CARD9

caspase recruitment domain family member 9, the group of Caspase recruitment domain containing

Basic information

Region (hg38): 9:136363956-136373681

Links

ENSG00000187796 ∙ NCBI:64170 ∙ OMIM:607212 ∙ HGNC:16391 ∙ Uniprot:Q9H257 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• predisposition to invasive fungal disease due to CARD9 deficiency (Supportive), mode of inheritance: AR
• predisposition to invasive fungal disease due to CARD9 deficiency (Strong), mode of inheritance: AR
• deep dermatophytosis (Strong), mode of inheritance: AR
• predisposition to invasive fungal disease due to CARD9 deficiency (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Immunodeficiency 103, susceptibility to fungal infections	AR	Allergy/Immunology/Infectious	Individuals can have recurrent (and lethal) fungal infections, and surveillance, prophylaxis, and early treatment may be beneficial	Allergy/Immunology/Infectious	19864672; 22703878; 23335372; 24131138

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CARD9 gene.

• Predisposition to invasive fungal disease due to CARD9 deficiency (15 variants)
• Inherited Immunodeficiency Diseases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CARD9 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			3	128	6	137
missense			210	8	1	219
nonsense	8		1			9
start loss						0
frameshift	8	1				9
inframe indel			7			7
splice donor/acceptor (+/-2bp)		3				3
splice region			8	16	1	25
non coding			10	64	10	84
Total	16	4	231	200	17

Highest pathogenic variant AF is 0.0000263

Variants in CARD9

This is a list of pathogenic ClinVar variants found in the CARD9 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
9-136364010-A-G		Predisposition to invasive fungal disease due to CARD9 deficiency • not specified	Benign (Jan 24, 2024)
9-136364056-G-C		Predisposition to invasive fungal disease due to CARD9 deficiency	Likely benign (Jan 13, 2018)
9-136364058-A-C		Predisposition to invasive fungal disease due to CARD9 deficiency	Uncertain significance (Jan 12, 2018)
9-136364163-C-T		Predisposition to invasive fungal disease due to CARD9 deficiency	Uncertain significance (Jan 12, 2018)
9-136364172-C-T		Predisposition to invasive fungal disease due to CARD9 deficiency	Uncertain significance (Jan 13, 2018)
9-136364245-G-A		Predisposition to invasive fungal disease due to CARD9 deficiency	Uncertain significance (Jan 13, 2018)
9-136364304-A-G		Predisposition to invasive fungal disease due to CARD9 deficiency	Uncertain significance (Oct 31, 2018)
9-136364308-G-A		Predisposition to invasive fungal disease due to CARD9 deficiency	Likely benign (Sep 01, 2023)
9-136364315-G-A		Predisposition to invasive fungal disease due to CARD9 deficiency	Uncertain significance (Aug 23, 2022)
9-136364317-G-A		Predisposition to invasive fungal disease due to CARD9 deficiency • CARD9-related disorder	Benign (Jan 29, 2024)
9-136364320-G-A		Predisposition to invasive fungal disease due to CARD9 deficiency	Likely benign (Dec 30, 2022)
9-136364321-G-A		Predisposition to invasive fungal disease due to CARD9 deficiency	Uncertain significance (Nov 22, 2022)
9-136364321-GTGT-G		Predisposition to invasive fungal disease due to CARD9 deficiency	Uncertain significance (Oct 25, 2022)
9-136364323-G-A		Predisposition to invasive fungal disease due to CARD9 deficiency	Likely benign (Jul 30, 2022)
9-136364335-C-T		Predisposition to invasive fungal disease due to CARD9 deficiency	Likely benign (Dec 17, 2018)
9-136364336-G-C		Predisposition to invasive fungal disease due to CARD9 deficiency	Uncertain significance (Jun 13, 2022)
9-136364337-T-C		Predisposition to invasive fungal disease due to CARD9 deficiency	Uncertain significance (Mar 17, 2021)
9-136364339-G-A		Predisposition to invasive fungal disease due to CARD9 deficiency	Uncertain significance (Jan 13, 2018)
9-136364342-T-G		Predisposition to invasive fungal disease due to CARD9 deficiency • Inborn genetic diseases	Uncertain significance (Nov 01, 2022)
9-136364346-C-G		Predisposition to invasive fungal disease due to CARD9 deficiency • Inborn genetic diseases	Uncertain significance (Sep 19, 2022)
9-136364348-C-T		Predisposition to invasive fungal disease due to CARD9 deficiency • Inborn genetic diseases	Conflicting classifications of pathogenicity (May 12, 2024)
9-136364350-G-C		Predisposition to invasive fungal disease due to CARD9 deficiency	Uncertain significance (Feb 14, 2021)
9-136364350-GTCC-G		Predisposition to invasive fungal disease due to CARD9 deficiency	Uncertain significance (Sep 01, 2021)
9-136364351-T-G		Predisposition to invasive fungal disease due to CARD9 deficiency	Uncertain significance (Apr 23, 2021)
9-136364352-C-G		Predisposition to invasive fungal disease due to CARD9 deficiency	Uncertain significance (May 07, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CARD9	protein_coding	protein_coding	ENST00000371732	12	11779

