CARD16

Summary

CARD16 (caspase recruitment domain family member 16, HGNC:33701) is a protein-coding gene on chromosome 11q22.3, encoding Caspase recruitment domain-containing protein 16 (Q5EG05). Caspase inhibitor.

Enables several functions, including CARD domain binding activity; cysteine-type endopeptidase inhibitor activity; and enzyme binding activity. Involved in cellular response to lipopolysaccharide; regulation of gene expression; and regulation of signal transduction. Part of protease inhibitor complex.

Source: NCBI Gene 114769 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 158 total — 2 pathogenic
• MANE Select transcript: NM_052889

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:33701
Approved symbol	CARD16
Name	caspase recruitment domain family member 16
Location	11q22.3
Locus type	gene with protein product
Status	Approved
Aliases	COP1, COP, PSEUDO-ICE, LLID-114769
Ensembl gene	ENSG00000204397
Ensembl biotype	protein_coding
OMIM	615680
Entrez	114769

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000525374, ENST00000527065, ENST00000528513, ENST00000672037, ENST00000673097, ENST00000870804

RefSeq mRNA: 2 — MANE Select: NM_052889 NM_001394580, NM_052889

CCDS: CCDS41705

Canonical transcript exons

ENST00000673097 — 4 exons

Exon	Start	End
ENSE00001650361	105041563	105041719
ENSE00002152089	105045291	105045335
ENSE00003936536	105043483	105043545
ENSE00003938076	105044392	105044658

Expression profiles

Bgee: expression breadth ubiquitous, 224 present calls, max score 99.51.

FANTOM5 (CAGE): breadth broad, TPM avg 8.5403 / max 254.7213, expressed in 913 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
122082	8.5403	913
122086	0.3382	68

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	99.51	gold quality
leukocyte	CL:0000738	99.47	gold quality
granulocyte	CL:0000094	99.20	gold quality
stromal cell of endometrium	CL:0002255	98.62	gold quality
spleen	UBERON:0002106	97.51	gold quality
vermiform appendix	UBERON:0001154	97.41	gold quality
germinal epithelium of ovary	UBERON:0001304	97.24	gold quality
bone marrow	UBERON:0002371	96.44	gold quality
bone marrow cell	CL:0002092	96.00	gold quality
mucosa of transverse colon	UBERON:0004991	95.94	gold quality
caecum	UBERON:0001153	95.39	gold quality
superficial temporal artery	UBERON:0001614	95.37	gold quality
blood	UBERON:0000178	95.20	gold quality
right lung	UBERON:0002167	95.16	gold quality
lymph node	UBERON:0000029	94.83	gold quality
rectum	UBERON:0001052	94.73	gold quality
lower lobe of lung	UBERON:0008949	94.73	silver quality
jejunal mucosa	UBERON:0000399	94.50	gold quality
colonic epithelium	UBERON:0000397	94.41	gold quality
mucosa of paranasal sinus	UBERON:0005030	94.19	gold quality
upper lobe of left lung	UBERON:0008952	94.00	gold quality
upper lobe of lung	UBERON:0008948	93.99	gold quality
visceral pleura	UBERON:0002401	93.60	gold quality
trabecular bone tissue	UBERON:0002483	93.09	gold quality
lung	UBERON:0002048	93.07	gold quality
gall bladder	UBERON:0002110	92.63	gold quality
duodenum	UBERON:0002114	92.09	gold quality
palpebral conjunctiva	UBERON:0001812	92.01	gold quality
small intestine Peyer’s patch	UBERON:0003454	91.64	gold quality
small intestine	UBERON:0002108	91.22	gold quality

Single-cell (SCXA)

Detected in 17 experiment(s), a significant marker in 15.

