CARD9

Summary

CARD9 (caspase recruitment domain family member 9, HGNC:16391) is a protein-coding gene on chromosome 9q34.3, encoding Caspase recruitment domain-containing protein 9 (Q9H257). Adapter protein that plays a key role in innate immune response against fungi by forming signaling complexes downstream of C-type lectin receptors.

The protein encoded by this gene is a member of the CARD protein family, which is defined by the presence of a characteristic caspase-associated recruitment domain (CARD). CARD is a protein interaction domain known to participate in activation or suppression of CARD containing members of the caspase family, and thus plays an important regulatory role in cell apoptosis. This protein was identified by its selective association with the CARD domain of BCL10, a postive regulator of apoptosis and NF-kappaB activation, and is thought to function as a molecular scaffold for the assembly of a BCL10 signaling complex that activates NF-kappaB. Several alternatively spliced transcript variants have been observed, but their full-length nature is not clearly defined.

Source: NCBI Gene 64170 — RefSeq curated summary.

At a glance

• Gene–disease (curated): predisposition to invasive fungal disease due to CARD9 deficiency (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 25
• Clinical variants (ClinVar): 630 total — 19 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 20
• MANE Select transcript: NM_052813

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16391
Approved symbol	CARD9
Name	caspase recruitment domain family member 9
Location	9q34.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000187796
Ensembl biotype	protein_coding
OMIM	607212
Entrez	64170

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 11 protein_coding, 6 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000371732, ENST00000371734, ENST00000460290, ENST00000485975, ENST00000489932, ENST00000556340, ENST00000641290, ENST00000695905, ENST00000695906, ENST00000695907, ENST00000695908, ENST00000892157, ENST00000892158, ENST00000892159, ENST00000892160, ENST00000892161, ENST00000892162, ENST00000892163, ENST00000892164, ENST00000967104

RefSeq mRNA: 2 — MANE Select: NM_052813 NM_052813, NM_052814

CCDS: CCDS48057, CCDS6997

Canonical transcript exons

ENST00000371732 — 13 exons

Exon	Start	End
ENSE00001384576	136367637	136367828
ENSE00003486914	136370841	136371145
ENSE00003498430	136371324	136371461
ENSE00003500610	136371895	136372094
ENSE00003505370	136363956	136364401
ENSE00003515236	136369750	136369875
ENSE00003522812	136365141	136365217
ENSE00003563619	136367216	136367257
ENSE00003564640	136364483	136364559
ENSE00003587528	136366800	136366845
ENSE00003617240	136370522	136370701
ENSE00003669733	136370294	136370437
ENSE00003896482	136373532	136373669

Expression profiles

Bgee: expression breadth ubiquitous, 172 present calls, max score 91.76.

FANTOM5 (CAGE): breadth broad, TPM avg 3.0694 / max 107.6742, expressed in 518 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
103150	2.5934	493
103149	0.4760	215

Top tissues by expression

280 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	91.76	gold quality
mononuclear cell	CL:0000842	91.10	gold quality
leukocyte	CL:0000738	90.55	gold quality
granulocyte	CL:0000094	90.53	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.07	gold quality
blood	UBERON:0000178	80.51	gold quality
spleen	UBERON:0002106	79.89	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	73.74	gold quality
bone marrow	UBERON:0002371	73.60	gold quality
stromal cell of endometrium	CL:0002255	73.24	gold quality
bone marrow cell	CL:0002092	73.07	gold quality
upper lobe of left lung	UBERON:0008952	72.37	gold quality
right coronary artery	UBERON:0001625	72.28	gold quality
vermiform appendix	UBERON:0001154	71.89	gold quality
right adrenal gland	UBERON:0001233	71.69	gold quality
endothelial cell	CL:0000115	71.57	gold quality
decidua	UBERON:0002450	71.44	silver quality
spinal cord	UBERON:0002240	70.62	gold quality
right adrenal gland cortex	UBERON:0035827	70.61	gold quality
upper lobe of lung	UBERON:0008948	70.46	gold quality
mucosa of transverse colon	UBERON:0004991	70.41	gold quality
right lung	UBERON:0002167	70.31	gold quality
left adrenal gland	UBERON:0001234	69.82	gold quality
gall bladder	UBERON:0002110	69.64	gold quality
left adrenal gland cortex	UBERON:0035825	69.60	gold quality
palpebral conjunctiva	UBERON:0001812	69.39	gold quality
right uterine tube	UBERON:0001302	69.14	gold quality
right hemisphere of cerebellum	UBERON:0014890	69.07	gold quality
right frontal lobe	UBERON:0002810	68.62	gold quality
cerebellar hemisphere	UBERON:0002245	68.51	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.64

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

6 targeting CARD9, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-4666B	99.64	68.69	1282
HSA-MIR-4672	99.50	71.58	2893
HSA-MIR-1909-5P	98.94	64.01	484

Literature-anchored findings (GeneRIF, showing 40)