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
8.15e-13	0.244	124676	2	856	125534	0.00342

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.0997	355	360	0.985	0.0000263	3444
Missense in Polyphen		79	108.54	0.72786		975
Synonymous	-1.56	184	159	1.16	0.0000113	1023
Loss of Function	1.04	22	27.9	0.788	0.00000128	312

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00215	0.00214
Ashkenazi Jewish	0.00722	0.00719
East Asian	0.000439	0.000435
Finnish	0.000926	0.000878
European (Non-Finnish)	0.00554	0.00547
Middle Eastern	0.000439	0.000435
South Asian	0.00210	0.00209
Other	0.00247	0.00245

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Adapter protein that plays a key role in innate immune response to a number of intracellular pathogens, such as C.albicans and L.monocytogenes. Is at the crossroads of ITAM- tyrosine kinase and the Toll-like receptors (TLR) and NOD2 signaling pathways. Probably controls various innate immune response pathways depending on the intracellular pathogen. In response to L.monocytogenes infection, acts by connecting NOD2 recognition of peptidoglycan to downstream activation of MAP kinases (MAPK) without activating NF-kappa-B. 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 (By similarity). Controls CLEC7A (dectin-1)-mediated myeloid cell activation induced by the yeast cell wall component zymosan, leading to cytokine production and innate anti-fungal immunity: acts by regulating BCL10-MALT1-mediated NF-kappa-B activation pathway. Activates NF-kappa-B via BCL10. In response to the hyphal form of C.albicans, mediates CLEC6A (dectin-2)-induced I-kappa-B kinase ubiquitination, leading to NF-kappa-B activation via interaction with BCL10. In response to fungal infection, may be required for the development and subsequent differentiation of interleukin 17-producing T helper (TH-17) cells. {ECO:0000250, ECO:0000269|PubMed:11053425}.
• Disease: DISEASE: Candidiasis, familial, 2 (CANDF2) [MIM:212050]: A 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. {ECO:0000269|PubMed:19864672, ECO:0000269|PubMed:23335372, ECO:0000269|PubMed:24131138}. Note=The disease is caused by mutations 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 (PubMed:23335372). {ECO:0000269|PubMed:23335372}.
• Pathway: NOD-like receptor signaling pathway - Homo sapiens (human);C-type lectin receptor signaling pathway - Homo sapiens (human);Tuberculosis - Homo sapiens (human);Nucleotide-binding Oligomerization Domain (NOD) pathway;NOD1/2 Signaling Pathway;Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways;CLEC7A (Dectin-1) signaling;C-type lectin receptors (CLRs);Innate Immune System;Immune System (Consensus)

Recessive Scores

• pRec: 0.139

Intolerance Scores

• loftool: 0.827
• rvis_EVS: -0.59
• rvis_percentile_EVS: 18.23

Haploinsufficiency Scores

• pHI: 0.0928
• hipred: Y
• hipred_score: 0.533
• ghis: 0.537

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.814

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Card9
• Phenotype: hematopoietic system phenotype; homeostasis/metabolism phenotype; immune system phenotype

Gene ontology

• Biological process: stimulatory C-type lectin receptor signaling pathway;I-kappaB kinase/NF-kappaB signaling;response to fungus;response to peptidoglycan;response to muramyl dipeptide;positive regulation of interleukin-6 production;positive regulation of tumor necrosis factor production;positive regulation of stress-activated MAPK cascade;regulation of tumor necrosis factor biosynthetic process;regulation of apoptotic process;positive regulation of I-kappaB kinase/NF-kappaB signaling;response to exogenous dsRNA;regulation of interleukin-2 biosynthetic process;innate immune response;regulation of interleukin-6 biosynthetic process;positive regulation of JNK cascade;defense response to Gram-positive bacterium;defense response to virus
• Cellular component: cytoplasm;cytosol;plasma membrane
• Molecular function: protein binding;protein homodimerization activity;CARD domain binding