patients With Extensive and Recalcitrant Alopecia Areata
NCT04003376	PHASE4	UNKNOWN	Efficacy of Fractional CO2 Laser as a Mono- or Adjuvant Therapy for Alopecia Areata
NCT04228029	PHASE4	UNKNOWN	Comparative Study for Treatment of Alopecia Areata Using Carboxytherapy and Intralesional Steroids
NCT04412148	PHASE4	UNKNOWN	Modified SALT Score for Alopecia Areata
NCT04793945	PHASE4	UNKNOWN	Excimer Light and Topical Steroid in Treatment of Alopecia Areata
NCT05278858	PHASE4	TERMINATED	Needle-free Delivery of Intralesional Triamcinolone for Pediatric Alopecia Areata
NCT05926882	PHASE4	COMPLETED	Efficacy of Oral Apremilast in the Treatment of Alopecia Areata at the Tertiary Care Hospital, Karachi.
NCT07174011	PHASE4	COMPLETED	Evaluation of the Efficacy and Safety of Oral Roflumilast Versus Intralesional Corticosteroids Injection (ILCs) in the Treatment of Alopecia Areata
NCT03898479	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	Extension Study to Evaluate Safety and Efficacy of CTP-543 in Adults With Alopecia Areata
NCT06012240	PHASE3	RECRUITING	A Study to Evaluate the Safety and Effectiveness of Upadacitinib Tablets in Adult and Adolescent Participants With Severe Alopecia Areata
NCT06873945	PHASE3	ACTIVE_NOT_RECRUITING	A Study of 2 Doses of Ritlecitinib in People 12 Years of Age and Older With Alopecia Areata
NCT07023302	PHASE3	RECRUITING	A Study to Evaluate the Safety and Effectiveness of Upadacitinib Tablets in Adult and Adolescent Participants in Japan With Alopecia Areata
NCT07029711	PHASE3	RECRUITING	A Study to Learn About Medicine Called Ritlecitinib in Children Aged Between 6 to 12 Years With Severe Alopecia Areata
NCT07029828	PHASE3	RECRUITING	A Long-Term Study to Learn About The Study Medicine Called Ritlecitinib in Children With Severe Alopecia Areata.
NCT07133308	PHASE3	RECRUITING	Study to Evaluate the Efficacy and Safety of Deuruxolitinib in Adolescents With Severe Alopecia Areata
NCT00063076	PHASE2/PHASE3	COMPLETED	Phase II Randomized Bilateral Comparison of Topical Targretin Gel 1% in Alopecia Areata
NCT01453686	PHASE3	COMPLETED	A Trial of Clobetasol Propionate Versus Hydrocortisone in Children With Alopecia Areata
NCT02037191	PHASE3	COMPLETED	The Efficiency Of The Methotrexate At Patients Affected By Grave Pelade
NCT02557074	PHASE3	COMPLETED	TREg Activation in the Treatment of the PELADE (Alopecia Areata)
NCT02691117	PHASE3	TERMINATED	Topical Garlic Concentrate for Alopecia Areata in Children
NCT03240627	PHASE2/PHASE3	COMPLETED	Efficacy and Safety of LH-8 in Paediatric Alopecia Areata
NCT03570749	PHASE2/PHASE3	COMPLETED	A Study of Baricitinib (LY3009104) in Participants With Severe or Very Severe Alopecia Areata
NCT03651752	PHASE3	TERMINATED	DPCP for the Treatment of Alopecia Areata
NCT03732807	PHASE2/PHASE3	COMPLETED	PF-06651600 for the Treatment of Alopecia Areata
NCT03899259	PHASE3	COMPLETED	A Study of Baricitinib (LY3009104) in Adults With Severe or Very Severe Alopecia Areata

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
TOFACITINIB	4	13
RITLECITINIB	4	12
TRIAMCINOLONE ACETONIDE	4	4
CALCIPOTRIENE	4	3
CRAVACITINIB	4	3
MINOXIDIL	4	3
UPADACITINIB	4	3
ABROCITINIB	4	2
BARICITINIB	4	2
BETAMETHASONE VALERATE	4	2
BIMATOPROST	4	2
CLOBETASOL PROPIONATE	4	2
ABATACEPT	4	1
ALEFACEPT	4	1
APREMILAST	4	1
AZATHIOPRINE	4	1
CAPSAICIN	4	1
CETIRIZINE	4	1
CRISABOROLE	4	1
ERGOCALCIFEROL	4	1
ETRASIMOD	4	1
HYDROCORTISONE	4	1
HYDROXYCHLOROQUINE	4	1
LACTIC ACID	4	1
LATANOPROST	4	1
MOMETASONE FUROATE	4	1
ROFLUMILAST	4	1
SIMVASTATIN	4	1
TRALOKINUMAB	4	1
DEURUXOLITINIB	3	9