• Data show that pVHL acts as an adaptor to promote the inhibitory phosphorylation of the NF-kappaB agonist Card9 by casein kinase 2. (PMID:17936701)
• CARD9 and IL18RAP are IBD loci important in innate immunity in the predisposition to both CD and UC. (PMID:18439550)
• Studies suggest that the apoptosome contains a 1:1 Apaf-1:caspase-9 stoichiometry. (PMID:19809088)
• An autosomal recessive form of susceptibility to chronic mucocutaneous candidiasis is associated with homozygous mutations in CARD9. (PMID:19864672)
• The single nucleotide polymorphisms most strongly associated with ankylosing spondylitis are those most associated with CARD9 expression. (PMID:20463747)
• Three ulcerative colitis susceptibility loci are associated with primary sclerosing cholangitis and indicate a role for IL2, REL, and CARD9. (PMID:21425313)
• High caspase-9 activity is associated with cervical malignancy. (PMID:21436691)
• genetic variation in CARD9 was not associated with susceptibility to candidemia. (PMID:21881131)
• variation in CARD9 genes was not associated with susceptibility to opportunistic fungal or bacterial infections in HIV-positive patients. (PMID:21985303)
• Human coronavirus-induced neuronal programmed cell death required cyclophilin d but not caspase 3 caspase 9 activities. (PMID:22013052)
• Rubicon as a specific feedback inhibitor of CARD9-mediated pattern recognition receptor-signal transduction, preventing unbalanced proinflammatory responses. (PMID:22423967)
• CARD9 may be involved in hepatic carcinogenesis associated with hepatitis C in Egyptian patients. (PMID:24018495)
• Our results confirmed significant association to rare non-synonymous coding variants in both IL23R and CARD9, previously identified from sequencing of CD loci, as well as identified a novel association in RNF186 (PMID:24068945)
• All the patients with deep dermatophytosis had autosomal recessive CARD9 deficiency. (PMID:24131138)
• CARD9 mutations linked to subcutaneous phaeohyphomycosis and TH17 cell deficiencies. (PMID:24231284)
• Our study confirmed that an SNP rs11145835 in 9q34.3 that harbors CARD9 and SNAPC4 is associated with ankylosing spondylitis in a Chinese Han population (PMID:24334645)
• Intestinal failure patients with CARD9 polymorphism are less likely to develop progressive liver disease. (PMID:24465786)
• There is emergening evidence that genetic component is inviolved in the development of onychomycosis.(review) (PMID:24686315)
• In a patient with CARD9 deficiency, clinical remission with adjunctive GM-CSF therapy suggested that a CARD9/GM-CSF axis contributes to susceptibility to candidiasis. (PMID:24704721)
• Results indicating that CARD9 is a regulator of metastasis-associated macrophages will lead to new insights into evolution of the microenvironments supporting tumor metastasis. (PMID:24722209)
• this study reports a direct cytosolic interaction between the DNA-damage sensor Rad50 and the innate immune system adaptor CARD9. (PMID:24777530)
• These are the first 2 patients with inherited CARD9 deficiency. (PMID:25057046)
• CARD9 regulates H-Ras activation by linking Ras-GRF1 to H-Ras, which mediates Dectin-1-induced extracellular signal-regulated protein kinase (ERK) activation and proinflammatory responses when stimulated by their ligands. (PMID:25267792)
• A new genome-wide significant association between CARD9 and IgA nephropathy. (PMID:25305756)
• MyD88 and CARD9 act in two discrete phases and in two cellular compartments to direct chemokine- and neutrophil-dependent host defense. (PMID:25621893)
• Invasive infections of the CNS or digestive tract caused by Candida species in previously healthy children and adults might be caused by inherited CARD9 deficiency. (PMID:25702837)
• These results indicate that CARD9 is indispensable for Phialophora verrucosa killing by polymorphonuclear neutrophils. (PMID:25790941)
• homozygous mutation results in deep dermatophytosis due to impaired neutrophil fungal killing (PMID:26044242)
• Data indicate that MINCLE receptor is able to mediate the response to trehalose-6,6-dimycolate (TDM) dependent on SYK kinase and CARD9 protein. (PMID:26202982)
• The findings linked, for the first time, mutations leading to CARD9 deficiencies with susceptibility to opportunistic filamentous fungi. (PMID:26440558)
• A CARD9 variant (protective against inflammatory bowel disease)is C-terminally truncated and acts in a dominant-negative manner for CARD9-mediated cytokine production. K125 is the CARD9 ubiquitinated residue. Ubiquitination is needed for CARD9 activity. (PMID:26488816)
• This study identified two novel independent loci (MAP3K14 and CARD9) strongly associated with joint damage in Mexican Americans and European Americans and a few shared loci showing suggestive evidence for association. (PMID:26498133)
• Impaired RASGRF1/ERK-mediated GM-CSF response characterizes CARD9 deficiency in French-Canadians. (PMID:26521038)
• CARD9 allele C (p = 0.012) and genotype CC (p = 0.012) were significant protective factors against ankylosing spondylitis only in HLA-B27-negative patients. (PMID:26590821)
• our data highlight the critical role of CARD9-dependent neutrophil trafficking into the central nervous system (PMID:26679537)
• We observed no significant association between the investigated CARD9 SNPs and the susceptibility of either Crohn’s disease or ulcerative colitis (PMID:26722558)
• Card9 in severe acute pancreatitis patients was overexpressed, suggesting the close correlation with the outcome and severity of pancreatic injury in patients. (PMID:26893103)
• Chronic and invasive fungal infections have been described in a Turkish consanguineous family with CARD9 deficiency. (PMID:26961233)
• The IBD risk allele at CARD9 rs10781499 is associated with reduced aryl hydrocarbon activation by microbiota-derived metabolites extracted from fecal samples of IBD patients. (PMID:27158904)
• Our results reveal a molecular mechanism for CLR-mediated Card9 regulation that controls innate immunity to fungal infections (PMID:27926862)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	card9	ENSDARG00000067672
mus_musculus	Card9	ENSMUSG00000026928
rattus_norvegicus	Card9	ENSRNOG00000051470

