Anti-neutrophil antibody associated vasculitis

Summary

Anti-neutrophil antibody associated vasculitis (MONDO:0005435) is a disease with 25 cohort genes (32 GWAS associations across 7 studies). The dominant Reactome pathway is Translocation of ZAP-70 to Immunological synapse (5 cohort genes).

At a glance

• Cohort genes: 25
• GWAS associations: 32

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	anti-neutrophil antibody associated vasculitis
Mondo ID	MONDO:0005435
EFO	EFO:0004826
Is cancer (heuristic)	no

Data availability: 32 GWAS associations (7 studies).

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › autoimmune disease › anti-neutrophil antibody associated vasculitis

Related subtypes (46): autoimmune disease, multisystem, infantile-onset, autoimmune disorder of endocrine system, autoimmune disorder of exocrine system, autoimmune disease of ear, nose and throat, autoimmune disorder of gastrointestinal tract, autoimmune disorder of musculoskeletal system, autoimmune disorder of blood, autoimmune disorder of cardiovascular system, phacolytic glaucoma, Jaccoud syndrome, autoimmune disorder of the nervous system, lupus erythematosus, cryoglobulinemia, CNS demyelinating autoimmune disease, type III hypersensitivity disease, vitiligo, anti-glomerular basement membrane disease, autoimmune pulmonary alveolar proteinosis, Reynolds syndrome, overlapping connective tissue disease, tempi syndrome, immunoglobulin G4-related sclerosing disease, rheumatic fever, autoerythrocyte sensitization syndrome, autoimmune lymphoproliferative syndrome, secondary neonatal autoimmune disease, euthyroid Graves orbitopathy, Kimura disease, autoimmune thrombocytopenia, autoimmune bullous skin disease, scleroderma, Susac syndrome, undifferentiated connective tissue syndrome, type II hypersensitivity reaction disease, autoimmune urticaria, autoimmune glomerulonephritis, multisystem autoimmune disease due to IKAROS gain of function, autoimmune pulmonary disease due to PD-1 deficiency, non-specific autoimmune supratentorial encephalitis with characteristic antibodies, non-specific autoimmune supratentorial encephalitis without characteristic antibodies, non-specific autoimmune brainstem encephalitis with characteristic antibodies, non-specific autoimmune brainstem encephalitis without characteristic antibodies, non-specific autoimmune cerebellar ataxia with characteristic antibodies, non-specific autoimmune cerebellar ataxia without characteristic antibodies, autoimmune disease with susceptibility to mycobacterium tuberculosis, antiphospholipid syndrome

Genetics & variants

GWAS landscape

32 GWAS associations across 7 studies. Top hits map to 12 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs141530233	1e-89	HLA-DPB1	?	2.99
rs3117242	1e-71	HLA-DPA2 - COL11A2P1	?	3.67
rs9277341	6e-71	HLA-DPA1	T	2.44
rs6638512	2e-25	MTCYBP12 - HADHBP1	?
rs7454108	5e-25	MTCO3P1 - HLA-DQB3	C	2.73
rs1972809	1e-24	GLRX5P1 - PA2G4P1	?	1.28
rs35242582	6e-23	HLA-DQA1	A	1.6
rs5941160	2e-20	CPXCR1 - SRIP2	?
rs2755459	9e-14	UBE2V1P9 - RNU6-555P	?	1.67
rs28929474	3e-12	SERPINA1	T	2.18
rs62132293	9e-11	AZU1 - PRTN3	G	1.29
rs1042544	4e-10	HLA-DPB1	?	0.26
HLA-DPB1*04	7e-10		?	0.34
rs7151526	2e-09	SERPINA1 - SERPINA11	?	1.69
rs5954596	5e-09	MAGEC2 - RNA5SP516	?
rs5904818	2e-08	FMR1 - FMR1NB	?
rs6679677	2e-08	PHTF1 - RSBN1	A	1.4
rs6618677	4e-08	PABPC5 - SERBP1P4	?	1.43
rs3130215	3e-07	COL11A2P1	?	5.67
rs17281398	4e-07	F8	?
rs17057678	6e-07	ARHGAP18 - RPL5P21	?	1.25
rs7059886	1e-06	ASS1P4 - SNORA48B	?	1.16
rs17065868	3e-06	TSC22D1	?
rs1623523	3e-06	MYL12B - LINC01895	?
rs185694	4e-06	KATNAL1 - LINC00427	?
rs6721691	4e-06	BABAM2	?	2.7
rs35859035	6e-06	LINC02208, LINC02147	?	3.42
rs11875185	7e-06	RSL24D1P11 - LINC01897	?
rs2111622	8e-06	ASB3	?	2.87
rs11010290	9e-06	RPL7P37 - PCAT5	?

