CARD14

Summary

CARD14 (caspase recruitment domain family member 14, HGNC:16446) is a protein-coding gene on chromosome 17q25.3, encoding Caspase recruitment domain-containing protein 14 (Q9BXL6). Acts as a scaffolding protein that can activate the inflammatory transcription factor NF-kappa-B and p38/JNK MAP kinase signaling pathways.

This gene encodes a caspase recruitment domain-containing protein that is a member of the membrane-associated guanylate kinase (MAGUK) family of proteins. Members of this protein family are scaffold proteins that are involved in a diverse array of cellular processes including cellular adhesion, signal transduction and cell polarity control. This protein has been shown to specifically interact with BCL10, a protein known to function as a positive regulator of cell apoptosis and NF-kappaB activation. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 79092 — RefSeq curated summary.

At a glance

• Gene–disease (curated): familial pityriasis rubra pilaris (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 1,198 total — 13 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 26
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001366385

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16446
Approved symbol	CARD14
Name	caspase recruitment domain family member 14
Location	17q25.3
Locus type	gene with protein product
Status	Approved
Aliases	CARMA2, BIMP2
Ensembl gene	ENSG00000141527
Ensembl biotype	protein_coding
OMIM	607211
Entrez	79092

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 9 nonsense_mediated_decay, 8 retained_intron, 7 protein_coding, 6 protein_coding_CDS_not_defined

ENST00000344227, ENST00000570421, ENST00000571427, ENST00000571450, ENST00000571861, ENST00000572838, ENST00000573489, ENST00000573754, ENST00000573882, ENST00000574148, ENST00000575465, ENST00000575500, ENST00000575666, ENST00000648128, ENST00000648509, ENST00000649277, ENST00000650806, ENST00000650867, ENST00000651068, ENST00000651388, ENST00000651672, ENST00000652599, ENST00000703566, ENST00000703567, ENST00000703568, ENST00000703569, ENST00000703570, ENST00000703571, ENST00000703572, ENST00000703573

RefSeq mRNA: 4 — MANE Select: NM_001366385 NM_001257970, NM_001366385, NM_024110, NM_052819

CCDS: CCDS11768, CCDS58605

Canonical transcript exons

ENST00000648509 — 24 exons

Exon	Start	End
ENSE00002205991	80183913	80184238
ENSE00002283320	80182653	80182790
ENSE00002632792	80179104	80179301
ENSE00002657052	80178508	80178655
ENSE00002661058	80172906	80173228
ENSE00003461225	80188377	80188544
ENSE00003468396	80198399	80198591
ENSE00003501287	80203822	80203885
ENSE00003547895	80205531	80205652
ENSE00003551103	80189753	80189872
ENSE00003588116	80201744	80201870
ENSE00003611360	80195558	80195652
ENSE00003622228	80192503	80192619
ENSE00003623556	80202180	80202420
ENSE00003638665	80195191	80195333
ENSE00003650930	80190774	80190899
ENSE00003672579	80198099	80198162
ENSE00003687536	80191323	80191472
ENSE00003692274	80206970	80207085
ENSE00003795698	80181419	80181649
ENSE00003833617	80170030	80170056
ENSE00003989361	80204227	80204341
ENSE00003989369	80205035	80205205
ENSE00003989387	80208138	80209331

Expression profiles

Bgee: expression breadth ubiquitous, 179 present calls, max score 89.19.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3267 / max 23.5313, expressed in 144 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
163223	0.1289	64
208437	0.0965	49
163222	0.0902	53
163220	0.0077	4
163219	0.0034	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	89.19	gold quality
skin of leg	UBERON:0001511	86.47	gold quality
skin of abdomen	UBERON:0001416	85.80	gold quality
esophagus mucosa	UBERON:0002469	85.60	gold quality
zone of skin	UBERON:0000014	83.73	gold quality
buccal mucosa cell	CL:0002336	83.39	silver quality
esophagus squamous epithelium	UBERON:0006920	79.71	gold quality
oral cavity	UBERON:0000167	79.12	gold quality
epithelium of esophagus	UBERON:0001976	78.24	gold quality
endothelial cell	CL:0000115	77.68	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.26	silver quality
vagina	UBERON:0000996	76.92	gold quality
upper arm skin	UBERON:0004263	76.64	silver quality
squamous epithelium	UBERON:0006914	74.93	gold quality
upper leg skin	UBERON:0004262	74.01	gold quality
pharyngeal mucosa	UBERON:0000355	73.56	gold quality
minor salivary gland	UBERON:0001830	73.40	gold quality
mouth mucosa	UBERON:0003729	73.11	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	73.03	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	72.44	gold quality
esophagus	UBERON:0001043	72.22	gold quality
spinal cord	UBERON:0002240	72.22	gold quality
tonsil	UBERON:0002372	72.16	gold quality
saliva-secreting gland	UBERON:0001044	71.98	gold quality
gingival epithelium	UBERON:0001949	71.32	gold quality
vena cava	UBERON:0004087	71.26	gold quality
right adrenal gland	UBERON:0001233	70.66	gold quality
gingiva	UBERON:0001828	70.52	gold quality
right adrenal gland cortex	UBERON:0035827	70.04	gold quality
left adrenal gland	UBERON:0001234	69.98	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-CURD-97	no	37.71
E-ANND-3	no	3.44