Paralogs (3): CARD10 (ENSG00000100065), CARD14 (ENSG00000141527), CARD11 (ENSG00000198286)

Protein

Protein identifiers

Caspase recruitment domain-containing protein 9 — Q9H257 (reviewed: Q9H257)

All UniProt accessions (1): Q9H257

UniProt curated annotations — full annotation on UniProt →

Function. Adapter protein that plays a key role in innate immune response against fungi by forming signaling complexes downstream of C-type lectin receptors. CARD9-mediated signals are essential for antifungal immunity against a subset of fungi from the phylum Ascomycota. Transduces signals in myeloid cells downstream of C-type lectin receptors CLEC7A (dectin-1), CLEC6A (dectin-2) and CLEC4E (Mincle), which detect pathogen-associated molecular pattern metabolites (PAMPs), such as fungal carbohydrates, and trigger CARD9 activation. Upon activation, CARD9 homooligomerizes to form a nucleating helical template that recruits BCL10 via CARD-CARD interaction, thereby promoting polymerization of BCL10 and subsequent recruitment of MALT1: this leads to activation of NF-kappa-B and MAP kinase p38 (MAPK11, MAPK12, MAPK13 and/or MAPK14) pathways which stimulate expression of genes encoding pro-inflammatory cytokines and chemokines. CARD9 signaling in antigen-presenting cells links innate sensing of fungi to the activation of adaptive immunity and provides a cytokine milieu that induces the development and subsequent of interleukin 17-producing T helper (Th17) cells. Also involved in activation of myeloid cells via classical ITAM-associated receptors and TLR: required for TLR-mediated activation of MAPK, while it is not required for TLR-induced activation of NF-kappa-B. CARD9 can also be engaged independently of BCL10: forms a complex with RASGRF1 downstream of C-type lectin receptors, which recruits and activates HRAS, leading to ERK activation and the production of cytokines. Acts as an important regulator of the intestinal commensal fungi (mycobiota) component of the gut microbiota. Plays an essential role in antifungal immunity against dissemination of gut fungi: acts by promoting induction of antifungal IgG antibodies response in CX3CR1(+) macrophages to confer protection against disseminated C.albicans or C.auris infection. Also mediates immunity against other pathogens, such as certain bacteria, viruses and parasites; CARD9 signaling is however redundant with other innate immune responses. In response to L.monocytogenes infection, required for the production of inflammatory cytokines activated by intracellular peptidoglycan: acts by connecting NOD2 recognition of peptidoglycan to downstream activation of MAP kinases (MAPK) without activating NF-kappa-B.

Subunit / interactions. Monomer. Homodimer; homodimerization is mediated by the CARD domain which forms an extensive interaction with the adjacent linker and coiled-coil regions; leads to an autoinhibited state. Homomultimer; polymerizes following activation, forming a nucleating helical template that seeds BCL10-filament formation via a CARD-CARD interaction. Interacts (via CARD domain) with BCL10 (via CARD domain); interaction takes place following CARD9 activation and polymerization, leading to the formation of a filamentous CBM complex assembly. Component of a CBM complex (CARD9-BCL10, MALT1), composed of CARD9, BCL10 and MALT1. Interacts with RASGRF1. Interacts with NOD2 (via NACHT domain); interaction is direct. Interacts with RIPK2. Interacts with VHL; without leading to protein degradation.

Subcellular location. Cytoplasm.

Tissue specificity. Expression is restricted to several populations of phagocytes, such as macrophages, monocytes, and dendritic cells. Highly expressed in spleen. Also detected in liver, placenta, lung, peripheral blood leukocytes and in brain.

