CARD6

Summary

CARD6 (caspase recruitment domain family member 6, HGNC:16394) is a protein-coding gene on chromosome 5p13.1, encoding Caspase recruitment domain-containing protein 6 (Q9BX69). May be involved in apoptosis.

This gene encodes a protein that contains a caspase recruitment domain (CARD), an antiparallel six-helical bundle that mediates homotypic protein-protein interactions. The encoded protein is a microtubule-associated protein that has been shown to interact with receptor-interacting protein kinases and positively modulate signal transduction pathways converging on activation of the inducible transcription factor NF-kB.

Source: NCBI Gene 84674 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 167 total
• MANE Select transcript: NM_032587

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16394
Approved symbol	CARD6
Name	caspase recruitment domain family member 6
Location	5p13.1
Locus type	gene with protein product
Status	Approved
Aliases	CINCIN1
Ensembl gene	ENSG00000132357
Ensembl biotype	protein_coding
OMIM	609986
Entrez	84674

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000254691, ENST00000381677, ENST00000894490

RefSeq mRNA: 1 — MANE Select: NM_032587 NM_032587

CCDS: CCDS3935

Canonical transcript exons

ENST00000254691 — 3 exons

Exon	Start	End
ENSE00000903766	40843152	40843709
ENSE00001143108	40852174	40855354
ENSE00001143118	40841367	40841665

Expression profiles

Bgee: expression breadth ubiquitous, 232 present calls, max score 94.91.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.6280 / max 125.9296, expressed in 1152 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
56238	4.0531	1082
56237	0.3811	197
56239	0.1938	101

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
epithelial cell of pancreas	CL:0000083	94.91	gold quality
esophagus squamous epithelium	UBERON:0006920	93.26	gold quality
palpebral conjunctiva	UBERON:0001812	92.64	gold quality
gingival epithelium	UBERON:0001949	91.84	gold quality
visceral pleura	UBERON:0002401	91.22	gold quality
gingiva	UBERON:0001828	90.91	gold quality
parietal pleura	UBERON:0002400	90.05	gold quality
oral cavity	UBERON:0000167	89.97	gold quality
nasal cavity epithelium	UBERON:0005384	88.77	gold quality
lower lobe of lung	UBERON:0008949	87.89	gold quality
cardiac muscle of right atrium	UBERON:0003379	87.65	silver quality
left ventricle myocardium	UBERON:0006566	87.41	silver quality
trabecular bone tissue	UBERON:0002483	86.56	gold quality
tibia	UBERON:0000979	86.47	gold quality
pericardium	UBERON:0002407	85.63	gold quality
endothelial cell	CL:0000115	85.39	silver quality
germinal epithelium of ovary	UBERON:0001304	84.80	gold quality
blood	UBERON:0000178	84.67	gold quality
right adrenal gland cortex	UBERON:0035827	84.49	gold quality
kidney epithelium	UBERON:0004819	84.25	silver quality
jejunal mucosa	UBERON:0000399	84.24	gold quality
layer of synovial tissue	UBERON:0007616	84.08	gold quality
parotid gland	UBERON:0001831	84.05	gold quality
monocyte	CL:0000576	83.82	gold quality
leukocyte	CL:0000738	83.78	gold quality
right adrenal gland	UBERON:0001233	83.51	gold quality
gall bladder	UBERON:0002110	83.07	gold quality
epithelium of mammary gland	UBERON:0003244	82.62	gold quality
mammary duct	UBERON:0001765	82.54	gold quality
adrenal gland	UBERON:0002369	82.47	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.43

