CFLAR

Summary

CFLAR (CASP8 and FADD like apoptosis regulator, HGNC:1876) is a protein-coding gene on chromosome 2q33.1, encoding CASP8 and FADD-like apoptosis regulator (O15519). Apoptosis regulator protein which may function as a crucial link between cell survival and cell death pathways in mammalian cells. In precision oncology, CFLAR EXPRESSION is associated with resistance to Bicalutamide in Prostate Cancer (CIViC Level D). It is a selective cancer dependency (DepMap: 54.1% of cell lines).

The protein encoded by this gene is a regulator of apoptosis and is structurally similar to caspase-8. However, the encoded protein lacks caspase activity and appears to be itself cleaved into two peptides by caspase-8. Several transcript variants encoding different isoforms have been found for this gene, and partial evidence for several more variants exists.

Source: NCBI Gene 8837 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 50 total
• Druggable target: yes
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• Cancer dependency (DepMap): dependent in 54.1% of screened cell lines
• MANE Select transcript: NM_003879

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1876
Approved symbol	CFLAR
Name	CASP8 and FADD like apoptosis regulator
Location	2q33.1
Locus type	gene with protein product
Status	Approved
Aliases	CASH, Casper, CLARP, FLAME, FLIP, I-FLICE, MRIT, c-FLIP, cFLIP
Ensembl gene	ENSG00000003402
Ensembl biotype	protein_coding
OMIM	603599
Entrez	8837

Gene structure

Transcript identifiers

Ensembl transcripts: 44 — 37 protein_coding, 5 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000309955, ENST00000341222, ENST00000341582, ENST00000342795, ENST00000395148, ENST00000417748, ENST00000423241, ENST00000425030, ENST00000433445, ENST00000439154, ENST00000440180, ENST00000441224, ENST00000443227, ENST00000457277, ENST00000460961, ENST00000461422, ENST00000461820, ENST00000462763, ENST00000470178, ENST00000470664, ENST00000474842, ENST00000479953, ENST00000490965, ENST00000494258, ENST00000890673, ENST00000890674, ENST00000890675, ENST00000890676, ENST00000890677, ENST00000890678, ENST00000890679, ENST00000890680, ENST00000890681, ENST00000948373, ENST00000948374, ENST00000948375, ENST00000948376, ENST00000948377, ENST00000948378, ENST00000948379, ENST00000948380, ENST00000948381, ENST00000948382, ENST00000948383

RefSeq mRNA: 15 — MANE Select: NM_003879 NM_001127183, NM_001127184, NM_001202515, NM_001202516, NM_001202517, NM_001202518, NM_001202519, NM_001308042, NM_001308043, NM_001351590, NM_001351591, NM_001351592, NM_001351593, NM_001351594, NM_003879

CCDS: CCDS2337, CCDS46487, CCDS56157, CCDS56158, CCDS59436, CCDS77503, CCDS77505

Canonical transcript exons

ENST00000309955 — 10 exons

Exon	Start	End
ENSE00001717236	201116164	201116481
ENSE00001931152	201163835	201176687
ENSE00002684918	201129729	201130146
ENSE00003055759	201140357	201140439
ENSE00003513466	201160432	201160942
ENSE00003640229	201145378	201145432
ENSE00003651940	201149003	201149052
ENSE00003682105	201135972	201136107
ENSE00003784075	201149754	201149835
ENSE00003790546	201133029	201133134

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 98.88.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 64.7905 / max 1661.4915, expressed in 1819 samples.

FANTOM5 promoters (39 alternative TSS)

Promoter ID	TPM avg	Samples expressed
24604	21.1076	1754
24616	7.2920	1104
24607	5.6791	1549
24640	5.5239	496
24617	5.0769	1033
24620	2.4031	774
24636	1.9899	504
24633	1.6404	600
24605	1.2365	463
24608	1.2169	711