Post-translational modifications. Phosphorylated at Thr-231 by PRKCD downstream of C-type lectin receptors activation: phosphorylation promotes interaction with BCL10, followed by activation of NF-kappa-B and MAP kinase p38 pathways. Phosphorylated at Thr-531 and Thr-533 by CK2 following interaction with VHL, leading to inhibit the ability to activate NF-kappa-B. Ubiquitinated at Lys-125 via ‘Lys-27’-linked ubiquitin by TRIM62 downstream of C-type lectin receptors activation; leading to CARD9 activation, followed by activation of NF-kappa-B and MAP kinase p38 pathways. Deubiquitinated at Lys-125 by USP15, inhibiting CARD9.

Disease relevance. Immunodeficiency 103, susceptibility to fungal infections (IMD103) [MIM:212050] An autosomal recessive primary immunodeficiency disorder with altered immune responses and impaired clearance of fungal infections, selective against Candida. It is characterized by persistent and/or recurrent infections of the skin, nails and mucous membranes caused by organisms of the genus Candida, mainly Candida albicans. The disease is caused by variants affecting the gene represented in this entry. Defects induce reduced numbers of CD4(+) Th17 lymphocytes as well as a lack of monocyte-derived cytokines in response to Candida strains. Neutrophils show a selective Candida albicans killing defect with abnormal ultrastructural phagolysosomes and outgrowth of hyphae.

Activity regulation. Maintained in an autoinhibited state via homodimerization in which the CARD domain forms an extensive interaction with the adjacent linker and coiled-coil regions. Activation downstream of C-type lectin receptors, by phosphorylation by PRKCD and/or ubiquitination by TRIM62, triggers disruption of the CARD domain-coiled coil interface, CARD9 homooligomerization and BCL10 recruitment, followed by activation of NF-kappa-B and MAP kinase p38 pathways. Zinc-binding inhibits activation by stabilizing the CARD ground-state conformation and restricting its capacity to form BCL10-nucleating filaments.

Domain organisation. The linker region, also named autoinhibitory interface, is required to prevent constitutive activation and maintain CARD9 in an autoinhibitory state. Disruption of this region triggers polymerization and activation, leading to formation of BCL10-nucleating filaments.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9H257-1	1	yes
Q9H257-2	2
Q9H257-3	3

RefSeq proteins (2): NP_434700, NP_434701 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001315	CARD	Domain
IPR011029	DEATH-like_dom_sf	Homologous_superfamily
IPR042142	CARD_CARD9	Domain

Pfam: PF00619

UniProt features (74 total): sequence variant 17, mutagenesis site 15, modified residue 12, helix 11, splice variant 4, binding site 3, region of interest 2, coiled-coil region 2, compositionally biased region 2, turn 2, chain 1, domain 1, cross-link 1, strand 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
6E28	X-RAY DIFFRACTION	1.36
9AVM	X-RAY DIFFRACTION	1.79
6E27	X-RAY DIFFRACTION	1.81
9AVN	X-RAY DIFFRACTION	2.73
6N2P	ELECTRON MICROSCOPY	4
6E25	SOLUTION NMR
6E26	SOLUTION NMR
6N2M	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H257-F1	81.24	0.61

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (3): 73; 3; 10

Post-translational modifications (13): 2, 231, 277, 424, 425, 431, 450, 460, 483, 498, 531, 533, 125

Mutagenesis-validated functional residues (15):

Position	Phenotype
10	strongly reduced zinc-binding.
15	abolished homooligomerization and formation of bcl10-nucleating filaments.
35	abolished homooligomerization and formation of bcl10-nucleating filaments.
37	does not affect zinc-binbing.
43	abolished homooligomerization and formation of bcl10-nucleating filaments.
58	abolished homooligomerization and formation of bcl10-nucleating filaments.
66	abolished homooligomerization and formation of bcl10-nucleating filaments.
73	strongly reduced zinc-binding.
101	disruption of the linker region, relieving autoinhibition and leading to activation of nf-kappa-b.
103	disruption of the linker region, relieving autoinhibition and leading to activation of nf-kappa-b.
107	disruption of the linker region, relieving autoinhibition and leading to activation of nf-kappa-b. constitutively forms
111	disruption of the linker region, relieving autoinhibition and leading to activation of nf-kappa-b.
114	disruption of the linker region, relieving autoinhibition and leading to activation of nf-kappa-b.
115	disruption of the linker region, relieving autoinhibition and leading to activation of nf-kappa-b. constitutively forms
125	reduced cytokine production in response to c.albicans infection. impaired nf-kappa-b transcriptional activity. does not

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-168638	NOD1/2 Signaling Pathway
R-HSA-5607764	CLEC7A (Dectin-1) signaling
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-168643	Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways
R-HSA-5621481	C-type lectin receptors (CLRs)

MSigDB gene sets: 263 (showing top): FUNG_IL2_SIGNALING_2, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, MULLIGHAN_NPM1_SIGNATURE_3_UP, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, REACTOME_NOD1_2_SIGNALING_PATHWAY, GOBP_REGULATION_OF_STRESS_ACTIVATED_PROTEIN_KINASE_SIGNALING_CASCADE, GOBP_INFLAMMATORY_RESPONSE, REACTOME_NUCLEOTIDE_BINDING_DOMAIN_LEUCINE_RICH_REPEAT_CONTAINING_RECEPTOR_NLR_SIGNALING_PATHWAYS, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_RESPONSE_TO_CORTICOSTEROID, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_MODULATION_OF_PROCESS_OF_ANOTHER_ORGANISM, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION