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST003976	Merkel PA	2016	1,015	3,258	Identification of Functional and Expression Polymorphisms Associated With Risk for Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis.
GCST001613	Lyons PA	2012	914	5,259	Genetically distinct subsets within ANCA-associated vasculitis.
GCST003978	Merkel PA	2016	882	882	Identification of Functional and Expression Polymorphisms Associated With Risk for Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis.
GCST003977	Merkel PA	2016	324	324	Identification of Functional and Expression Polymorphisms Associated With Risk for Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis.
GCST90270215	Gibson KM	2022	119	0	HLA-DPB1 is associated with ANCA-associated vasculitis in children.
GCST90270213	Gibson KM	2022	63	0	HLA-DPB1 is associated with ANCA-associated vasculitis in children.
GCST90270214	Gibson KM	2022	56	0	HLA-DPB1 is associated with ANCA-associated vasculitis in children.

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	27

MAF distribution

Bucket	Variants
common (>=0.05)	29
low_freq (0.01-0.05)	1
rare (<0.01)	0
unknown	1

Functional consequences

Consequence	Count
intron_variant	14
intergenic_variant	12
frameshift_variant	1
missense_variant	1
3_prime_UTR_variant	1
unknown	1
regulatory_region_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs141530233	6	33080912	G>GA	0.3	frameshift_variant	HLA-DPB1	1e-89	Tier 1: coding
rs3117242	6	33102116	A>G	0.05	intergenic_variant	HLA-DPA2 - COL11A2P1	1e-71	Tier 4: intronic/intergenic
rs9277341	6	33071848	T>A,C,G	0.3	intron_variant	HLA-DPA1	6e-71	Tier 4: intronic/intergenic
rs6638512	X	5266661	C>G,T	0.05	intergenic_variant	MTCYBP12 - HADHBP1	2e-25	Tier 4: intronic/intergenic
rs7454108	6	32713706	T>C	0.1	intergenic_variant	MTCO3P1 - HLA-DQB3	5e-25	Tier 4: intronic/intergenic
rs1972809	X	120733621	A>G	0.05	intron_variant	GLRX5P1 - PA2G4P1	1e-24	Tier 4: intronic/intergenic
rs35242582	6	32632280	A>G	0.26	intergenic_variant	HLA-DQA1	6e-23	Tier 4: intronic/intergenic
rs5941160	X	89275066	T>G	0.05	intergenic_variant	CPXCR1 - SRIP2	2e-20	Tier 4: intronic/intergenic
rs2755459	X	90549128	A>C,G	0.05	intergenic_variant	UBE2V1P9 - RNU6-555P	9e-14	Tier 4: intronic/intergenic
rs28929474	14	94378610	C>A,G,T	0.02	missense_variant	SERPINA1	3e-12	Tier 1: coding
rs62132293	19	838178	C>G	0.31	intergenic_variant	AZU1 - PRTN3	9e-11	Tier 4: intronic/intergenic
rs1042544	6	33086680	A>G	0.05	3_prime_UTR_variant	HLA-DPB1	4e-10	Tier 2: splice/UTR
HLA-DPB1*04							7e-10	Tier 4: intronic/intergenic
rs7151526	14	94397299	C>A	0.05	intron_variant	SERPINA1 - SERPINA11	2e-09	Tier 4: intronic/intergenic
rs5954596	X	142272785	C>T	0.05	intron_variant	MAGEC2 - RNA5SP516	5e-09	Tier 4: intronic/intergenic
rs5904818	X	147961254	C>T	0.05	intergenic_variant	FMR1 - FMR1NB	2e-08	Tier 4: intronic/intergenic
rs6679677	1	113761186	C>A,T	0.09	intergenic_variant	PHTF1 - RSBN1	2e-08	Tier 4: intronic/intergenic
rs6618677	X	91557719	A>G,T	0.05	intergenic_variant	PABPC5 - SERBP1P4	4e-08	Tier 4: intronic/intergenic
rs3130215	6	33107186	A>C,G,T	0.05	intron_variant	COL11A2P1	3e-07	Tier 4: intronic/intergenic
rs17281398	X	155005499	A>G	0.05	intron_variant	F8	4e-07	Tier 4: intronic/intergenic
rs17057678	6	129710348	T>C,G	0.05	regulatory_region_variant	ARHGAP18 - RPL5P21	6e-07	Tier 3: regulatory
rs7059886	X	3492628	A>G	0.05	intron_variant	ASS1P4 - SNORA48B	1e-06	Tier 4: intronic/intergenic
rs17065868	13	44480955	T>C	0.05	intron_variant	TSC22D1	3e-06	Tier 4: intronic/intergenic
rs1623523	18	3328748	T>A,C,G	0.05	intron_variant	MYL12B - LINC01895	3e-06	Tier 4: intronic/intergenic
rs185694	13	30311086	A>C,G,T	0.05	intron_variant	KATNAL1 - LINC00427	4e-06	Tier 4: intronic/intergenic
rs6721691	2	28302592	T>A,C	0.05	intron_variant	BABAM2	4e-06	Tier 4: intronic/intergenic
rs35859035	5	118202863	C>G,T	0.05	intron_variant	LINC02208, LINC02147	6e-06	Tier 4: intronic/intergenic
rs11875185	18	57960608	A>G	0.05	intergenic_variant	RSL24D1P11 - LINC01897	7e-06	Tier 4: intronic/intergenic
rs2111622	2	53757686	A>G	0.05	intron_variant	ASB3	8e-06	Tier 4: intronic/intergenic
rs11010290	10	35771381	A>C,G	0.05	intergenic_variant	RPL7P37 - PCAT5	9e-06	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 29 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 1

