CARD18

Summary

CARD18 (caspase recruitment domain family member 18, HGNC:28861) is a protein-coding gene on chromosome 11q22.3, encoding Caspase recruitment domain-containing protein 18 (P57730). Inhibits generation of IL-1-beta by interacting with caspase-1 and preventing its association with RIP2.

Enables CARD domain binding activity and caspase binding activity. Involved in negative regulation of interleukin-1 beta production. Part of protein-containing complex.

Source: NCBI Gene 59082 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 14 total
• MANE Select transcript: NM_021571

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28861
Approved symbol	CARD18
Name	caspase recruitment domain family member 18
Location	11q22.3
Locus type	gene with protein product
Status	Approved
Aliases	UNQ5804, ICEBERG, pseudo-ICE
Ensembl gene	ENSG00000255501
Ensembl biotype	protein_coding
OMIM	605354
Entrez	59082

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000526823, ENST00000528811, ENST00000530950, ENST00000532895, ENST00000649856

RefSeq mRNA: 1 — MANE Select: NM_021571 NM_021571

CCDS: CCDS53705

Canonical transcript exons

ENST00000530950 — 3 exons

Exon	Start	End
ENSE00002456923	105139720	105139769
ENSE00003551693	105138812	105139078
ENSE00003891014	105137714	105138098

Expression profiles

Bgee: expression breadth ubiquitous, 111 present calls, max score 97.28.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0830 / max 53.6543, expressed in 22 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
122087	0.0830	22

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
upper arm skin	UBERON:0004263	97.28	gold quality
mammalian vulva	UBERON:0000997	96.58	gold quality
upper leg skin	UBERON:0004262	96.57	gold quality
penis	UBERON:0000989	94.89	gold quality
skin of abdomen	UBERON:0001416	89.75	gold quality
zone of skin	UBERON:0000014	87.41	gold quality
skin of leg	UBERON:0001511	85.14	gold quality
nipple	UBERON:0002030	84.43	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.52	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	78.56	gold quality
lower esophagus mucosa	UBERON:0035834	77.48	gold quality
pancreatic ductal cell	CL:0002079	71.99	silver quality
skin of hip	UBERON:0001554	71.35	gold quality
buccal mucosa cell	CL:0002336	66.02	gold quality
esophagus mucosa	UBERON:0002469	63.36	gold quality
ileal mucosa	UBERON:0000331	61.51	silver quality
tibialis anterior	UBERON:0001385	60.80	silver quality
right testis	UBERON:0004534	60.31	gold quality
left testis	UBERON:0004533	60.07	gold quality
testis	UBERON:0000473	59.24	gold quality
esophagus squamous epithelium	UBERON:0006920	58.90	silver quality
gingiva	UBERON:0001828	57.81	silver quality
gingival epithelium	UBERON:0001949	56.54	silver quality
cardiac muscle of right atrium	UBERON:0003379	54.34	gold quality
left ventricle myocardium	UBERON:0006566	54.23	gold quality
kidney epithelium	UBERON:0004819	53.93	gold quality
deltoid	UBERON:0001476	53.84	gold quality
placenta	UBERON:0001987	51.70	gold quality
apex of heart	UBERON:0002098	51.32	gold quality
myocardium	UBERON:0002349	50.25	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.52
E-GEOD-111727	no	40.28

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

63 targeting CARD18, 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-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-548O-5P	99.94	71.24	3488
HSA-MIR-548W	99.94	71.24	3488
HSA-MIR-548Y	99.94	71.28	3514
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-6835-3P	99.93	70.49	2904

Literature-anchored findings (GeneRIF, showing 3)

• CARD18 may be both a promising marker for prognosis and a target protein for treatment of gastric cancer. (PMID:23948415)
• CARD18 expression differs in healthy and psoriatic skin; moreover, CARD18 demonstrated altered response under inflammatory conditions in healthy and psoriatic skin (PMID:27023378)
• In lesional epidermis of patients with lichen planus, CARD18 expression was either greatly diminished or entirely absent whereas in non-lesional areas expression was comparable to normal skin. (PMID:28506683)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	casp8	ENSDARG00000058325
danio_rerio	casp3l	ENSDARG00000086266
danio_rerio	casp20	ENSDARG00000104367
danio_rerio		ENSDARG00000112575
drosophila_melanogaster	Dronc	FBGN0026404
drosophila_melanogaster	Decay	FBGN0028381
caenorhabditis_elegans		WBGENE00000417
caenorhabditis_elegans		WBGENE00000819
caenorhabditis_elegans		WBGENE00000820
caenorhabditis_elegans	csp-3	WBGENE00000821

Paralogs (16): CASP10 (ENSG00000003400), CFLAR (ENSG00000003402), CASP8 (ENSG00000064012), PYCARD (ENSG00000103490), CASP14 (ENSG00000105141), CASP2 (ENSG00000106144), CASP9 (ENSG00000132906), CASP1 (ENSG00000137752), CASP5 (ENSG00000137757), CASP6 (ENSG00000138794), CASP3 (ENSG00000164305), CASP7 (ENSG00000165806), PYDC1 (ENSG00000169900), CASP4 (ENSG00000196954), CARD16 (ENSG00000204397), CASP12 (ENSG00000204403)

Protein

Protein identifiers

Caspase recruitment domain-containing protein 18 — P57730 (reviewed: P57730)

Alternative names: Caspase-1 inhibitor Iceberg

All UniProt accessions (2): P57730, G5EA35

UniProt curated annotations — full annotation on UniProt →

Function. Inhibits generation of IL-1-beta by interacting with caspase-1 and preventing its association with RIP2. Down-regulates the release of IL1B.