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

35 targeting CARD6, 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-4455	100.00	65.48	1587
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-498-5P	99.76	69.64	1807
HSA-MIR-200A-5P	99.76	69.10	949
HSA-MIR-200B-5P	99.76	69.05	948
HSA-MIR-4645-3P	99.76	69.33	993
HSA-MIR-4489	99.50	65.56	785
HSA-MIR-5695	99.41	67.48	1047
HSA-MIR-580-5P	99.28	70.94	1776
HSA-MIR-5693	99.24	66.67	1106
HSA-MIR-196A-3P	99.19	67.34	1204
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-371A-5P	99.08	66.51	1914
HSA-MIR-4260	98.78	65.37	848
HSA-MIR-4686	98.77	66.87	964
HSA-MIR-767-3P	98.61	67.69	1192
HSA-MIR-3187-5P	98.36	65.74	1776
HSA-MIR-4704-3P	98.28	69.33	1300
HSA-MIR-6742-3P	97.95	64.50	1490
HSA-MIR-1285-3P	97.72	67.02	1932

Literature-anchored findings (GeneRIF, showing 7)

• identification as a modulator of NF-kappa B activation by Nod1- and Cardiak-mediated pathways (PMID:12775719)
• CARD6 is a regulator of NF-kappaB activation that modulates the functions of RICK protein (PMID:16418290)
• review of the regulation of interactions of CARD6 with RICK and microtubules [review] (PMID:16582588)
• The increased expression of CARD6 in esophageal squamous cell carcinoma,gastric and colorectal adenocarcinoma suggested that neoexpression of CARD6 might be related to activation of NF-kappaB pathway. (PMID:20025480)
• Data show that NOD-like receptor signaling genes NOD2, PYCARD, CARD6, and IFI16 are upregulated in psoriatic epidermis. (PMID:26976200)
• expression markedly reduced in nonalcoholic fatty liver disease livers (PMID:29729191)
• Exosome-transmitted circ-CARD6 facilitates posterior capsule opacification development by miR-31/FGF7 axis. (PMID:33844960)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Card6	ENSMUSG00000041849
rattus_norvegicus	Card6	ENSRNOG00000001271

Paralogs (1): NOL3 (ENSG00000140939)

Protein

Protein identifiers

Caspase recruitment domain-containing protein 6 — Q9BX69 (reviewed: Q9BX69)

All UniProt accessions (2): Q9BX69, A0A0B4J1T5

UniProt curated annotations — full annotation on UniProt →

Function. May be involved in apoptosis.

RefSeq proteins (1): NP_115976* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001315	CARD	Domain
IPR011029	DEATH-like_dom_sf	Homologous_superfamily
IPR052685	Apoptosis_Repressor_CARD	Family
IPR057365	URGCP	Domain

Pfam: PF00619, PF25496

UniProt features (22 total): compositionally biased region 7, sequence variant 6, modified residue 3, region of interest 3, initiator methionine 1, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BX69-F1	55.25	0.13

Functional residue map

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

Post-translational modifications (3): 2, 154, 985

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 158 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_UP, GOBP_ORGANIC_HYDROXY_COMPOUND_TRANSPORT, GOBP_CHOLESTEROL_EFFLUX, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, GOBP_MYELOID_LEUKOCYTE_ACTIVATION, GATA6_01, KINSEY_TARGETS_OF_EWSR1_FLII_FUSION_DN, MARZEC_IL2_SIGNALING_DN, GOBP_MACROPHAGE_ACTIVATION, NAKAMURA_TUMOR_ZONE_PERIPHERAL_VS_CENTRAL_DN, CHARAFE_BREAST_CANCER_LUMINAL_VS_BASAL_DN, RYTTCCTG_ETS2_B, GOBP_STEROL_TRANSPORT, KEGG_NOD_LIKE_RECEPTOR_SIGNALING_PATHWAY, RICKMAN_TUMOR_DIFFERENTIATED_MODERATELY_VS_POORLY_UP

GO Biological Process (2): apoptotic process (GO:0006915), regulation of apoptotic process (GO:0042981)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (0):

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
apoptotic process	1
regulation of programmed cell death	1
binding	1