Experiment	Marker?	Max mean expression
E-CURD-89	yes	841.45
E-CURD-95	yes	822.19
E-HCAD-4	yes	57.84
E-MTAB-8142	yes	44.16
E-MTAB-6701	yes	36.00
E-CURD-122	yes	35.26
E-HCAD-10	yes	28.36
E-MTAB-8410	yes	27.19
E-CURD-112	yes	25.06
E-CURD-46	yes	21.96
E-GEOD-125970	yes	20.95
E-HCAD-1	yes	17.30
E-ANND-3	yes	7.79
E-MTAB-10042	yes	7.25
E-MTAB-5061	yes	5.93

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 3)

• Caspase-1-mediated cell death is regulated, at least in part, by the balance of Rip2 and Cop; alterations of this balance may contribute to aberrant caspase-1-mediated pathogenesis in Huntington’s disease. (PMID:16354923)
• Cop inhibition of cell death, at least to a certain extent, results from its interference with the activation of caspase-1 and caspase-4. (PMID:16920334)
• Expression of NOX4/p22(phox) as well as ROS production is enhanced by IL-1beta. On the other hand, the use of NOX4 inhibitors decreased IL-1beta-induced collagenase synthesis by chondrocytes. (PMID:26521743)

Cross-species orthologs

12 orthologs

Organism	Symbol	Gene ID
danio_rerio	casp8	ENSDARG00000058325
danio_rerio	casp3l	ENSDARG00000086266
danio_rerio	casp20	ENSDARG00000104367
danio_rerio		ENSDARG00000112575
mus_musculus	Casp1	ENSMUSG00000025888
rattus_norvegicus	Casp1	ENSRNOG00000007372
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), CASP12 (ENSG00000204403), CARD18 (ENSG00000255501)

Protein

Protein identifiers

Caspase recruitment domain-containing protein 16 — Q5EG05 (reviewed: Q5EG05)

Alternative names: Caspase recruitment domain-only protein 1, Caspase-1 inhibitor COP, Pseudo interleukin-1 beta converting enzyme

All UniProt accessions (2): A0A8I5KS59, Q5EG05

UniProt curated annotations — full annotation on UniProt →

Function. Caspase inhibitor. Acts as a regulator of procaspase-1/CASP1 activation implicated in the regulation of the proteolytic maturation of pro-interleukin-1 beta (IL1B) and its release during inflammation. Inhibits the release of IL1B in response to LPS in monocytes. Also induces NF-kappa-B activation during the pro-inflammatory cytokine response. Also able to inhibit CASP1-mediated neuronal cell death, TNF-, hypoxia-, UV-, and staurosporine-mediated cell death but not ER stress-mediated cell death. Acts by preventing activation of caspases CASP1 and CASP4, possibly by preventing the interaction between CASP1 and RIPK2.

Subunit / interactions. Homooligomer. Interacts with CASP1, CASP4, CARD8 and RIPK2.

Tissue specificity. Widely expressed. Expressed at higher level in placenta, spleen, lymph node and bone marrow. Weakly or not expressed in thymus.

Induction. Down-regulated in patients suffering of Huntington disease.

Isoforms (2)

UniProt ID	Names	Canonical?
Q5EG05-1	1	yes
Q5EG05-2	2

RefSeq proteins (2): NP_001381509, NP_443121* (*=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 (7 total): sequence variant 4, chain 1, domain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5EG05-F1	64.89	0.00

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 317 (showing top): GOBP_RESPONSE_TO_IONIZING_RADIATION, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, GOBP_REGULATION_OF_PROTEIN_BINDING, GOBP_NEGATIVE_REGULATION_OF_INTERLEUKIN_1_PRODUCTION, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_NEGATIVE_REGULATION_OF_LIPID_METABOLIC_PROCESS, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, chr11q22, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_LIPID_BIOSYNTHETIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_TUMOR_NECROSIS_FACTOR_MEDIATED_SIGNALING_PATHWAY

GO Biological Process (10): proteolysis (GO:0006508), negative regulation of tumor necrosis factor-mediated signaling pathway (GO:0010804), negative regulation of lipopolysaccharide-mediated signaling pathway (GO:0031665), negative regulation of protein binding (GO:0032091), negative regulation of interleukin-1 beta production (GO:0032691), regulation of apoptotic process (GO:0042981), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), obsolete positive regulation of NF-kappaB transcription factor activity (GO:0051092), cellular response to lipopolysaccharide (GO:0071222), regulation of interleukin-1 beta production (GO:0032651)