Subunit / interactions. Interacts with pro-CASP1. Interacts with CARD8.

Tissue specificity. Primarily expressed in the heart and placenta.

Induction. Up-regulated in response to TNF and bacterial lipopolysaccharides (LPS).

RefSeq proteins (1): NP_067546* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001315	CARD	Domain
IPR002398	Pept_C14	Family
IPR011029	DEATH-like_dom_sf	Homologous_superfamily

Pfam: PF00619

UniProt features (9 total): helix 7, chain 1, domain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1DGN	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P57730-F1	90.56	0.73

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 47 (showing top): GOBP_REGULATION_OF_PROTEIN_BINDING, GOBP_NEGATIVE_REGULATION_OF_INTERLEUKIN_1_PRODUCTION, GOBP_INFLAMMATORY_RESPONSE, chr11q22, GOBP_INTERLEUKIN_1_PRODUCTION, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_BINDING, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOMF_CYSTEINE_TYPE_PEPTIDASE_ACTIVITY, GOBP_CYTOKINE_PRODUCTION, GOBP_NEGATIVE_REGULATION_OF_MOLECULAR_FUNCTION, KEGG_NOD_LIKE_RECEPTOR_SIGNALING_PATHWAY, MODULE_207, GOBP_NEGATIVE_REGULATION_OF_CYTOKINE_PRODUCTION, XU_GH1_EXOGENOUS_TARGETS_DN, GOBP_PROTEOLYSIS

GO Biological Process (6): proteolysis (GO:0006508), inflammatory response (GO:0006954), negative regulation of protein binding (GO:0032091), negative regulation of interleukin-1 beta production (GO:0032691), regulation of apoptotic process (GO:0042981), regulation of interleukin-1 beta production (GO:0032651)

GO Molecular Function (7): cysteine-type endopeptidase activity (GO:0004197), cysteine-type endopeptidase inhibitor activity (GO:0004869), CARD domain binding (GO:0050700), caspase binding (GO:0089720), protein binding (GO:0005515), enzyme binding (GO:0019899), peptidase inhibitor activity (GO:0030414)

GO Cellular Component (1): protein-containing complex (GO:0032991)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	2
interleukin-1 beta production	2
protein metabolic process	1
defense response	1
regulation of protein binding	1
negative regulation of binding	1
regulation of interleukin-1 beta production	1
negative regulation of interleukin-1 production	1
apoptotic process	1
regulation of programmed cell death	1
regulation of interleukin-1 production	1
endopeptidase activity	1
cysteine-type peptidase activity	1
cysteine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
protein domain specific binding	1
protease binding	1
binding	1
enzyme inhibitor activity	1
peptidase activity	1
peptidase regulator activity	1
cellular_component	1

Protein interactions and networks

STRING

386 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CARD18	CARD8	Q9Y2G2	692
CARD18	PYCARD	Q9ULZ3	683
CARD18	CASP5	P51878	661
CARD18	IL1B	P01584	632
CARD18	MEFV	O15553	624
CARD18	NLRP1	Q9C000	592
CARD18	APAF1	O14727	572
CARD18	CASP1	P29466	554
CARD18	NLRP3	Q96P20	552
CARD18	NLRP2	Q9NX02	488
CARD18	FADD	Q13158	483
CARD18	NLRC4	Q9NPP4	465
CARD18	NLRP2B	P0DMW2	455
CARD18	ANKRD20A3P	Q5VUR7	447
CARD18	CRADD	P78560	435

IntAct

4 interactions, top by confidence:

A	B	Type	Score
CASP1	CARD18	psi-mi:“MI:0407”(direct interaction)	0.600

BioGRID (2): CARD18 (Affinity Capture-Western), CARD18 (Affinity Capture-MS)

ESM2 similar proteins: A6QLE5, B0FPE9, D4A523, O08736, O14862, O35732, O62640, O77736, O89110, O95786, P25445, P29452, P43527, P55865, P55867, P57730, P70343, Q13158, Q14790, Q15121, Q153Z0, Q504J1, Q5R529, Q5RAV7, Q5U318, Q61160, Q62048, Q63199, Q645M6, Q6GZR1, Q6Q899, Q7RTR0, Q8HXK9, Q8IXQ6, Q8R4B8, Q8WXC3, Q91VJ1, Q920D5, Q92851, Q96P20