GO Biological Process (40): positive regulation of cytokine production (GO:0001819), neutrophil mediated immunity (GO:0002446), JNK cascade (GO:0007254), response to xenobiotic stimulus (GO:0009410), immunoglobulin mediated immune response (GO:0016064), response to peptidoglycan (GO:0032494), response to muramyl dipeptide (GO:0032495), regulation of interleukin-2 production (GO:0032663), positive regulation of chemokine production (GO:0032722), positive regulation of granulocyte macrophage colony-stimulating factor production (GO:0032725), positive regulation of interleukin-17 production (GO:0032740), positive regulation of interleukin-6 production (GO:0032755), positive regulation of tumor necrosis factor production (GO:0032760), positive regulation of stress-activated MAPK cascade (GO:0032874), regulation of apoptotic process (GO:0042981), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), response to exogenous dsRNA (GO:0043330), positive regulation of innate immune response (GO:0045089), positive regulation of JNK cascade (GO:0046330), host-mediated modulation of intestinal microbiota composition (GO:0048874), regulation of immune response (GO:0050776), defense response to Gram-positive bacterium (GO:0050830), obsolete positive regulation of NF-kappaB transcription factor activity (GO:0051092), protein homooligomerization (GO:0051260), stress-activated MAPK cascade (GO:0051403), defense response to virus (GO:0051607), positive regulation of macrophage cytokine production (GO:0060907), antifungal innate immune response (GO:0061760), positive regulation of ERK1 and ERK2 cascade (GO:0070374), apoptotic signaling pathway (GO:0097190), positive regulation of cytokine production involved in inflammatory response (GO:1900017), response to aldosterone (GO:1904044), positive regulation of T-helper 17 type immune response (GO:2000318), adaptive immune response (GO:0002250), immune system process (GO:0002376), response to fungus (GO:0009620), positive regulation of macromolecule metabolic process (GO:0010604), regulation of interleukin-6 production (GO:0032675), regulation of tumor necrosis factor production (GO:0032680), innate immune response (GO:0045087)

GO Molecular Function (6): signaling adaptor activity (GO:0035591), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), metal ion binding (GO:0046872), CARD domain binding (GO:0050700), protein binding (GO:0005515)

GO Cellular Component (5): cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), CBM complex (GO:0032449), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Innate Immune System	2
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	1
C-type lectin receptors (CLRs)	1
Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of cytokine production	4
regulation of cytokine production	2
response to nitrogen compound	2
response to oxygen-containing compound	2
positive regulation of MAPK cascade	2
cellular anatomical structure	2
cytokine production	1
positive regulation of gene expression	1
positive regulation of multicellular organismal process	1
myeloid leukocyte mediated immunity	1
MAPK cascade	1
response to chemical	1
B cell mediated immunity	1
response to molecule of bacterial origin	1
interleukin-2 production	1
chemokine production	1
regulation of chemokine production	1
granulocyte macrophage colony-stimulating factor production	1
regulation of granulocyte macrophage colony-stimulating factor production	1
positive regulation of protein metabolic process	1
interleukin-17 production	1
regulation of interleukin-17 production	1
interleukin-6 production	1
regulation of interleukin-6 production	1
tumor necrosis factor production	1
regulation of tumor necrosis factor production	1
positive regulation of tumor necrosis factor superfamily cytokine production	1
regulation of stress-activated MAPK cascade	1
stress-activated MAPK cascade	1
positive regulation of stress-activated protein kinase signaling cascade	1
apoptotic process	1
regulation of programmed cell death	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
response to dsRNA	1
positive regulation of response to biotic stimulus	1
positive regulation of defense response	1
positive regulation of response to external stimulus	1
innate immune response	1

Protein interactions and networks

STRING

3172 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CARD9	BCL10	O95999	998
CARD9	SYK	P43405	997
CARD9	MALT1	Q9UDY8	997
CARD9	NOD2	Q9HC29	990
CARD9	CASP8	Q14790	975
CARD9	CLEC7A	Q9BXN2	972
CARD9	CLEC6A	Q6EIG7	922
CARD9	CLEC4E	Q9ULY5	872
CARD9	RIGI	O95786	833
CARD9	MYD88	P78397	828
CARD9	FCER1G	P30273	796
CARD9	CASP1	P29466	796
CARD9	TRAF6	Q9Y4K3	744
CARD9	IFIH1	Q9BYX4	742
CARD9	NLRP3	Q96P20	740

IntAct

236 interactions, top by confidence:

A	B	Type	Score
CARD9	ZNF572	psi-mi:“MI:0915”(physical association)	0.670
FAM161A	CARD9	psi-mi:“MI:0915”(physical association)	0.670
PPP1R18	CARD9	psi-mi:“MI:0915”(physical association)	0.670
CARD9	KRT19	psi-mi:“MI:0915”(physical association)	0.670
TRIM23	CARD9	psi-mi:“MI:0915”(physical association)	0.670
CARD9	TLE5	psi-mi:“MI:0915”(physical association)	0.670
CARD9	PAK5	psi-mi:“MI:0915”(physical association)	0.670
CARD9	CDCA7L	psi-mi:“MI:0915”(physical association)	0.670
CARD9	USP15	psi-mi:“MI:0915”(physical association)	0.670
TLE5	CARD9	psi-mi:“MI:0915”(physical association)	0.670
PAK5	CARD9	psi-mi:“MI:0915”(physical association)	0.670
CDCA7L	CARD9	psi-mi:“MI:0915”(physical association)	0.670
ZNF572	CARD9	psi-mi:“MI:0915”(physical association)	0.670
CARD9	FAM161A	psi-mi:“MI:0915”(physical association)	0.670
CARD9	PPP1R18	psi-mi:“MI:0915”(physical association)	0.670
USP15	CARD9	psi-mi:“MI:0915”(physical association)	0.670

BioGRID (228): CARD9 (Two-hybrid), CARD9 (Two-hybrid), CARD9 (Two-hybrid), CARD9 (Two-hybrid), CARD9 (Two-hybrid), CARD9 (Two-hybrid), CARD9 (Two-hybrid), CARD9 (Two-hybrid), CARD9 (Two-hybrid), CARD9 (Two-hybrid), CARD9 (Two-hybrid), CARD9 (Two-hybrid), CARD9 (Two-hybrid), CARD9 (Two-hybrid), CARD9 (Two-hybrid)

ESM2 similar proteins: A0JMK8, A0JNT9, A2AIV8, A6NI79, A9QT41, B2RZ86, B3DLE8, B8JK76, B9V5F5, F1R4Y7, O35550, O35551, O88522, P0CF95, Q08DR9, Q0IHN7, Q0V9T6, Q15276, Q29RS0, Q2MJU7, Q3KR99, Q3SWS9, Q502I3, Q5BIX7, Q5HZK9, Q5U4E6, Q60952, Q6DCD4, Q6DIX6, Q6GLX3, Q6NRW2, Q6P402, Q6PGZ0, Q6TMG5, Q6ZP65, Q6ZU80, Q86SQ7, Q8BI22, Q8BVL9, Q8CHW5

Diamond homologs: A2AIV8, P58660, Q8CIS0, Q99KF0, Q9BWT7, Q9BXL6, Q9BXL7, Q9EPY0, Q9H257

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
CSNK2A1	down-regulates	CARD9	phosphorylation
CSNK2A1	“down-regulates activity”	CARD9	phosphorylation
CARD9	“up-regulates quantity by stabilization”	BCL10	binding
VHL	“down-regulates activity”	CARD9	binding
TRIM62	“up-regulates activity”	CARD9	polyubiquitination
PRKCD	“up-regulates activity”	CARD9	phosphorylation
TRIM62	“up-regulates activity”	CARD9	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

630 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	19
Likely pathogenic	6
Uncertain significance	283
Likely benign	257
Benign	22

Top pathogenic / likely-pathogenic (25)

Variant ID	HGVS	Classification
1366255	NM_052813.5(CARD9):c.579dup (p.Glu194Ter)	Pathogenic
1453058	NM_052813.5(CARD9):c.1045C>T (p.Gln349Ter)	Pathogenic
2008637	NM_052813.5(CARD9):c.106C>T (p.Gln36Ter)	Pathogenic
2013317	NM_052813.5(CARD9):c.273C>G (p.Tyr91Ter)	Pathogenic
2040735	NM_052813.5(CARD9):c.1350dup (p.Asp451fs)	Pathogenic
2062936	NM_052813.5(CARD9):c.1348_1349del (p.Ser450fs)	Pathogenic
2101675	NM_052813.5(CARD9):c.575del (p.Gln192fs)	Pathogenic
2103982	NM_052813.5(CARD9):c.1213C>T (p.Gln405Ter)	Pathogenic
2737986	NM_052813.5(CARD9):c.1000A>T (p.Lys334Ter)	Pathogenic
2779176	NM_052813.5(CARD9):c.205C>T (p.Gln69Ter)	Pathogenic
3245126	NC_000009.11:g.(?139265559)(139333126_?)del	Pathogenic
3245198	NC_000009.11:g.(?139258754)(139266530_?)del	Pathogenic
3406	NM_052813.5(CARD9):c.883C>T (p.Gln295Ter)	Pathogenic
393947	GRCh37/hg19 9q34.3(chr9:138222049-141018925)x1	Pathogenic
4733950	NM_052813.5(CARD9):c.475G>T (p.Glu159Ter)	Pathogenic
567137	NM_052813.5(CARD9):c.1289dup (p.Ser431fs)	Pathogenic
827689	NM_052813.5(CARD9):c.638del (p.Leu213fs)	Pathogenic
836732	NM_052813.5(CARD9):c.766del (p.Leu256fs)	Pathogenic
88852	NM_052813.5(CARD9):c.865C>T (p.Gln289Ter)	Pathogenic
1500511	NM_052813.5(CARD9):c.1078-1G>A	Likely pathogenic
1897178	NM_052813.5(CARD9):c.807+1G>T	Likely pathogenic
2871709	NM_052813.5(CARD9):c.1358-1G>A	Likely pathogenic
3245199	NC_000009.11:g.(?139264852)(139265707_?)del	Likely pathogenic
3779479	NM_052813.5(CARD9):c.808-1G>C	Likely pathogenic
4772367	NM_052813.5(CARD9):c.1357+1G>A	Likely pathogenic