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

9 targeting CARD14, 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-5696	99.98	72.36	4487
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-4667-3P	99.26	65.45	1608
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-6884-3P	98.05	65.32	750

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Chromosome 17q25 harbors a susceptibility locus for psoriasis. Non-parametric linkage analysis revealed a linkage peak lying close to a novel cluster of genes from the immunoglobulin (Ig) superfamily. (PMID:12483297)
• Our results confirmed the published linkage with the PSORS1 locus, as well as the PSORS2 locus, which has not been previously shown in the Chinese population. (PMID:12709815)
• These results fail to support rs734232 as a psoriasis susceptibility factor in German psoriasis patients. (PMID:15654961)
• PSORS2 alleles are not susceptibility factors in arthritis psoriatic patients of Italian origin (PMID:16733365)
• Results demonstrate that multiple transcripts encoding several CARMA2 isoforms exist in vivo and regulate NF-kappaB activation and apoptosis. (PMID:21302310)
• Here, rare, highly penetrant mutations in CARD14 have been shown to cause psoriasis. (PMID:22521418)
• A range of NF-kB responses in the skin are mediated by CARD14 and that a subset of rare CARD14 variants leads to psoriasis and psoriatic arthritis. (PMID:22521419)
• we identified three different heterozygous mutations in CARD14 causing familial pityriasis rubra pilaris. (PMID:22703878)
• Results show genetic heterogeneity of psoriasis in the Tunisian population, provide confirmatory evidence for a novel psoriasis locus at chromosome 2p12 and reveal a psoriasis family with a mutation at PSORS2. (PMID:23013406)
• Pityriasis rubra pilaris autosomal dominant family is an allelic disease to certain genetic forms of familial psoriasis. (PMID:23328365)
• the association between SNP rs11652075 at the CARD14 gene and psoriasis (PMID:23905699)
• Owing to the relatively small number of cases analysed in this study, we cannot rule out the possibility that CARD14 mutations may be an exceptional cause of sporadic pityriasis rubra pilaris, as previously found in sporadic psoriasis (PMID:24359224)
• CARD14 c.526G>C (p.Asp176His) may have a role in generalized pustular psoriasis with psoriasis vulgaris in Japanese patients (PMID:24476623)
• no definite causative genetic mutation in CARD14 as identified in familial pityriasis rubra pilaris after screening 8 non-familial patients of type I, type III and type IV pityriasis rubra pilaris (PMID:24577624)
• Mutations and variants are causal or disease susceptibility factors of psoriasis vulgaris, generalized pustular psoriasis, or pityriasis rubra pilaris. [review] (PMID:24656634)
• Variant analysis of CARD14 in a Chinese Han population with psoriasis vulgaris and generalized pustular psoriasis shows that CARD14 may play a role in the pathogenesis of generalized pustular psoriasis. (PMID:24999592)
• Transfection of dermal ECs with psoriasis-associated CARD14 mutations resulted in increased expression of several chemokines, including CXCL10, IL-8, and CCL2. (PMID:25369198)
• The study identified the DEP domain-containing protein DEPDC7 as cellular binding partner of CARMA2 and CARMA3 proteins. (PMID:25541973)
• CARD14 mutation maybe responsible for activation of NF-kB signaling pathway in patients with pityriasis rubra pilaris. (PMID:25734815)
• CARD14 protein missense mutation found in patients diagnosed with psoriasis. (PMID:25989471)
• analysis of 105 individuals with generalized pustular psoriasis (GPP) identified a low-frequency variant (p.Asp176His) that causes constitutive CARD14 oligomerization (PMID:26203641)
• SNP c.C2458T may have significant effects on heritability of psoriasis vulgaris in our Chinese population. The CC genotype was more common in familial cases than in sporadic cases. (PMID:26249641)
• The authors observations provide further insights into the genetics of psoriasis and functional information on novel CARD14 mutational variants seen in cases from Tunisia and other populations. (PMID:26358359)
• Genetic interactions of SNPs in CARD14, SENP1 and VEGFA might represent a functional mechanism in the pathogenesis of high altitude polycythemia. (PMID:26852650)
• The results indicate that the common CARD14 p.Arg820Trp variant might have a significant effect on the response to anti-TNF therapies among patients with psoriasis. In addition, rare CARD14 missense variants could also predispose to a better response. (PMID:26854129)
• We found five rare mutations and four of them are annotated or reported. Only the variant (c.1291C>G) has not been reported and annotated, but the variant was also found in controls. None of the new definite variants were pathogenic (PMID:26982778)
• Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-kappaB activation (PMID:27071417)
• MALT1 deficiency or pharmacological inhibition of MALT1 catalytic activity inhibits pathogenic mutant CARD14-induced cytokine and chemokine expression in human primary keratinocytes. (PMID:27113748)
• genetic evidence suggests association of the CARD14 single nucleotide polymorphism rs11652075 and other rare mutations in this gene with psoriasis. To assess whether combined data support the relationship between CARD14 rs11652075 and susceptibility to this disease, we conducted a meta-analysis. Our results demonstrate a significant association between the CARD14 rs11652075 polymorphism and psoriasis. (PMID:27706581)
• Our findings, combined with the published literature, suggest that Pityriasis Rubra Pilaris Type V, both familial and sporadic, can be caused by CARD14 mutations. (PMID:27760266)
• CARD14/MALT1-mediated signaling in keratinocytes has a role in psoriasis [review] (PMID:27939769)
• The serine/threonine kinase ULK2 binds to and phosphorylates CARMA2sh. (PMID:28230860)
• The results illustrate that the positive response to treatment with ustekinumab in both the mother and son highlights the efficacy of this biological therapy in PRP, with the discovery of an underlying mutation in CARD14 being the driver towards pursuing this particular targeted anti-inflammatory therapy. (PMID:28301045)
• Results identified RNF7 to interact with CARMA2 regulating its NF-kappaB-activating capacity. Mechanistically, RNF7 influences CARMA2 signaling by regulating the ubiquitination state of MALT1 and the NF-kappaB-regulatory molecule NEMO. Interestingly, CARMA2short (CARMA2sh) mutants associated with psoriasis susceptibility escape the negative control exerted by RNF7. (PMID:29194363)
• CARD14 mutations are independently associated with psoriasis and familial PRP, providing a pathophysiologic link between these disorders. The subjects in this series provide striking clinical evidence for this connection and display findings characteristic of both PRP and psoriasis. (PMID:29477734)
• Although dominant gain-of-function mutations in CARD14 are associated with psoriasis and related diseases, loss-of-function mutations in the same gene are associated with a severe variant of Atopic dermatitis. (PMID:30248356)
• Review provides an overview on the molecular mechanisms mediating CARD14/CARMA2 signaling and its implication in understanding of the pathogenesis of human inflammatory skin disorders. (PMID:30319628)
• Study performed a comparative analysis of CARD14 variants between generalized pustular psoriasis (GPP) subtypes in a Chinese Han descent population. Results suggest that GPP with psoriasis vulgaris (PV) and GPP alone have a different CARD14 genetic background and CARD14 variants may play an essential role in the pathogenesis of PV-related disease. (PMID:30387497)
• data support the previous observation that CARD14 genetic variants are not specific to pityriasis rubra pilaris, although they may indicate chronic inflammation (PMID:30697821)
• Our data indicate that there is a significant association between CARD14 mutation and palmoplantar pustulosis. Three novel, rare heterozygous missense variants, c.149G > A (p.Cys50Tyr), c.1436C > G (p.Pro479Arg), and c.1942G > A (p.Gly648Ser), were found in CARD14 exons (RefSeqNM_024110.4). (PMID:30998217)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	card14	ENSDARG00000103485
mus_musculus	Card14	ENSMUSG00000013483
rattus_norvegicus	Card14	ENSRNOG00000047367