GO Molecular Function (9): cysteine-type endopeptidase activity (GO:0004197), cysteine-type endopeptidase inhibitor activity (GO:0004869), kinase binding (GO:0019900), identical protein binding (GO:0042802), 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 (2): protein-containing complex (GO:0032991), protease inhibitor complex (GO:0097179)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	3
interleukin-1 beta production	2
protein metabolic process	1
negative regulation of cytokine-mediated signaling pathway	1
regulation of tumor necrosis factor-mediated signaling pathway	1
tumor necrosis factor-mediated signaling pathway	1
negative regulation of response to biotic stimulus	1
negative regulation of signal transduction	1
lipopolysaccharide-mediated signaling pathway	1
regulation of lipopolysaccharide-mediated signaling pathway	1
negative regulation of response to external stimulus	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
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
response to lipopolysaccharide	1
cellular response to molecule of bacterial origin	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
regulation of interleukin-1 production	1
endopeptidase activity	1
cysteine-type peptidase activity	1
cysteine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
enzyme binding	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
peptidase inhibitor complex	1

Protein interactions and networks

STRING

960 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CARD16	CARD8	Q9Y2G2	776
CARD16	GPKOW	Q92917	728
CARD16	PYCARD	Q9ULZ3	667
CARD16	NDUFAF3	Q9BU61	667
CARD16	BHLHE40	O14503	664
CARD16	CASP5	P51878	626
CARD16	MEFV	O15553	606
CARD16	NLRP1	Q9C000	603
CARD16	IL1B	P01584	577
CARD16	NLRP3	Q96P20	553
CARD16	NLRP2	Q9NX02	546
CARD16	CASP1	P29466	525
CARD16	APAF1	O14727	506
CARD16	BCO2	Q9BYV7	455
CARD16	CASP9	P55211	439

IntAct

3 interactions, top by confidence:

A	B	Type	Score
CARD16	CASP1	psi-mi:“MI:0914”(association)	0.350
TRIB2	CARD16	psi-mi:“MI:0914”(association)	0.350

BioGRID (10): RIPK2 (Affinity Capture-Western), CARD16 (Affinity Capture-Western), CASP1 (Affinity Capture-Western), CARD16 (Affinity Capture-Western), CASP1 (Affinity Capture-MS), HERC4 (Affinity Capture-MS), FAT3 (Affinity Capture-MS), FAT4 (Affinity Capture-MS), CARD16 (Reconstituted Complex), CARD16 (Affinity Capture-Western)

ESM2 similar proteins: A4Q9F3, A6QPH9, O15444, P01344, P01346, P05017, P05019, P07455, P07456, P08025, P09535, P10763, P10764, P16501, P16545, P17085, P17647, P18254, P33712, P51457, P51458, P51459, P51462, Q02815, Q3U2E2, Q4R3D6, Q5EG05, Q5RDW3, Q5XI57, Q68LC0, Q6GUL6, Q6IVA5, Q6JLX1, Q80UW0, Q8C4U2, Q8K214, Q8N554, Q8N8I0, Q8R0A6, Q8TAG5

Diamond homologs: F1NV61, O08736, O75601, P29452, P29466, P42574, P43527, P49662, P51878, P55213, P55865, P55867, P70343, P70677, Q075B4, Q153Z0, Q2PFV2, Q504J1, Q5E9C1, Q5EG05, Q5IS54, Q5IS99, Q60431, Q6UXS9, Q8MJC3, Q8MJU1, Q920D5, Q95ND5, Q9I9L7, Q9MZV6, Q9MZV7, Q9N2I1, Q9TV13, A0A1D5PPP7, O89094, P42573, P45436, P57730, Q08DY9, Q5XLA6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	105
Likely benign	11
Benign	5