SpliceAI

2153 predictions. Top by Δscore:

Variant	Effect	Δscore
9:136365523:AAAC:A	donor_gain	1.0000
9:136366850:C:CT	acceptor_gain	1.0000
9:136367701:CA:C	donor_gain	1.0000
9:136369747:CACCT:C	donor_loss	1.0000
9:136369748:ACC:A	donor_loss	1.0000
9:136369749:C:CA	donor_loss	1.0000
9:136369772:T:TA	donor_gain	1.0000
9:136369872:TGCA:T	acceptor_gain	1.0000
9:136369874:CA:C	acceptor_gain	1.0000
9:136369876:C:CC	acceptor_gain	1.0000
9:136370313:C:CA	donor_gain	1.0000
9:136370541:T:TA	donor_gain	1.0000
9:136371320:TCA:T	donor_loss	1.0000
9:136371322:A:AC	donor_gain	1.0000
9:136371323:C:CA	donor_gain	1.0000
9:136371323:CCG:C	donor_gain	1.0000
9:136371457:CACAC:C	acceptor_gain	1.0000
9:136371458:ACAC:A	acceptor_gain	1.0000
9:136371459:CAC:C	acceptor_gain	1.0000
9:136371459:CACC:C	acceptor_gain	1.0000
9:136371460:AC:A	acceptor_gain	1.0000
9:136371460:ACCTG:A	acceptor_loss	1.0000
9:136371461:CC:C	acceptor_gain	1.0000
9:136371462:C:CC	acceptor_gain	1.0000
9:136371463:T:A	acceptor_loss	1.0000
9:136371894:CCCA:C	donor_gain	1.0000
9:136371897:A:AC	donor_gain	1.0000
9:136371898:C:CC	donor_gain	1.0000
9:136371901:T:A	donor_gain	1.0000
9:136372093:GG:G	acceptor_gain	1.0000

AlphaMissense

3509 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:136371400:G:C	S82R	0.998
9:136371400:G:T	S82R	0.998
9:136371402:T:G	S82R	0.998
9:136371398:A:G	L83P	0.997
9:136371410:A:G	F79S	0.997
9:136371978:A:G	L34P	0.997
9:136371443:A:G	L68P	0.996
9:136371375:A:C	Y91D	0.994
9:136371423:C:G	G75R	0.994
9:136371455:A:G	L64P	0.994
9:136371978:A:T	L34Q	0.994
9:136371443:A:T	L68Q	0.993
9:136369757:C:G	R357P	0.992
9:136371982:A:C	Y33D	0.992
9:136371365:A:T	V94D	0.991
9:136371392:A:G	L85P	0.991
9:136371413:G:T	A78D	0.991
9:136371975:C:G	R35P	0.991
9:136372046:C:A	W11C	0.991
9:136372046:C:G	W11C	0.991
9:136371398:A:C	L83R	0.990
9:136371422:C:T	G75D	0.990
9:136371978:A:C	L34R	0.990
9:136372017:A:T	L21H	0.990
9:136372048:A:G	W11R	0.990
9:136372048:A:T	W11R	0.990
9:136371398:A:T	L83Q	0.989
9:136371407:A:G	L80P	0.989
9:136371443:A:C	L68R	0.989
9:136371404:T:A	E81V	0.988

dbSNP variants (sampled 300 via entrez): RS1000184768 (9:136374102 G>T), RS1000239655 (9:136372980 A>C), RS1000307276 (9:136368943 C>T), RS1000395266 (9:136371800 C>A,G,T), RS1000708650 (9:136363740 G>A,C), RS1000829251 (9:136363608 G>A,C), RS1001634738 (9:136372384 C>G,T), RS1001677208 (9:136367987 G>A,C,T), RS1001855082 (9:136365764 C>T), RS1001997186 (9:136363757 C>G,T), RS1002284277 (9:136363966 C>T), RS1002512596 (9:136364071 G>A), RS1002952433 (9:136364269 G>C), RS1003073822 (9:136374486 G>A,C), RS1003210794 (9:136373154 T>G)

Disease associations

OMIM: gene MIM:607212 | disease phenotypes: MIM:212050, MIM:213300, MIM:616028

GenCC curated gene-disease

Disease	Classification	Inheritance
predisposition to invasive fungal disease due to CARD9 deficiency	Strong	Autosomal recessive
deep dermatophytosis	Strong	Autosomal recessive