Paralogs (3): CARD10 (ENSG00000100065), CARD9 (ENSG00000187796), CARD11 (ENSG00000198286)

Protein

Protein identifiers

Caspase recruitment domain-containing protein 14 — Q9BXL6 (reviewed: Q9BXL6)

Alternative names: CARD-containing MAGUK protein 2

All UniProt accessions (10): A0A3B3ITQ9, A0A494BZY0, A0A494C0J4, A0A494C199, A0A494C1N2, A0A994J6G4, Q9BXL6, I3L1Z7, I3L3F1, I3L414

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a scaffolding protein that can activate the inflammatory transcription factor NF-kappa-B and p38/JNK MAP kinase signaling pathways. Forms a signaling complex with BCL10 and MALT1, and activates MALT1 proteolytic activity and inflammatory gene expression. MALT1 is indispensable for CARD14-induced activation of NF-kappa-B and p38/JNK MAP kinases. May play a role in signaling mediated by TRAF2, TRAF3 and TRAF6 and protects cells against apoptosis. Not able to activate the inflammatory transcription factor NF-kappa-B and may function as a dominant negative regulator.

Subunit / interactions. Interacts (via CARD domain) with BCL10 (via CARD domain). Forms a complex with MALT1 and BCL10; resulting in the formation of a CBM (CARD14-BLC10-MALT1) complex. Interacts with TRAF2, TRAF3 and TRAF6.

Subcellular location. Cytoplasm Cytoplasm Cytoplasm.

Tissue specificity. Isoform 1 is detected in placenta and epidermal keratinocytes. Isoform 2 is detected in leukocytes and fetal brain.