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

Gene	HGNC	Evidence routes
FMR1	FMR1	GWAS, Orphanet

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
WNT9B	Orphanet:1848	Renal agenesis, bilateral
COL11A2	Orphanet:1427	Autosomal recessive otospondylomegaepiphyseal dysplasia
COL11A2	Orphanet:166100	Autosomal dominant otospondylomegaepiphyseal dysplasia
COL11A2	Orphanet:2021	Fibrochondrogenesis
COL11A2	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
COL11A2	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
F8	Orphanet:169802	Severe hemophilia A
F8	Orphanet:169805	Moderate hemophilia A
F8	Orphanet:169808	Mild hemophilia A
F8	Orphanet:177926	Bleeding disorder in hemophilia A carriers
FMR1	Orphanet:261483	Xq27.3q28 duplication syndrome
FMR1	Orphanet:642691	Fragile X-associated primary ovarian insufficiency
FMR1	Orphanet:908	Fragile X syndrome
FMR1	Orphanet:93256	Fragile X-associated tremor/ataxia syndrome
HLA-DPA1	Orphanet:900	Granulomatosis with polyangiitis
HLA-DPB1	Orphanet:133	Chronic beryllium disease
HLA-DPB1	Orphanet:900	Granulomatosis with polyangiitis
HLA-DQA1	Orphanet:391490	Adult-onset myasthenia gravis
HLA-DQA1	Orphanet:930	Idiopathic achalasia
SERPINA1	Orphanet:178396	Hemorrhagic disease due to alpha-1-antitrypsin Pittsburgh mutation
SERPINA1	Orphanet:586	Cystic fibrosis
SERPINA1	Orphanet:60	Alpha-1-antitrypsin deficiency
PRTN3	Orphanet:900	Granulomatosis with polyangiitis
PTPN22	Orphanet:3437	Vogt-Koyanagi-Harada disease
PTPN22	Orphanet:397	Giant cell arteritis
PTPN22	Orphanet:536	Systemic lupus erythematosus
PTPN22	Orphanet:85408	Rheumatoid factor-negative polyarticular juvenile idiopathic arthritis
PTPN22	Orphanet:85410	Oligoarticular juvenile idiopathic arthritis
PTPN22	Orphanet:900	Granulomatosis with polyangiitis