Protein interactions and networks

STRING

552 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CARD6	RIPK2	O43353	955
CARD6	NOD1	Q9Y239	849
CARD6	MINDY3	Q9H8M7	805
CARD6	CARD8	Q9Y2G2	728
CARD6	BCL10	O95999	594
CARD6	RIPK1	Q13546	594
CARD6	NLRP1	Q9C000	592
CARD6	NOD2	Q9HC29	590
CARD6	CARD10	Q9BWT7	541
CARD6	CASP1	P29466	528
CARD6	CARD11	Q9BXL7	506
CARD6	CARD14	Q9BXL6	489
CARD6	IFNG	P01579	462
CARD6	TTC33	Q6PID6	450
CARD6	CARD9	Q9H257	434

IntAct

7 interactions, top by confidence:

A	B	Type	Score
CARD6	RIPK2	psi-mi:“MI:0915”(physical association)	0.400
RIPK2	CARD6	psi-mi:“MI:0915”(physical association)	0.400
CARD6	RIPK1	psi-mi:“MI:0915”(physical association)	0.400
CARD6	CARD6	psi-mi:“MI:0915”(physical association)	0.400
PB2		psi-mi:“MI:0914”(association)	0.350
AFG2A	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (13): CARD6 (Affinity Capture-MS), NOD1 (Affinity Capture-Western), RIPK2 (Affinity Capture-Western), XK (Affinity Capture-Western), CARD8 (Affinity Capture-Western), CARD6 (Proximity Label-MS), CARD6 (Affinity Capture-RNA), MIB2 (Affinity Capture-Western), CARD6 (Affinity Capture-Western), CARD6 (Affinity Capture-MS), CARD6 (Cross-Linking-MS (XL-MS)), HSP90AB1 (Cross-Linking-MS (XL-MS)), PRPF8 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A6H5X4, B2RX14, D0QMC3, D3ZF42, F6QRE9, O14862, O35368, P0C6Y7, P0DOV1, P0DOV2, P23497, P41218, Q13342, Q15361, Q16666, Q17RS7, Q3KRF1, Q504N7, Q5H9K5, Q5I0E2, Q5RD14, Q5RF97, Q5T4T6, Q5VYS8, Q5W0A0, Q62187, Q66JT0, Q6K0P9, Q6NYJ3, Q6ZMT9, Q7RTT4, Q80VH0, Q86X53, Q8BUH8, Q8BV49, Q8BVK9, Q8C0V1, Q8CGE8, Q8NDB2, Q8SPH9

Diamond homologs: A0JN92, Q5NCI0, Q5RFJ8, Q8TCY9, Q9BX69, O60936, Q62881, Q9D1X0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	139
Likely benign	16
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

375 predictions. Top by Δscore:

Variant	Effect	Δscore
5:40843150:A:AG	acceptor_gain	1.0000
5:40843151:G:GG	acceptor_gain	1.0000
5:40843151:GAA:G	acceptor_gain	1.0000
5:40843710:G:C	donor_loss	1.0000
5:40841661:GCATG:G	donor_gain	0.9900
5:40841662:CATG:C	donor_gain	0.9900
5:40841662:CATGG:C	donor_loss	0.9900
5:40841664:TGGT:T	donor_loss	0.9900
5:40841665:GGT:G	donor_loss	0.9900
5:40841666:G:GG	donor_gain	0.9900
5:40841666:GTAAG:G	donor_loss	0.9900
5:40841667:T:G	donor_loss	0.9900
5:40843151:GAAGT:G	acceptor_gain	0.9900
5:40843706:GAAG:G	donor_gain	0.9900
5:40841664:TG:T	donor_gain	0.9800
5:40841665:GG:G	donor_gain	0.9800
5:40843148:GCAGA:G	acceptor_loss	0.9800
5:40843150:AGA:A	acceptor_loss	0.9800
5:40843151:GA:G	acceptor_gain	0.9800
5:40843639:TG:T	donor_gain	0.9800
5:40841584:G:GT	donor_gain	0.9700
5:40841663:ATG:A	donor_gain	0.9700
5:40843146:TTGCA:T	acceptor_loss	0.9700
5:40843147:TGCA:T	acceptor_loss	0.9700
5:40843710:G:GG	donor_gain	0.9700
5:40841556:G:GT	donor_gain	0.9600
5:40841574:AC:A	donor_gain	0.9600
5:40841662:C:T	donor_gain	0.9500
5:40843700:A:AG	donor_gain	0.9500
5:40843701:G:GG	donor_gain	0.9500