Disease relevance. Psoriasis 2 (PSORS2) [MIM:602723] A common, chronic inflammatory disease of the skin with multifactorial etiology. It is characterized by red, scaly plaques usually found on the scalp, elbows and knees. These lesions are caused by abnormal keratinocyte proliferation and infiltration of inflammatory cells into the dermis and epidermis. Disease susceptibility is associated with variants affecting the gene represented in this entry. Pityriasis rubra pilaris (PRP) [MIM:173200] A rare, papulosquamous skin disease characterized by the appearance of keratotic follicular papules, well-demarcated salmon-colored erythematous plaques covered with fine powdery scales interspersed with distinct islands of uninvolved skin, and palmoplantar keratoderma. Most cases are sporadic. The rare familial cases show autosomal dominant inheritance with incomplete penetrance and variable expression. Familial PRP usually presents at birth or appears during the first years of life and runs a chronic course. It is characterized by prominent follicular hyperkeratosis, diffuse palmoplantar keratoderma, and erythema. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. A linker region between the coiled-coil and PDZ region holds the protein in an inactive state.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9BXL6-1	1, CARD14fl, CARMA2fl	yes
Q9BXL6-2	2, Short, CARD14sh, CARMA2sh
Q9BXL6-3	3, Cardless, CARD14cardless, CARMA2cl

RefSeq proteins (4): NP_001244899, NP_001353314, NP_077015, NP_438170 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001315	CARD	Domain
IPR001478	PDZ	Domain
IPR008144	Guanylate_kin-like_dom	Domain
IPR011029	DEATH-like_dom_sf	Homologous_superfamily
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR036034	PDZ_sf	Homologous_superfamily

Pfam: PF00619

UniProt features (50 total): sequence variant 39, splice variant 4, domain 3, chain 1, region of interest 1, coiled-coil region 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BXL6-F1	75.89	0.38

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 (1): 544

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 134 (showing top): GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_ACTIVATION_OF_NF_KAPPAB_INDUCING_KINASE_ACTIVITY, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, GOBP_POSITIVE_REGULATION_OF_CATALYTIC_ACTIVITY, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_POSITIVE_REGULATION_OF_MOLECULAR_FUNCTION, GOBP_POSITIVE_REGULATION_OF_PHOSPHORUS_METABOLIC_PROCESS, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_5, GOBP_NON_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_TUMOR_NECROSIS_FACTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_POSITIVE_REGULATION_OF_DNA_BINDING_TRANSCRIPTION_FACTOR_ACTIVITY, GOBP_POSITIVE_REGULATION_OF_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION

GO Biological Process (10): positive regulation of protein phosphorylation (GO:0001934), apoptotic process (GO:0006915), activation of NF-kappaB-inducing kinase activity (GO:0007250), tumor necrosis factor-mediated signaling pathway (GO:0033209), negative regulation of apoptotic process (GO:0043066), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), regulation of immune response (GO:0050776), obsolete positive regulation of NF-kappaB transcription factor activity (GO:0051092), positive regulation of macromolecule metabolic process (GO:0010604), regulation of apoptotic process (GO:0042981)

GO Molecular Function (2): CARD domain binding (GO:0050700), protein binding (GO:0005515)

GO Cellular Component (4): cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), aggresome (GO:0016235)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
apoptotic process	2
cellular anatomical structure	2
regulation of protein phosphorylation	1
protein phosphorylation	1
positive regulation of protein modification process	1
positive regulation of phosphorylation	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
activation of protein kinase activity	1
non-canonical NF-kappaB signal transduction	1
cytokine-mediated signaling pathway	1
cellular response to tumor necrosis factor	1
regulation of apoptotic process	1
negative 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
regulation of immune system process	1
immune response	1
regulation of response to stimulus	1
positive regulation of metabolic process	1
macromolecule metabolic process	1
regulation of macromolecule metabolic process	1
regulation of programmed cell death	1
protein domain specific binding	1
binding	1
intracellular anatomical structure	1
cytoplasm	1
membrane	1
cell periphery	1
inclusion body	1

Protein interactions and networks

STRING

1848 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CARD14	BCL10	O95999	977
CARD14	MALT1	Q9UDY8	853
CARD14	NAT9	Q9BTE0	807
CARD14	AP1S3	Q96PC3	773
CARD14	IL36RN	Q9UBH0	771
CARD14	NOD2	Q9HC29	766
CARD14	TRAF6	Q9Y4K3	687
CARD14	HLA-C	P04222	665
CARD14	CDSN	Q15517	637
CARD14	DEPDC7	Q96QD5	631
CARD14	TNFAIP3	P21580	626
CARD14	IL1RL2	Q9HB29	621
CARD14	IL23R	Q5VWK5	620
CARD14	CARD9	Q9H257	602
CARD14	TRAF3IP2	O43734	595

IntAct

31 interactions, top by confidence:

A	B	Type	Score
CARD14		psi-mi:“MI:0915”(physical association)	0.560
CARD14	E6	psi-mi:“MI:0407”(direct interaction)	0.440
E6	CARD14	psi-mi:“MI:0407”(direct interaction)	0.440
ABCC4	CARD14	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGEF16	CARD14	psi-mi:“MI:0407”(direct interaction)	0.440
ASIC3	CARD14	psi-mi:“MI:0407”(direct interaction)	0.440
ATP2B4	CARD14	psi-mi:“MI:0407”(direct interaction)	0.440
CYSLTR2	CARD14	psi-mi:“MI:0407”(direct interaction)	0.440
DGKK	CARD14	psi-mi:“MI:0407”(direct interaction)	0.440
DGKZ	CARD14	psi-mi:“MI:0407”(direct interaction)	0.440
DOCK4	CARD14	psi-mi:“MI:0407”(direct interaction)	0.440
FRMPD4	CARD14	psi-mi:“MI:0407”(direct interaction)	0.440
FZD7	CARD14	psi-mi:“MI:0407”(direct interaction)	0.440
TAMALIN	CARD14	psi-mi:“MI:0407”(direct interaction)	0.440
ORF putative E6	CARD14	psi-mi:“MI:0407”(direct interaction)	0.440
KCNA5	CARD14	psi-mi:“MI:0407”(direct interaction)	0.440
KIR3DL3	CARD14	psi-mi:“MI:0407”(direct interaction)	0.440
MAP2K2	CARD14	psi-mi:“MI:0407”(direct interaction)	0.440
PBK	CARD14	psi-mi:“MI:0407”(direct interaction)	0.440
RALBP1	CARD14	psi-mi:“MI:0407”(direct interaction)	0.440
CARD14	RASSF6	psi-mi:“MI:0407”(direct interaction)	0.440
SLC15A5	CARD14	psi-mi:“MI:0407”(direct interaction)	0.440
SLCO1C1	CARD14	psi-mi:“MI:0407”(direct interaction)	0.440
TJP2	CARD14	psi-mi:“MI:0407”(direct interaction)	0.440
TRIP13	CARD14	psi-mi:“MI:0915”(physical association)	0.370
CARD14	UBA1	psi-mi:“MI:0220”(ubiquitination reaction)	0.000

BioGRID (23): CARD14 (Two-hybrid), CARD14 (Biochemical Activity), CARD14 (Two-hybrid), CARD14 (Affinity Capture-MS), CARD14 (Affinity Capture-MS), RNF7 (Two-hybrid), RNF7 (Affinity Capture-Western), CARD14 (Affinity Capture-Western), CARD14 (Affinity Capture-Western), CARD14 (Affinity Capture-Western), CARD14 (Affinity Capture-MS), CARD14 (Two-hybrid), ZNF648 (Two-hybrid), CARD14 (Affinity Capture-MS), UBAC1 (Affinity Capture-Western)

ESM2 similar proteins: A1IGU3, A1IGU4, A1IGU5, A6QP29, B1AVH7, B2RUP2, B5DFA1, D2H0G5, D3ZFJ3, O15068, O55043, P00530, P07332, P14238, P16879, P55194, P98171, Q0GNC1, Q14155, Q15052, Q27J81, Q3U5C8, Q3UMR0, Q58EX7, Q5VV41, Q5XXR3, Q5ZLR6, Q60I26, Q63406, Q64096, Q6PFY1, Q6PGG2, Q70J99, Q7TNH6, Q80TT2, Q80VK6, Q86WN1, Q8C2K1, Q8C6B2, Q8CJ00

Diamond homologs: A2AIV8, P58660, Q8CIS0, Q99KF0, Q9BWT7, Q9BXL6, Q9BXL7, Q9EPY0, Q9H257, A0A0G2K2P5, A2AFR3, A8E0R9, E2QYC9, O62683, O88952, O95049, O97758, P39447, Q07157, Q09506, Q0P5F3, Q12923, Q14CM0, Q32LE7, Q5EBL8, Q5F425, Q5RAA5, Q5ZIK2, Q64512, Q68DX3, Q6NXB2, Q6QA76, Q792I0, Q80VW5, Q810W9, Q95168, Q9CZG9, Q9NUP9, Q9P202, Q9QXY1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1198 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	13
Likely pathogenic	2
Uncertain significance	593
Likely benign	378
Benign	87

Top pathogenic / likely-pathogenic (15)