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lung	UBERON:0002167	98.88	gold quality
apex of heart	UBERON:0002098	98.87	gold quality
upper lobe of left lung	UBERON:0008952	98.69	gold quality
upper lobe of lung	UBERON:0008948	98.62	gold quality
right atrium auricular region	UBERON:0006631	98.60	gold quality
heart left ventricle	UBERON:0002084	98.48	gold quality
colonic epithelium	UBERON:0000397	98.46	gold quality
cardiac ventricle	UBERON:0002082	98.46	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.30	gold quality
cardiac atrium	UBERON:0002081	98.29	gold quality
lower esophagus	UBERON:0013473	98.29	gold quality
blood	UBERON:0000178	98.27	gold quality
heart	UBERON:0000948	98.13	gold quality
granulocyte	CL:0000094	98.07	gold quality
gastrocnemius	UBERON:0001388	98.01	gold quality
bone marrow cell	CL:0002092	97.95	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.90	gold quality
monocyte	CL:0000576	97.89	gold quality
renal medulla	UBERON:0000362	97.89	gold quality
spleen	UBERON:0002106	97.89	gold quality
lymph node	UBERON:0000029	97.88	gold quality
omental fat pad	UBERON:0010414	97.86	gold quality
peritoneum	UBERON:0002358	97.85	gold quality
pylorus	UBERON:0001166	97.70	gold quality
mucosa of stomach	UBERON:0001199	97.69	gold quality
muscle of leg	UBERON:0001383	97.68	gold quality
tonsil	UBERON:0002372	97.56	gold quality
nipple	UBERON:0002030	97.54	gold quality
leukocyte	CL:0000738	97.52	gold quality
adipose tissue of abdominal region	UBERON:0007808	97.52	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-GEOD-75367	yes	918.35
E-GEOD-81547	yes	916.10
E-MTAB-8142	yes	73.67
E-MTAB-9221	yes	18.07
E-CURD-46	yes	16.35
E-CURD-88	yes	15.05
E-GEOD-130148	yes	5.47
E-GEOD-110499	no	3140.94
E-MTAB-7606	no	1772.75
E-MTAB-7381	no	1423.71
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, ATM, CAPN3, CEBPA, DEDD, ESR1, FOS, FOXC1, FOXO1, FOXO3, GLI1, GLI2, HDAC9, IRF8, JUN, MYC, NFATC2, NFKB1, NFKB, NFKBID, PPARG, RELA, RELB, RUNX3, SIRT1, SP1, SP3, STAT3, TCF3

miRNA regulators (miRDB)

279 targeting CFLAR, 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-3163	100.00	77.23	8605
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-433-3P	99.98	69.37	1203