AlphaMissense

6830 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:40852966:T:C	F545S	0.963
5:40852733:G:C	K467N	0.962
5:40852733:G:T	K467N	0.962
5:40841561:T:C	L60P	0.956
5:40852857:T:A	W509R	0.956
5:40852857:T:C	W509R	0.956
5:40853281:C:A	A650D	0.953
5:40841555:G:C	R58P	0.948
5:40852732:A:T	K467M	0.944
5:40852701:T:C	F457L	0.942
5:40852703:T:A	F457L	0.942
5:40852703:T:G	F457L	0.942
5:40852539:T:C	F403L	0.941
5:40852541:T:A	F403L	0.941
5:40852541:T:G	F403L	0.941
5:40853296:T:C	I655T	0.939
5:40852788:T:C	F486L	0.938
5:40852790:T:A	F486L	0.938
5:40852790:T:G	F486L	0.938
5:40852959:T:C	F543L	0.935
5:40852961:T:A	F543L	0.935
5:40852961:T:G	F543L	0.935
5:40841606:T:C	F75S	0.934
5:40852317:T:C	F329L	0.930
5:40852319:C:A	F329L	0.930
5:40852319:C:G	F329L	0.930
5:40841564:T:C	L61S	0.927
5:40852927:T:C	L532P	0.927
5:40841447:T:C	L22P	0.926
5:40841480:T:C	L33S	0.926

dbSNP variants (sampled 300 via entrez): RS1000301987 (5:40851189 G>T), RS1000315813 (5:40843895 A>G), RS1000431972 (5:40844170 G>C), RS1000523757 (5:40848845 A>G,T), RS1000769698 (5:40842647 T>C), RS1000992001 (5:40845933 T>A), RS1001039925 (5:40849198 T>C), RS1001532353 (5:40844274 C>T), RS1001633499 (5:40844473 T>C,G), RS1001973732 (5:40851743 G>A,T), RS1001980636 (5:40842910 T>C), RS1002386820 (5:40839644 T>A), RS1002427565 (5:40850015 T>A,C), RS1002639819 (5:40846005 T>A), RS1002890042 (5:40849643 T>C)

Disease associations

OMIM: gene MIM:609986 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002889_4	Psoriasis	6.000000e-09
GCST003784_5	Multiple system atrophy	5.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	decreases expression	3
Estradiol	affects expression, decreases expression, increases expression	3
Particulate Matter	decreases expression, increases abundance	3
sodium arsenite	increases expression	2
Acetaminophen	decreases expression	2
Air Pollutants	decreases expression, increases abundance	2
Tretinoin	increases expression	2
Aflatoxin B1	affects expression, increases expression	2
Cadmium Chloride	increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
methylmercuric chloride	increases expression	1
alpha phellandrene	increases expression	1
sanguinarine	affects cotreatment, increases expression	1
bisphenol A	affects cotreatment, increases expression	1
afimoxifene	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
zinc chromate	increases abundance, increases expression	1
cupric oxide	increases expression	1
1,1-bis(4-hydroxyphenyl)-2-phenylbut-1-ene	increases expression	1
chromium hexavalent ion	increases abundance, increases expression	1
pentabromodiphenyl ether	decreases expression	1
cylindrospermopsin	increases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	affects cotreatment, decreases expression	1
brevetoxin 2	increases expression	1

Clinical trials (associated diseases)

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