Variant ID	HGVS	Classification
280130	NM_001366385.1(CARD14):c.349+1G>A	Pathogenic
31606	NM_001366385.1(CARD14):c.349G>A (p.Gly117Ser)	Pathogenic
31607	NM_001366385.1(CARD14):c.349+5G>A	Pathogenic
31608	NM_001366385.1(CARD14):c.425A>G (p.Glu142Gly)	Pathogenic
31609	NM_001366385.1(CARD14):c.413A>C (p.Glu138Ala)	Pathogenic
31610	NM_001366385.1(CARD14):c.424G>A (p.Glu142Lys)	Pathogenic
3756582	NM_001366385.1(CARD14):c.349+2T>C	Pathogenic
5107	NM_000199.5(SGSH):c.734G>A (p.Arg245His)	Pathogenic
597197	NM_001366385.1(CARD14):c.412G>A (p.Glu138Lys)	Pathogenic
684673	NM_001366385.1(CARD14):c.380G>C (p.Cys127Ser)	Pathogenic
684675	NM_001366385.1(CARD14):c.356T>G (p.Met119Arg)	Pathogenic
684676	NM_001366385.1(CARD14):c.371T>C (p.Leu124Pro)	Pathogenic
684677	NM_001366385.1(CARD14):c.470A>C (p.Gln157Pro)	Pathogenic
35574	NM_001366385.1(CARD14):c.409GAG[1] (p.Glu138del)	Likely pathogenic
660052	NM_001366385.1(CARD14):c.356T>C (p.Met119Thr)	Likely pathogenic

SpliceAI

5837 predictions. Top by Δscore:

Variant	Effect	Δscore
17:80181604:G:GT	donor_gain	1.0000
17:80181645:GGCCG:G	donor_gain	1.0000
17:80181646:GCCG:G	donor_gain	1.0000
17:80181646:GCCGG:G	donor_gain	1.0000
17:80181648:CGGT:C	donor_loss	1.0000
17:80181649:GGTGA:G	donor_loss	1.0000
17:80181650:G:GG	donor_gain	1.0000
17:80181650:GTG:G	donor_loss	1.0000
17:80181651:T:A	donor_loss	1.0000
17:80182651:A:G	acceptor_gain	1.0000
17:80182779:G:GG	donor_gain	1.0000
17:80182788:GCG:G	donor_gain	1.0000
17:80183908:CACA:C	acceptor_loss	1.0000
17:80183911:A:AG	acceptor_gain	1.0000
17:80183912:G:GG	acceptor_gain	1.0000
17:80184233:G:GT	donor_gain	1.0000
17:80184236:G:GT	donor_gain	1.0000
17:80188540:GCCTG:G	donor_gain	1.0000
17:80188542:CTGG:C	donor_loss	1.0000
17:80188543:TGG:T	donor_loss	1.0000
17:80188544:GGT:G	donor_loss	1.0000
17:80188545:G:GG	donor_gain	1.0000
17:80188545:GT:G	donor_loss	1.0000
17:80188546:T:A	donor_loss	1.0000
17:80189748:CCCA:C	acceptor_loss	1.0000
17:80189749:CCA:C	acceptor_loss	1.0000
17:80189750:CA:C	acceptor_loss	1.0000
17:80189751:A:AG	acceptor_gain	1.0000
17:80189751:A:C	acceptor_loss	1.0000
17:80189752:G:A	acceptor_loss	1.0000

AlphaMissense

6573 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:80182712:A:C	S91R	0.998
17:80182714:C:A	S91R	0.998
17:80182714:C:G	S91R	0.998
17:80182716:T:C	L92P	0.997
17:80182749:T:A	V103D	0.996
17:80182691:G:T	G84W	0.995
17:80182704:T:C	F88S	0.995
17:80181566:T:C	L43P	0.994
17:80182671:T:C	L77P	0.994
17:80182739:T:G	Y100D	0.994
17:80198520:T:C	F594L	0.994
17:80198522:C:A	F594L	0.994
17:80198522:C:G	F594L	0.994
17:80182692:G:A	G84E	0.993
17:80182671:T:A	L77Q	0.992
17:80182701:C:A	A87D	0.992
17:80181496:T:A	W20R	0.991
17:80181496:T:C	W20R	0.991
17:80181498:G:C	W20C	0.991
17:80181498:G:T	W20C	0.991
17:80181566:T:A	L43Q	0.991
17:80182683:G:T	G81V	0.991
17:80182707:T:C	L89P	0.991
17:80183946:T:C	L128P	0.991
17:80181568:C:A	R44S	0.990
17:80181569:G:C	R44P	0.990
17:80181562:T:G	Y42D	0.989
17:80182671:T:G	L77R	0.989
17:80182716:T:G	L92R	0.989
17:80181574:G:C	A46P	0.988

dbSNP variants (sampled 300 via entrez): RS1000024542 (17:80197403 C>T), RS1000063683 (17:80200900 C>A,T), RS1000342217 (17:80172578 G>A), RS1000452359 (17:80191787 C>G,T), RS1000572563 (17:80176901 C>T), RS1000630020 (17:80175912 A>G), RS1000647163 (17:80171360 C>A,T), RS1000817930 (17:80193351 C>A,G,T), RS1000979063 (17:80178547 G>A,T), RS1000994722 (17:80182205 C>G,T), RS1001011531 (17:80178745 T>A), RS1001026706 (17:80177057 G>A), RS1001189160 (17:80197775 T>C), RS1001224853 (17:80192755 A>G), RS1001377123 (17:80197797 C>T)