Cohort genes → proteins

25 cohort genes, 25 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	25

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
WNT9B	HGNC:12779	ENSG00000158955	O14905	Protein Wnt-9b	gwas
MAGEC2	HGNC:13574	ENSG00000046774	Q9UBF1	Melanoma-associated antigen C2	gwas
PABPC5	HGNC:13629	ENSG00000174740	Q96DU9	Polyadenylate-binding protein 5	gwas
PCDH11Y	HGNC:15813	ENSG00000099715	Q9BZA8	Protocadherin-11 Y-linked	gwas
TSC22D1	HGNC:16826	ENSG00000102804	Q15714	TSC22 domain family protein 1	gwas
TGIF2LX	HGNC:18570	ENSG00000153779	Q8IUE1	Homeobox protein TGIF2LX	gwas
SERPINA11	HGNC:19193	ENSG00000186910	Q86U17	Serpin A11	gwas
ARHGAP18	HGNC:21035	ENSG00000146376	Q8N392	Rho GTPase-activating protein 18	gwas
COL11A2	HGNC:2187	ENSG00000204248	P13942	Collagen alpha-2(XI) chain	gwas
CPXCR1	HGNC:2332	ENSG00000147183	Q8N123	CPX chromosomal region candidate gene 1 protein	gwas
FMR1NB	HGNC:26372	ENSG00000176988	Q8N0W7	FMR1 neighbor protein	gwas
KATNAL1	HGNC:28361	ENSG00000102781	Q9BW62	Katanin p60 ATPase-containing subunit A-like 1	gwas
MYL11	HGNC:29824	ENSG00000180209	Q96A32	Myosin regulatory light chain 11	gwas
F8	HGNC:3546	ENSG00000185010	P00451	Coagulation factor VIII	gwas
FMR1	HGNC:3775	ENSG00000102081	Q06787	Fragile X messenger ribonucleoprotein 1	gwas
FZD8	HGNC:4046	ENSG00000177283	Q9H461	Frizzled-8	gwas
HLA-DPA1	HGNC:4938	ENSG00000231389	P20036	HLA class II histocompatibility antigen, DP alpha 1 chain	gwas
HLA-DPB1	HGNC:4940	ENSG00000223865	P04440	HLA class II histocompatibility antigen, DP beta 1 chain	gwas
HLA-DQA1	HGNC:4942	ENSG00000196735	P01909	HLA class II histocompatibility antigen, DQ alpha 1 chain	gwas
HLA-DQA2	HGNC:4943	ENSG00000237541	P01906	HLA class II histocompatibility antigen, DQ alpha 2 chain	gwas
MXRA5	HGNC:7539	ENSG00000101825	Q9NR99	Matrix-remodeling-associated protein 5	gwas
PCDH11X	HGNC:8656	ENSG00000102290	Q9BZA7	Protocadherin-11 X-linked	gwas
SERPINA1	HGNC:8941	ENSG00000197249	P01009	Alpha-1-antitrypsin	gwas
PRTN3	HGNC:9495	ENSG00000196415	P24158	Myeloblastin	gwas
PTPN22	HGNC:9652	ENSG00000134242	Q9Y2R2	Tyrosine-protein phosphatase non-receptor type 22	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
WNT9B	Protein Wnt-9b	Ligand for members of the frizzled family of seven transmembrane receptors.
MAGEC2	Melanoma-associated antigen C2	Proposed to enhance ubiquitin ligase activity of RING-type zinc finger-containing E3 ubiquitin-protein ligases.
PABPC5	Polyadenylate-binding protein 5	Binds the poly(A) tail of mRNA.
PCDH11Y	Protocadherin-11 Y-linked	Potential calcium-dependent cell-adhesion protein.
TSC22D1	TSC22 domain family protein 1	Transcriptional repressor.
TGIF2LX	Homeobox protein TGIF2LX	May have a transcription role in testis.
ARHGAP18	Rho GTPase-activating protein 18	Rho GTPase activating protein that suppresses F-actin polymerization by inhibiting Rho.
COL11A2	Collagen alpha-2(XI) chain	May play an important role in fibrillogenesis by controlling lateral growth of collagen II fibrils.
KATNAL1	Katanin p60 ATPase-containing subunit A-like 1	Regulates microtubule dynamics in Sertoli cells, a process that is essential for spermiogenesis and male fertility.
MYL11	Myosin regulatory light chain 11	Myosin regulatory subunit that plays an essential role to maintain muscle integrity during early development.
F8	Coagulation factor VIII	Factor VIII, along with calcium and phospholipid, acts as a cofactor for F9/factor IXa when it converts F10/factor X to the activated form, factor Xa.
FMR1	Fragile X messenger ribonucleoprotein 1	Multifunctional polyribosome-associated RNA-binding protein that plays a central role in neuronal development and synaptic plasticity through the regulation of alternative mRNA splicing, mRNA stability, mRNA dendritic transport and postsyn…
FZD8	Frizzled-8	Receptor for Wnt proteins.
HLA-DPA1	HLA class II histocompatibility antigen, DP alpha 1 chain	Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells.
HLA-DPB1	HLA class II histocompatibility antigen, DP beta 1 chain	Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells.
HLA-DQA1	HLA class II histocompatibility antigen, DQ alpha 1 chain	Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells.
HLA-DQA2	HLA class II histocompatibility antigen, DQ alpha 2 chain	Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells.
MXRA5	Matrix-remodeling-associated protein 5	In kidney, has anti-inflammatory and anti-fibrotic properties by limiting the induction of chemokines, fibronectin and collagen expression in response to TGB1 and pro-inflammatory stimuli.
PCDH11X	Protocadherin-11 X-linked	Potential calcium-dependent cell-adhesion protein.
SERPINA1	Alpha-1-antitrypsin	Inhibitor of serine proteases.
PRTN3	Myeloblastin	Serine protease that degrades elastin, fibronectin, laminin, vitronectin, and collagen types I, III, and IV (in vitro).
PTPN22	Tyrosine-protein phosphatase non-receptor type 22	Acts as a negative regulator of T-cell receptor (TCR) signaling by direct dephosphorylation of the Src family kinases LCK and FYN, ITAMs of the TCRz/CD3 complex, as well as ZAP70, VAV, VCP and other key signaling molecules.