Mondo (4): predisposition to invasive fungal disease due to CARD9 deficiency (MONDO:0008905), Joubert syndrome (MONDO:0018772), Adams-Oliver syndrome 5 (MONDO:0014459), (MONDO:0018335)

Orphanet (3): Predisposition to invasive fungal disease due to CARD9 deficiency (Orphanet:457088), Isolated Joubert syndrome (Orphanet:475), Adams-Oliver syndrome (Orphanet:974)

HPO phenotypes

20 total (20 of 20 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001287	Meningitis
HP:0001871	Abnormality of blood and blood-forming tissues
HP:0002716	Lymphadenopathy
HP:0002721	Immunodeficiency
HP:0003212	Increased circulating IgE concentration
HP:0003621	Juvenile onset
HP:0009098	Chronic oral candidiasis
HP:0010975	Abnormal B cell count
HP:0011463	Childhood onset
HP:0012203	Onychomycosis
HP:0025708	Early young adult onset
HP:0031392	Abnormal CD4+ T cell subset proportion
HP:0031393	Abnormal CD8+ T cell proportion
HP:0032061	Severely increased total eosinophil count
HP:0032259	Chronic tinea infection
HP:0032515	Deep dermatophytosis
HP:0040089	Abnormal total natural killer cell count
HP:0040303	Decreased circulating iron concentration
HP:6000031	Phaeohyphomycosis

GWAS associations

25 associations (top):

Study	Trait	p-value
GCST000527_5	Ulcerative colitis	7.000000e-06
GCST000624_18	Ulcerative colitis	5.000000e-08
GCST000879_23	Crohn’s disease	1.000000e-36
GCST000964_39	Ulcerative colitis	3.000000e-19
GCST001149_7	Ankylosing spondylitis	1.000000e-06
GCST001652_10	Crohn’s disease	4.000000e-06
GCST001691_3	Monocyte chemoattractant protein-1 levels	5.000000e-08
GCST001725_102	Inflammatory bowel disease	4.000000e-56
GCST001762_43	Obesity-related traits	5.000000e-06
GCST002655_2	IgA nephropathy	2.000000e-08
GCST002655_8	IgA nephropathy	1.000000e-09
GCST003097_18	Pediatric autoimmune diseases	3.000000e-08
GCST004131_21	Inflammatory bowel disease	5.000000e-36
GCST004132_11	Crohn’s disease	6.000000e-30
GCST004133_17	Ulcerative colitis	2.000000e-16
GCST005529_22	Ankylosing spondylitis	2.000000e-09
GCST005529_40	Ankylosing spondylitis	7.000000e-09
GCST005537_177	Chronic inflammatory diseases (ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis) (pleiotropy)	6.000000e-45
GCST005537_178	Chronic inflammatory diseases (ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis) (pleiotropy)	1.000000e-31
GCST006677_1	Acute insulin response (insulin secretion adjusted)	4.000000e-08
GCST007991_8	Large artery stroke	4.000000e-06
GCST008643_2	Joint damage in rheumatoid arthritis	1.000000e-06
GCST011938_3	Takayasu arteritis	2.000000e-06
GCST90020028_31	Hip circumference adjusted for BMI	1.000000e-09
GCST90020028_32	Hip circumference adjusted for BMI	8.000000e-10

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006831	acute insulin response measurement
EFO:0005413	joint damage measurement
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

35 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
Silicon Dioxide	increases expression	2
Cyclosporine	decreases expression, decreases methylation	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
sodium bichromate	decreases expression	1
ferrous chloride	decreases expression	1
abrine	increases expression	1
licochalcone B	increases expression	1
jinfukang	decreases expression	1
prothioconazole	increases expression	1
Bortezomib	affects cotreatment, increases expression	1
Arsenic Trioxide	affects cotreatment, increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Amiodarone	increases expression	1
Atrazine	decreases expression	1
Caffeine	decreases phosphorylation	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Diazinon	increases methylation	1
Endosulfan	increases expression	1
Menthol	increases expression	1
Smoke	decreases expression, increases abundance	1
Tetrachlorodibenzodioxin	affects expression	1
Tobacco Smoke Pollution	affects expression	1
Tretinoin	decreases expression	1
Tunicamycin	increases expression	1
Urethane	decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B8CE	Abcam HCT 116 CARD9 KO	Cancer cell line	Male
CVCL_B9EK	Abcam A-549 CARD9 KO	Cancer cell line	Male
CVCL_D2E3	Abcam MCF-7 CARD9 KO	Cancer cell line	Female

Clinical trials (associated diseases)

3 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00873678	Not specified	COMPLETED	Assessment of the Prevalence of Genes AHI1, NPHP1 and CEP290 in Joubert Syndrome
NCT01401998	Not specified	RECRUITING	ARPKD Database Study
NCT04874909	Not specified	COMPLETED	Classification, Functional Stratification and Biomarkers in Ciliopathy (CILLICORIRCM)