Disease associations

OMIM: gene MIM:607211 | disease phenotypes: MIM:602723, MIM:173200, MIM:252900, MIM:607014

GenCC curated gene-disease

Disease	Classification	Inheritance
familial pityriasis rubra pilaris	Definitive	Autosomal dominant
psoriasis 2	Definitive	Autosomal dominant

Mondo (8): psoriasis 2 (MONDO:0011269), pityriasis rubra pilaris (MONDO:0100017), autoinflammatory syndrome (MONDO:0019751), familial pityriasis rubra pilaris (MONDO:0008251), mucopolysaccharidosis type 3A (MONDO:0009655), neurodegenerative disease (MONDO:0005559), mucopolysaccharidosis type 3 (MONDO:0018937), mucopolysaccharidosis (MONDO:0019249)

Orphanet (5): Pityriasis rubra pilaris (Orphanet:2897), Autoinflammatory syndrome (Orphanet:93665), Mucopolysaccharidosis type 3 (Orphanet:581), Sanfilippo syndrome type A (Orphanet:79269), Mucopolysaccharidosis (Orphanet:79213)

HPO phenotypes

26 total (26 of 26 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000163	Abnormal oral cavity morphology
HP:0000656	Ectropion
HP:0000962	Hyperkeratosis
HP:0000964	Eczematoid dermatitis
HP:0000982	Palmoplantar keratoderma
HP:0000989	Pruritus
HP:0001019	Erythroderma
HP:0001036	Parakeratosis
HP:0001072	Thickened skin
HP:0001597	Abnormal nail morphology
HP:0002664	Neoplasm
HP:0003593	Infantile onset
HP:0003765	Psoriasiform dermatitis
HP:0007400	Irregular hyperpigmentation
HP:0008064	Ichthyosis
HP:0008392	Subungual hyperkeratosis
HP:0025092	Epidermal acanthosis
HP:0025114	Hypergranulosis
HP:0025474	Erythematous plaque
HP:0032152	Keratosis pilaris
HP:0040162	Orthokeratosis
HP:0040189	Scaling skin
HP:0100725	Lichenification
HP:0200034	Papule
HP:0200039	Pustule

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST005527_34	Psoriasis	3.000000e-08
GCST005575_1	Moyamoya disease	1.000000e-17
GCST008016_2	Hirschsprung disease	8.000000e-06
GCST012047_11	Fasting glucose	9.000000e-07