Diamond homologs: A0A1D5PPP7, O08736, O75601, O89094, P29452, P29466, P42573, P42574, P43527, P45436, P49662, P51878, P55213, P55865, P55867, P57730, P70343, P70677, Q075B4, Q08DY9, Q153Z0, Q2PFV2, Q504J1, Q5E9C1, Q5EG05, Q5IS54, Q5IS99, Q5XLA6, Q60431, Q6UXS9, Q8MJC3, Q8MJU1, Q8MKI5, Q920D5, Q95ND5, Q9I9L7, Q9MZV6, Q9MZV7, Q9N2I1, Q9TV13

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	13
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

308 predictions. Top by Δscore:

Variant	Effect	Δscore
11:105138807:CTTAC:C	donor_loss	1.0000
11:105138809:TA:T	donor_loss	1.0000
11:105138811:C:CT	donor_loss	1.0000
11:105138095:CTCT:C	acceptor_gain	0.9900
11:105138096:TCTC:T	acceptor_loss	0.9900
11:105138097:CT:C	acceptor_gain	0.9900
11:105138098:TCTGT:T	acceptor_loss	0.9900
11:105138099:C:CC	acceptor_gain	0.9900
11:105138099:CTGTG:C	acceptor_loss	0.9900
11:105138100:T:G	acceptor_loss	0.9900
11:105138810:A:AC	donor_gain	0.9900
11:105138811:C:CC	donor_gain	0.9900
11:105138827:T:C	donor_gain	0.9900
11:105139079:C:CC	acceptor_gain	0.9800
11:105139082:T:TC	acceptor_gain	0.9800
11:105138096:TCT:T	acceptor_gain	0.9700
11:105138097:CTC:C	acceptor_gain	0.9700
11:105138098:TCT:T	acceptor_gain	0.9700
11:105139076:GGTC:G	acceptor_loss	0.9700
11:105139078:TC:T	acceptor_loss	0.9700
11:105139079:C:CG	acceptor_loss	0.9700
11:105139080:T:A	acceptor_loss	0.9700
11:105138811:CCTTA:C	donor_gain	0.9600
11:105139075:TGGT:T	acceptor_gain	0.9600
11:105139082:T:C	acceptor_gain	0.9600
11:105138094:TCTCT:T	acceptor_gain	0.9500
11:105138095:CTCTC:C	acceptor_gain	0.9500
11:105138096:TCTCT:T	acceptor_gain	0.9500
11:105138101:G:C	acceptor_gain	0.9500
11:105139074:TTGGT:T	acceptor_gain	0.9500

AlphaMissense

596 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:105139047:A:C	F13L	0.872
11:105139047:A:T	F13L	0.872
11:105139049:A:G	F13L	0.872
11:105139056:T:A	R10S	0.868
11:105139056:T:G	R10S	0.868
11:105139069:A:G	L6S	0.849
11:105138916:A:G	L57S	0.841
11:105138922:C:G	R55P	0.839
11:105138904:A:T	V61D	0.836
11:105138927:C:A	K53N	0.832
11:105138927:C:G	K53N	0.832
11:105138870:A:C	F72L	0.815
11:105138870:A:T	F72L	0.815
11:105138872:A:G	F72L	0.815
11:105138893:C:G	G65R	0.804
11:105138893:C:T	G65R	0.804
11:105138909:G:C	D59E	0.802
11:105138909:G:T	D59E	0.802
11:105139048:A:G	F13S	0.799
11:105139012:A:G	L25S	0.795
11:105138846:G:C	D80E	0.748
11:105138846:G:T	D80E	0.748
11:105138926:C:G	A54P	0.737
11:105139057:C:G	R10T	0.737
11:105139040:A:G	S16P	0.719
11:105138892:C:T	G65E	0.714
11:105139005:A:C	D27E	0.714
11:105139005:A:T	D27E	0.714
11:105139048:A:C	F13C	0.707
11:105139021:A:T	I22K	0.701

dbSNP variants (sampled 300 via entrez): RS1000874513 (11:105140865 C>T), RS1001531130 (11:105137565 G>A), RS1001930927 (11:105141415 A>T), RS1002171367 (11:105137876 A>G), RS1002380808 (11:105140457 G>A), RS1002756926 (11:105137669 T>C), RS1002942414 (11:105138982 A>G), RS1004991391 (11:105141603 T>C,G), RS1005714025 (11:105137265 C>T), RS1005769760 (11:105138512 G>A,T), RS1006003834 (11:105141252 T>C), RS1006234809 (11:105138277 A>G), RS1006280883 (11:105141463 A>G,T), RS1006516368 (11:105137439 C>T), RS1006809782 (11:105138319 A>G)

Disease associations

OMIM: gene MIM:605354 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Arsenic	affects methylation, decreases expression, increases abundance	2
sanguinarine	affects cotreatment, increases expression	1
bisphenol A	affects methylation, affects cotreatment, increases methylation	1
sodium arsenate	decreases expression, increases abundance	1
4-phenylenediamine	increases expression	1
hydroquinone	increases expression	1
pentabromodiphenyl ether	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
Arsenic Trioxide	affects cotreatment, increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Asbestos	affects response to substance	1
Benzo(a)pyrene	increases methylation	1
Menthol	decreases expression	1
Valproic Acid	decreases methylation	1
Cyclosporine	increases expression	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	increases expression	1
Lactic Acid	affects expression	1

Clinical trials (associated diseases)

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