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
58921	GRCh38/hg38 11q22.3(chr11:104510196-105323725)x1	Pathogenic
625613	GRCh37/hg19 1q24.2-25.3(chr1:169423492-180367623)	Pathogenic

SpliceAI

1574 predictions. Top by Δscore:

Variant	Effect	Δscore
11:105044386:CCTTA:C	donor_loss	1.0000
11:105044387:CTTAC:C	donor_loss	1.0000
11:105044389:TACCT:T	donor_loss	1.0000
11:105044391:CCTG:C	donor_gain	0.9900
11:105092582:AACCT:A	acceptor_loss	0.9900
11:105092585:CTGAA:C	acceptor_loss	0.9900
11:105092586:T:G	acceptor_loss	0.9900
11:105095475:T:TA	donor_gain	0.9900
11:105095508:T:TA	donor_gain	0.9900
11:105092585:C:CC	acceptor_gain	0.9800
11:105095490:A:AC	donor_gain	0.9700
11:105095491:C:CC	donor_gain	0.9700
11:105041720:C:CC	acceptor_gain	0.9600
11:105095479:T:TA	donor_gain	0.9600
11:105095492:T:C	donor_gain	0.9600
11:105095471:AAAAT:A	donor_gain	0.9500
11:105095974:AGC:A	donor_gain	0.9500
11:105092580:TGAAC:T	acceptor_gain	0.9400
11:105095590:C:G	acceptor_gain	0.9400
11:105099621:A:AC	donor_gain	0.9400
11:105044654:CTTGT:C	acceptor_gain	0.9300
11:105095589:TCTG:T	acceptor_gain	0.9300
11:105044390:A:AC	donor_gain	0.9200
11:105044391:C:CC	donor_gain	0.9200
11:105095976:C:CA	donor_gain	0.9100
11:105100915:A:AC	donor_gain	0.9100
11:105100916:C:CC	donor_gain	0.9100
11:105041719:GCT:G	acceptor_loss	0.9000
11:105041719:GCTGC:G	acceptor_gain	0.9000
11:105041720:CTG:C	acceptor_loss	0.9000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000008375 (11:105045009 T>C), RS1001091529 (11:105047273 G>T), RS1001949638 (11:105046381 T>C), RS1002611213 (11:105043246 T>G), RS1002862596 (11:105046996 T>C), RS1003356567 (11:105047105 T>C), RS1004801945 (11:105044721 A>C), RS1005566284 (11:105042815 A>G), RS1005931637 (11:105045565 T>C), RS1006090071 (11:105046908 C>T), RS1006100747 (11:105041808 C>T), RS1006208186 (11:105046573 A>G), RS1006340158 (11:105041123 G>A,T), RS1006695929 (11:105043080 A>G), RS1006859225 (11:105046755 G>T)

Disease associations

OMIM: gene MIM:615680 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90000025_778	Appendicular lean mass	3.000000e-13

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004980	appendicular lean mass

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1503391	CARD16		0.00	0
rs1792774	CARD16		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, decreases expression	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Formaldehyde	increases expression	2
Valproic Acid	affects expression, decreases expression	2
Cyclosporine	decreases expression	2
Aflatoxin B1	increases methylation, affects expression	2
afuresertib	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
zinc chromate	increases abundance, increases expression	1
potassium chromate(VI)	decreases expression	1
triadimefon	decreases expression	1
chromium hexavalent ion	increases abundance, increases expression	1
2,2’,4,4’,5-brominated diphenyl ether	increases expression	1
Resveratrol	increases expression	1
Arsenic Trioxide	increases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Cannabidiol	decreases expression	1
Demecolcine	increases expression	1
Doxorubicin	increases expression	1
Estradiol	affects cotreatment, decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Methyl Methanesulfonate	increases expression	1
Nickel	increases expression	1
Ozone	increases abundance, affects expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	increases expression	1
Triclosan	increases expression	1

Clinical trials (associated diseases)

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