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D009083	Mucopolysaccharidoses	C16.320.565.202.715; C16.320.565.595.600; C17.300.550.575; C18.452.648.202.715; C18.452.648.595.600
D019636	Neurodegenerative Diseases	C10.574
D010916	Pityriasis Rubra Pilaris	C17.800.859.600.685
C531784	Familial pityriasis rubra pilaris (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, affects methylation, decreases expression	3
Endosulfan	decreases expression	2
aristolochic acid I	increases expression	1
2-anisidine	decreases expression	1
manganese chloride	increases methylation	1
CGP 52608	affects binding, increases reaction	1
bisphenol S	decreases methylation	1
Rosiglitazone	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Estradiol	affects cotreatment, decreases expression	1
Menthol	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Silicon Dioxide	increases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases methylation	1
8-Bromo Cyclic Adenosine Monophosphate	increases expression	1
1-Methyl-4-phenylpyridinium	increases expression	1
Aflatoxin B1	increases expression	1
Okadaic Acid	increases expression	1
Lactic Acid	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00815633	PHASE4	TERMINATED	A Pilot Study of Alefacept for the Treatment of Pityriasis Rubra Pilaris
NCT04320498	PHASE4	COMPLETED	Short Term Results of Platelet-rich Plasma in the Treatment of Chronic Anal Fissure
NCT04586361	PHASE4	UNKNOWN	Prospective Analysis of Introperative RegenLab PRP and Hyaluronic Acid in Patients With Knee ACL Tear
NCT05827484	PHASE4	COMPLETED	The Effect of Combined Use of Anti-fibrotic Agent With Platelet Rich Plasma on Skeletal Muscle Healing After Acute Injuries
NCT07497620	PHASE4	NOT_YET_RECRUITING	Bimzelx (Bimekizumab) For The Treatment Of Adult Onset PRP
NCT01662414	PHASE4	COMPLETED	Effect of Undenatured Cysteine-Rich Whey Protein Isolate (HMS 90®) in Patients With Parkinson’s Disease
NCT04871464	PHASE4	UNKNOWN	Role and Mechanism of Probiotics in Improving Motor Symptoms in Mild to Moderate Parkinson’s Disease
NCT05357612	PHASE4	RECRUITING	Characterization of the Serotonin 2A Receptor Selective PET Tracer [18F]MH.MZ in Patients With Neurodegenerative Diseases
NCT05494593	PHASE4	WITHDRAWN	A Study of ELAPRASE in Treatment-naïve Participants With Hunter Syndrome (Mucopolysaccharidosis [MPS] II)
NCT05160441	PHASE3	COMPLETED	Comparing Platelet Rich Plasma and Corticosteroid for Military & Civilian Patients With Glenohumeral Osteoarthritis
NCT05412381	PHASE3	RECRUITING	PRP in ACLR to Prevent PTOA
NCT04360265	PHASE3	ENROLLING_BY_INVITATION	Follow-up Study of AAV-Mediated Gene Transfer (UX111; Previously Known as ABO-102) for MPS Type IIIA
NCT05508789	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Donanemab (LY3002813) in Participants With Early Symptomatic Alzheimer’s Disease (TRAILBLAZER-ALZ 5)
NCT05738486	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Different Donanemab (LY3002813) Dosing Regimens in Adults With Early Alzheimer’s Disease (TRAILBLAZER-ALZ 6)
NCT06111014	PHASE3	TERMINATED	Continuation Study for Latozinemab
NCT06672237	PHASE3	RECRUITING	A Phase 3 Study of NTLA-2001 in ATTRv-PN
NCT00654433	PHASE3	TERMINATED	ALD-101 Adjuvant Therapy of Unrelated Umbilical Cord Blood Transfusion (UCBT) in Patients With Inherited Metabolic Diseases
NCT02230566	PHASE3	COMPLETED	A Phase 3 Study of UX003 Recombinant Human Betaglucuronidase (rhGUS) Enzyme Replacement Therapy in Patients With Mucopolysaccharidosis Type 7 (MPS 7)
NCT02432144	PHASE3	COMPLETED	A Study of UX003 Recombinant Human Beta-Glucuronidase (rhGUS) Enzyme Replacement Therapy in Subjects With Mucopolysaccharidosis Type 7, Sly Syndrome (MPS 7)
NCT03485976	PHASE2	COMPLETED	Ixekizumab in the Treatment of Pityriasis Rubra Pilaris (PRP)
NCT03975153	PHASE2	COMPLETED	Guselkumab in the Treatment of Pityriasis Rubra Pilaris (PRP)
NCT06444399	PHASE2	RECRUITING	Deucravacitinib (BMS-986165) for Pityriasis Rubra Pilaris
NCT07470359	PHASE2	RECRUITING	Comparison of Functional Outcomes Following Arthroscopic ACL Reconstruction With Peroneus Longus Autograft With and Without Intra-articular Platelet-Rich Plasma Injection.
NCT00442182	PHASE2	UNKNOWN	The Efficacy and Safety of ITF2357 in AIS
NCT00001365	PHASE2	COMPLETED	Dextromethorphan for the Treatment of Parkinson’s Disease and Similar Conditions of the Nervous System
NCT00406029	PHASE2	COMPLETED	Dyskinesia in Parkinson’s Disease (Study P04501)
NCT00537017	PHASE2	COMPLETED	Follow Up Safety Study of SCH 420814 in Subjects With Parkinson’s Disease (P05175)
NCT00907283	PHASE2	UNKNOWN	Ferrochelating Treatment in Patients Affected by Neurodegeneration With Brain Iron Accumulation (NBIA)
NCT01518374	PHASE2	COMPLETED	Clinical Evaluation of Florbetapir F 18 (18F-AV-45)
NCT02656498	PHASE2	COMPLETED	[18F]THK-5351 Positron Emission Computed Tomography Study of Normal, Mild Cognitive Impairment, Alzheimer’s Disease and Other Neurodegenerative Disease
NCT03127514	PHASE2	COMPLETED	AMX0035 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT03538522	PHASE2	COMPLETED	A Double-Blind, Placebo-Controlled Safety and Efficacy Study of NA-831
NCT04838301	PHASE2	RECRUITING	Allopregnanolone Regenerative Therapeutic for Mild Alzheimer’s Disease
NCT04937452	PHASE2	COMPLETED	Dopaminergic Therapy for Frontotemporal Dementia Patients
NCT05318976	PHASE2	COMPLETED	A Study of XPro1595 in Patients With Early Alzheimer’s Disease With Biomarkers of Inflammation
NCT05321498	PHASE2	WITHDRAWN	Study to Assess the Efficacy of XPro1595 in Patients With Mild Cognitive Impairment With Biomarkers of Inflammation
NCT05479981	PHASE2	COMPLETED	Extension of AOC 1001-CS1 (MARINA) Study in Adult Myotonic Dystrophy Type 1 (DM1) Patients
NCT05522387	PHASE2	TERMINATED	An Open-Label Extension of XPro1595 in Patients With Alzheimer’s Disease
NCT00383448	PHASE2	COMPLETED	HSCT for High Risk Inherited Inborn Errors
NCT02060526	PHASE2	COMPLETED	Randomized, Controlled, Open-label, Multicenter, Safety and Efficacy Study of rhHNS Administration Via an IDDD in Pediatric Patients With Early Stage MPS IIIA Disease