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 54.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• The human herpes virus 8-encoded viral FLICE inhibitory protein physically associates with and persistently activates the Ikappa B kinase complex. (PMID:11830587)
• Higher levels of expression of FLIP were present in TRAIL-resistant multiple myeloma cells, and sensitivity to TRAIL was restored by lowered FLIP protein levels. (PMID:11877293)
• An inducible pathway for degradation of FLIP protein sensitizes tumor cells to TRAIL-induced apoptosis (PMID:11940602)
• cFLIP may have an impact on the outcome of death receptor-triggered responses by directing the intracellular signals from beta-cell death to beta-cell survival (PMID:12031968)
• switches Fas-mediated glucose signaling in human pancreatic beta cells from apoptosis to cell replication switches Fas-mediated glucose signaling in human pancreatic beta cells from apoptosis to cell (PMID:12060768)
• FLICE-inhibitory protein expression in synovial fibroblasts and at sites of cartilage and bone erosion in rheumatoid arthritis. (PMID:12115181)
• results demonstrate a definite role for FLIP in the stem cell factor-induced protection of erythroid colony forming cells from IFNgamma-initiated apoptosis (PMID:12393527)
• These results provide new insights into the mechanisms of bile acid cytotoxicity and the proapoptotic effects of cFLIP phosphorylation in TRAIL signaling. (PMID:12407100)
• c-FLIP may play a critical role in regulating Fas-mediated apoptosis in prostate cancer cells (PMID:12432255)
• The consequences of FasL overexpression depend on the subcellular compartment and species in which FasL enforced expression is targeted and this is at least partially related to FLIP levels (PMID:12477972)
• c-FLIP expression is regulated by calcium/calmodulin-dependent protein kinase II and modulates Fas-mediated signaling in glioma cells (PMID:12496285)
• In response to doxorubicin, the level of FLIP decreased in all prostatic cell lines tested and correlated with the onset and magnitude of CASP8 and PARP cleavage in PC3 cells. (PMID:12496481)
• The metabolism of FLIP is essential to the death of prostatic cells in culture. (PMID:12496482)
• Adenovirus E1A inhibited TNF-alpha-dependent induction of c-FLIP(S) mRNA and stimulated ubiquitination- and proteasome-dependent degradation of c-FLIP(S) protein in Hela cells (PMID:12552004)
• Our results show that c-FLIP(L) and c-FLIP(S) potently control TRAIL responses, both by distinct regulatory features, and further imply that the differentiation state of malignant cells determines their sensitivity to death receptor signals. (PMID:12556488)
• Constitutive expression of the long form of human FLIP leads to an enhanced and prolonged inflammatory response in the central nervous system during experimental allergic encephalitis in DBA mice. (PMID:12574377)
• Constitutively active Akt1 protects HL60 leukemia cells from TRAIL-induced apoptosis through a mechanism involving NF-kappaB activation and up-regulation of this protein (PMID:12592338)
• Expression is increased in stomach cancer (PMID:12716387)
• cFLIP-L exerts its anti-apoptotic activity, in part, by inhibiting p38 MAPK activation, an additional anti-apoptotic effect for this protein. (PMID:12746452)
• cFLIP is an important determinant of susceptibility to death receptor-induced apoptosis in bladder carcinomas. (PMID:12820373)
• FLIP(L) and FLIP(S) are differentially regulated, and that the relative levels of both isoforms play a role in the regulation of apoptosis in myelodysplastic syndrome (PMID:14562111)
• In T cells, c-FLIP expression led to inhibition of IL-2 production, in contrast to the readily detectable c-FLIP-induced activation in Jurkat cells. (PMID:14578361)
• In this study, we show that c-FLIP(L) but not c-FLIP(S) physically binds to Daxx through interaction between C-terminal domain of c-FLIP(L) and Fas-binding domain of Daxx, an alternative Fas signaling adaptor. (PMID:14637155)
• Akt activity promotes human gastric cancer cell survival against TRAIL-induced apoptosis via upregulation of FLIP(S), and that the cytotoxic effect of TRAIL can be enhanced by modulating the Akt/FLIP(S) pathway in human gastric cancers. (PMID:14662022)
• Results demonstrate that FLIP(p43) processed by caspase 8 specifically interacts with TRAF2 and subsequently induces activation of the NF-kappaB signaling pathway. (PMID:15024054)
• the selective down-regulation of c-FLIP by small interfering RNA oligoribonucleotides was sufficient to sensitize Hodgkin/Reed-Sternberg cells to CD95 and tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis (PMID:15078899)
• down-regulation of cellular FLICE-inhibitory protein through the use of specific small inhibitory RNAs leads to reduced viability of the L428 and L591 HL-derived cell lines (PMID:15096587)
• The frequent expression and coexpression of Fas, FasL, and c-FLIP in urothelial carcinomas implicates c-FLIP as an inhibitor of the Fas-FasL-induced death pathway in these tumors. (PMID:15183989)
• FLIP plays a significant role in the regulation of apoptosis in human ovarian cancer cells and their sensitivity to cisplatin. (PMID:15258564)
• Regulation by AMP-activated protein kinase-related kinase 5 (PMID:15273717)
• the inhibitory protein c-FLIP(L) is involved in resistance to CD95-mediated apoptosis in ovarian carcinoma cells with wild-type p53 (PMID:15297424)
• When fusesd with Tat protein, prevesnts adverse apoptosis nd prolongs survival in tumor cells. (PMID:15304499)
• Malignant mesothelioma cells develop an intrinsic resistance to apoptosis induced by death receptors upregulating the expression of the antiapoptotic protein c-FLIP. (PMID:15334061)
• strong c-FLIP expression in nodular lymphocyte-predominant Hodgkin lymphoma was associated with transformation to diffuse large B-cell lymphoma; the majority of DLBCL cases tested were strongly c-FLIP-positive. (PMID:15354734)
• cFLIP(L) is not only a central antiapoptotic modulator of TRAIL-mediated apoptosis but also an inhibitor of TRAIL-induced NF-kappaB activation and subsequent proinflammatory target gene expression (PMID:15459191)
• c-FLIPL is recruited to death receptor 5 independent of Fas-associated protein with death domain (FADD) (PMID:15485835)
• Results indicate that some tumor cells are resistant to death receptor-mediated apoptosis by expressing cellular FLIP, and that histone deacetylase inhibitors sensitize such resistant tumor cells by directly downregulating cellular FLIP mRNA. (PMID:15540114)
• Constitutive overexpression of c-FLIP (long form) in T cells is sufficient to drive Th2 polarization of effector T cell responses and indicates that it might function as a key regulator of T helper (Th) cell differentiation. (PMID:15557152)
• DDB2 regulates TNF signaling-mediated apoptosis via cFLIP and contributes to acquired cross-resistance. (PMID:15644494)
• T cell blasts surviving activation-induced cell deathare memory CD44high cells with increased c-FLIP expression. (PMID:15653751)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	cflara	ENSDARG00000055966
danio_rerio	cflarb	ENSDARG00000074802
mus_musculus	Cflar	ENSMUSG00000026031
rattus_norvegicus	Cflar	ENSRNOG00000012473
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), 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), CARD18 (ENSG00000255501)