Protein-family classification

Druggable: 9 · Difficult: 2 · Unknown: 14 · Druggable fraction: 0.36

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Antibody/Immunoglobulin	5	5.8×	0.010
Phosphatase	1	3.4×	0.887
Protease	1	1.5×	0.887
Other/Unknown	14	1.0×	0.887
GPCR	1	1.0×	0.887
Transcription factor	2	0.7×	0.887
Enzyme (other)	1	0.5×	0.887

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
WNT9B	Other/Unknown	no		Wnt, Wnt_CS, Wnt_C
MAGEC2	Other/Unknown	no		MHD_dom, MAGE, MAGE_WH1
PABPC5	Other/Unknown	no		RRM_dom, RRM_euk-type, PABP_1234
PCDH11Y	Other/Unknown	no		Cadherin-like_dom, Cadherin_N, Protocadherin
TSC22D1	Other/Unknown	no		TSC22/Bun, TSC22/BUN_CS
TGIF2LX	Transcription factor	no		HD, KN_HD, Homeodomain-like_sf
SERPINA11	Other/Unknown	no		Serpin_fam, Serpin_dom, Serpin_sf
ARHGAP18	Other/Unknown	no		RhoGAP_dom, Rho_GTPase_activation_prot, RHG40/28/18_ubiquitin
COL11A2	Other/Unknown	no		Fib_collagen_C, Laminin_G, Collagen
CPXCR1	Transcription factor	no		Znf_C2H2_type
FMR1NB	Other/Unknown	no		FMR1-like
KATNAL1	Enzyme (other)	yes	5.6.1.1	AAA+_ATPase, ATPase_AAA_core, ATPase_AAA_CS
MYL11	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
F8	Other/Unknown	no		FA58C, Cupredoxin, Galactose-bd-like_sf
FMR1	Other/Unknown	no		KH_dom, KH_dom_type_1, Agenet-like_dom
FZD8	GPCR	yes		Frizzled/Smoothened_7TM, Frizzled/SFRP, GPCR_2-like_7TM
HLA-DPA1	Antibody/Immunoglobulin	yes		MHC_II_a_N, Ig/MHC_CS, Ig_C1-set
HLA-DPB1	Antibody/Immunoglobulin	yes		MHC_II_b_N, Ig/MHC_CS, Ig_C1-set
HLA-DQA1	Antibody/Immunoglobulin	yes		MHC_II_a_N, Ig/MHC_CS, Ig_C1-set
HLA-DQA2	Antibody/Immunoglobulin	yes		MHC_II_a_N, Ig/MHC_CS, Ig_C1-set
MXRA5	Antibody/Immunoglobulin	yes		LRRNT, Cys-rich_flank_reg_C, Leu-rich_rpt
PCDH11X	Other/Unknown	no		Cadherin-like_dom, Cadherin_N, Protocadherin
SERPINA1	Other/Unknown	no		Serpin_fam, Serpin_CS, Serpin_dom
PRTN3	Protease	yes	3.4.21.76	Trypsin_dom, Peptidase_S1A, Peptidase_S1_PA
PTPN22	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, Tyr_Pase_cat

Expression context

Cohort genes with no expression data: 0.

19 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)	2
broad (>20)	23
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	7
primordial germ cell in gonad	3
granulocyte	3
monocyte	3
right testis	2
testis	2
liver	2
right lobe of liver	2
left testis	2
ganglionic eminence	2
vermiform appendix	2
bone marrow	2
bone marrow cell	2
metanephros cortex	1
quadriceps femoris	1
adrenal tissue	1
calcaneal tendon	1
right adrenal gland cortex	1
corpus callosum	1
prefrontal cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
WNT9B	114	tissue_specific	yes	quadriceps femoris, metanephros cortex, primordial germ cell in gonad
MAGEC2	28	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, right testis
PABPC5	157	broad	yes	adrenal tissue, calcaneal tendon, right adrenal gland cortex
PCDH11Y	111	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, corpus callosum, prefrontal cortex
TSC22D1	308	ubiquitous	marker	endothelial cell, Brodmann (1909) area 23, middle temporal gyrus
TGIF2LX	14	tissue_specific	yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, testis
SERPINA11	50	tissue_specific	yes	right lobe of liver, liver, minor salivary gland
ARHGAP18	254	ubiquitous	marker	germinal epithelium of ovary, oviduct epithelium, bronchial epithelial cell
COL11A2	134	broad	yes	pituitary gland, male germ line stem cell (sensu Vertebrata) in testis, adenohypophysis
CPXCR1	16		yes	sperm, male germ line stem cell (sensu Vertebrata) in testis, left testis
FMR1NB	39	tissue_specific	marker	right testis, left testis, testis
KATNAL1	249	ubiquitous	marker	secondary oocyte, oocyte, cardiac muscle of right atrium
MYL11	184	broad	marker	biceps brachii, skeletal muscle tissue of biceps brachii, skeletal muscle tissue of rectus abdominis
F8	266	broad	marker	left ventricle myocardium, heart right ventricle, myocardium
FMR1	296	ubiquitous	marker	caput epididymis, corpus epididymis, sural nerve
FZD8	223	ubiquitous	marker	ventricular zone, cartilage tissue, ganglionic eminence
HLA-DPA1	133	ubiquitous	marker	monocyte, leukocyte, granulocyte
HLA-DPB1	135	ubiquitous	marker	granulocyte, lymph node, vermiform appendix
HLA-DQA1	244	broad	marker	gall bladder, rectum, monocyte
HLA-DQA2	127	broad	marker	granulocyte, vermiform appendix, male germ line stem cell (sensu Vertebrata) in testis
MXRA5	238	broad	marker	tendon of biceps brachii, hair follicle, skin of hip
PCDH11X	74	broad	marker	cortical plate, male germ line stem cell (sensu Vertebrata) in testis, ganglionic eminence
SERPINA1	133	ubiquitous	marker	right lobe of liver, liver, blood
PRTN3	106	tissue_specific	marker	bone marrow, bone marrow cell, spleen
PTPN22	190	broad	marker	bone marrow cell, bone marrow, monocyte

Protein interactions among cohort

Intra-cohort edges: 9.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FMR1	4,726
SERPINA1	3,617
PTPN22	2,480
MYL11	2,170
KATNAL1	1,975
F8	1,900
PABPC5	1,650
HLA-DQA2	1,611
COL11A2	1,583
PCDH11X	1,435

Intra-cohort edges

A	B	Sources
CPXCR1	TGIF2LX	string_interaction
FMR1	FMR1NB	string_interaction
HLA-DPA1	HLA-DPB1	intact
HLA-DQA1	HLA-DQA2	intact
PABPC5	PCDH11X	string_interaction
PABPC5	TGIF2LX	string_interaction
PCDH11X	PCDH11Y	biogrid_interaction
PCDH11X	TGIF2LX	string_interaction
PRTN3	SERPINA1	biogrid_interaction

Structural data

PDB: 11 · AlphaFold-only: 14 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SERPINA1	P01009	46
HLA-DQA1	P01909	28
F8	P00451	25
PTPN22	Q9Y2R2	14
FMR1	Q06787	12
HLA-DPA1	P20036	10
HLA-DPB1	P04440	10
FZD8	Q9H461	7
PRTN3	P24158	2
TGIF2LX	Q8IUE1	1
KATNAL1	Q9BW62	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PABPC5	Q96DU9	91.44
HLA-DQA2	P01906	89.29
WNT9B	O14905	84.50
MYL11	Q96A32	84.43
SERPINA11	Q86U17	83.27
ARHGAP18	Q8N392	75.05
MAGEC2	Q9UBF1	66.43
PCDH11Y	Q9BZA8	64.62
PCDH11X	Q9BZA7	64.22
FMR1NB	Q8N0W7	61.95
COL11A2	P13942	50.18
CPXCR1	Q8N123	49.90
TSC22D1	Q15714	43.12
MXRA5	Q9NR99

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 58. Enrichment computed across 25 evidence-associated genes (14 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 14 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Translocation of ZAP-70 to Immunological synapse	5	226.6×	6e-10	HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQA2, PTPN22
Phosphorylation of CD3 and TCR zeta chains	5	194.2×	7e-10	HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQA2, PTPN22
Co-inhibition by PD-1	4	148.3×	2e-07	HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQA2
Generation of second messenger molecules	4	98.9×	8e-07	HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQA2
Downstream TCR signaling	4	36.7×	3e-05	HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQA2
Interferon gamma signaling	4	35.9×	3e-05	HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQA2
MHC class II antigen presentation	4	25.5×	1e-04	HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQA2
Cargo concentration in the ER	2	48.0×	0.006	F8, SERPINA1
Defective F8 accelerates dissociation of the A2 domain	1	815.7×	0.006	F8
Defective F8 binding to the cell membrane	1	815.7×	0.006	F8
Defective F8 secretion	1	815.7×	0.006	F8
Regulation of clotting cascade	2	33.3×	0.008	F8, PRTN3
Defective F8 binding to von Willebrand factor	1	407.9×	0.010	F8
Class B/2 (Secretin family receptors)	2	27.2×	0.010	WNT9B, FZD8
Defective factor IX causes thrombophilia	1	271.9×	0.011	F8
Defective F8 cleavage by thrombin	1	271.9×	0.011	F8
Defective cofactor function of FVIIIa variant	1	271.9×	0.011	F8
Defective F9 variant does not activate FX	1	271.9×	0.011	F8
Defective F8 sulfation at Y1699	1	271.9×	0.011	F8
COPII-mediated vesicle transport	2	23.3×	0.011	F8, SERPINA1
Signaling by RNF43 mutants	1	90.6×	0.029	FZD8
Platelet degranulation	2	12.6×	0.029	F8, SERPINA1
POU5F1 (OCT4), SOX2, NANOG repress genes related to differentiation	1	81.6×	0.031	TSC22D1
Nephron development	1	62.8×	0.038	WNT9B
Amplification and propagation of coagulation cascade	1	45.3×	0.051	F8
Regulation of FZD by ubiquitination	1	37.1×	0.059	FZD8
Other interleukin signaling	1	34.0×	0.060	PRTN3
Initiation of coagulation cascade	1	34.0×	0.060	F8
Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation	1	30.2×	0.063	F8
WNT ligand biogenesis and trafficking	1	30.2×	0.063	WNT9B

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 21 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
peptide antigen assembly with MHC class II protein complex	4	200.6×	5e-07	HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQA2
antigen processing and presentation of exogenous peptide antigen via MHC class II	4	103.5×	4e-06	HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQA2
positive regulation of immune response	4	91.7×	4e-06	HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQA2
positive regulation of T cell activation	4	84.5×	5e-06	HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQA2
positive regulation of type II interferon production	3	32.1×	0.003	HLA-DPA1, HLA-DPB1, PTPN22
adaptive immune response	4	16.1×	0.003	HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQA2
non-canonical Wnt signaling pathway	2	55.3×	0.012	WNT9B, FZD8
regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis	1	802.5×	0.014	WNT9B
regulation of tube size	1	802.5×	0.014	WNT9B
phosphoanandamide dephosphorylation	1	802.5×	0.014	PTPN22
kidney rudiment formation	1	802.5×	0.014	WNT9B
positive regulation of intracellular transport of viral material	1	802.5×	0.014	FMR1
acute-phase response	2	40.1×	0.014	F8, SERPINA1
regulation of natural killer cell proliferation	1	401.2×	0.019	PTPN22
actin-myosin filament sliding	1	401.2×	0.019	MYL11
mesenchymal stem cell maintenance involved in nephron morphogenesis	1	401.2×	0.019	WNT9B
establishment of planar polarity involved in nephron morphogenesis	1	401.2×	0.019	WNT9B
metanephric tubule formation	1	401.2×	0.019	WNT9B
mesonephric duct formation	1	401.2×	0.019	WNT9B
positive regulation of T cell proliferation	2	24.7×	0.022	HLA-DPA1, HLA-DPB1
negative regulation of miRNA-mediated gene silencing	1	267.5×	0.022	FMR1
regulation of translation at presynapse, modulating synaptic transmission	1	267.5×	0.022	FMR1
negative regulation of long-term synaptic depression	1	267.5×	0.022	FMR1
negative regulation of hematopoietic stem cell proliferation	1	267.5×	0.022	TSC22D1
roof of mouth development	2	23.6×	0.022	WNT9B, COL11A2
regulation of asymmetric cell division	1	200.6×	0.024	WNT9B
negative regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway	1	200.6×	0.024	PTPN22
collecting duct development	1	200.6×	0.024	WNT9B
mature conventional dendritic cell differentiation	1	200.6×	0.024	PRTN3
regulation of neuronal action potential	1	200.6×	0.024	FMR1

Therapeutics

Drugs indicated or in trials for this disease

1 approved drug — disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Status
Avacopan	Approved (phase 4)

10 drugs in clinical trials for this disease (phase 2–3, investigational): efficacy not established — a trial record, not an indication.

Drug	Highest phase
Abatacept	Phase 3
Azathioprine	Phase 3
Methylprednisolone	Phase 3
Mycophenolate Mofetil	Phase 3
Prednisolone	Phase 3
Prednisone	Phase 3
Rituximab	Phase 3
Rosuvastatin	Phase 3
Eculizumab	Phase 2
Tretinoin	Phase 2

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 24

Druggability breadth: 6 of 25 evidence-associated genes (24%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PRTN3	1	3
WNT9B	0	0
MAGEC2	0	0
PABPC5	0	0
PCDH11Y	0	0
TSC22D1	0	0
TGIF2LX	0	0
SERPINA11	0	0
ARHGAP18	0	0
COL11A2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SIVELESTAT	3	PRTN3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
PTPN22	137	Binding:122, Functional:10, ADMET:5
PRTN3	63	Binding:62, ADMET:1
F8	8	Binding:8
HLA-DQA1	2	Binding:2
FZD8	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KATNAL1	5.6.1.1	microtubule-severing ATPase
PRTN3	3.4.21.76	Myeloblastin
PTPN22	3.1.3.48	protein-tyrosine-phosphatase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
PTPN22	137

Pharmacogenomics

Cohort genes with a PharmGKB record: 25; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
SIVELESTAT	3	PRTN3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	PRTN3
C	Druggable family + PDB, no drug	6	KATNAL1, FZD8, HLA-DPA1, HLA-DPB1, HLA-DQA1, PTPN22
D	Druggable family + AlphaFold only, no drug	2	HLA-DQA2, MXRA5
E	Difficult family or no structure, no drug	16	WNT9B, MAGEC2, PABPC5, PCDH11Y, TSC22D1, TGIF2LX, SERPINA11, ARHGAP18, COL11A2, CPXCR1 (+6 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PTPN22	137	—
WNT9B	0	—
MAGEC2	0	—
PABPC5	0	—
PCDH11Y	0	—
TSC22D1	0	—
TGIF2LX	0	—
SERPINA11	0	—
ARHGAP18	0	—
COL11A2	0	—
CPXCR1	0	—
FMR1NB	0	—
KATNAL1	0	—
MYL11	0	—
F8	8	—
FMR1	0	—
FZD8	1	—
HLA-DPA1	0	—
HLA-DPB1	0	—
HLA-DQA1	2	—
HLA-DQA2	0	—
MXRA5	0	—
PCDH11X	0	—
SERPINA1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.