Protein

Protein identifiers

CASP8 and FADD-like apoptosis regulator — O15519 (reviewed: O15519)

Alternative names: Caspase homolog, Caspase-eight-related protein, Caspase-like apoptosis regulatory protein, Cellular FLICE-like inhibitory protein, FADD-like antiapoptotic molecule 1, Inhibitor of FLICE, MACH-related inducer of toxicity, Usurpin

All UniProt accessions (12): O15519, A0A024R3Y4, A0A336TY74, C9J408, C9J4Q0, C9JSU3, C9JV51, E9PAP3, F8WBH9, M0QY57, M0QYM0, M0R1A8

UniProt curated annotations — full annotation on UniProt →

Function. Apoptosis regulator protein which may function as a crucial link between cell survival and cell death pathways in mammalian cells. Acts as an inhibitor of TNFRSF6 mediated apoptosis. A proteolytic fragment (p43) is likely retained in the death-inducing signaling complex (DISC) thereby blocking further recruitment and processing of caspase-8 at the complex. Full length and shorter isoforms have been shown either to induce apoptosis or to reduce TNFRSF-triggered apoptosis. Lacks enzymatic (caspase) activity.

Subunit / interactions. TNFRSF6 stimulation triggers recruitment to the death-inducing signaling complex (DISC) formed by TNFRSF6, FADD and CASP8. A proteolytic fragment (p43) stays associated with the DISC. Also interacts with FADD, CASP8, CASP3, TRAF1, TRAF2 and Bcl-X(L) (in vitro). Interacts with RIPK1. Interacts with GMEB1. (Microbial infection) Interacts with HBV protein X.

Tissue specificity. Widely expressed. Higher expression in skeletal muscle, pancreas, heart, kidney, placenta, and peripheral blood leukocytes. Also detected in diverse cell lines. Isoform 8 is predominantly expressed in testis and skeletal muscle.

Post-translational modifications. Proteolytically processed by CASP8 generating subunit p43 and p12. Deubiquitinated by USP40, leading to stabilization.

Domain organisation. The caspase domain lacks the active site residues involved in catalysis.

Induction. Repressed by IL2/interleukin-2 after TCR stimulation, during progression to the S phase of the cell cycle.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the peptidase C14A family.

Isoforms (15)

UniProt ID	Names	Canonical?
O15519-1	1, FLIP-L, CLARP1, MRIT alpha-1, CASH alpha, I-FLICE 1, FLAME-1 gamma, Usurpin alpha	yes
O15519-2	2, FLIP-S, CLARP2, MRIT beta-1, CASH beta
O15519-3	3, MRIT alpha-2
O15519-4	4, I-FLICE 2
O15519-5	5, I-FLICE 3
O15519-6	6, I-FLICE 4
O15519-7	7, I-FLICE 5
O15519-8	8, FLAME-1 alpha
O15519-9	9, FLAME-1 beta
O15519-10	10, FLAME-1 delta
O15519-11	11, Usurpin beta
O15519-12	12, Usurpin gamma
O15519-13	13
O15519-14	14
O15519-15	15

RefSeq proteins (14): NP_001120655, NP_001120656, NP_001189445, NP_001189446, NP_001189447, NP_001189448, NP_001294971, NP_001294972, NP_001338519, NP_001338520, NP_001338521, NP_001338522, NP_001338523, NP_003870* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001309	Pept_C14_p20	Domain
IPR001875	DED_dom	Domain
IPR011029	DEATH-like_dom_sf	Homologous_superfamily
IPR011600	Pept_C14_caspase	Domain
IPR015917	Pept_C14A	Domain
IPR029030	Caspase-like_dom_sf	Homologous_superfamily

Pfam: PF00656, PF01335

UniProt features (73 total): helix 21, splice variant 18, region of interest 9, sequence conflict 7, strand 7, chain 2, site 2, domain 2, mutagenesis site 2, turn 2, sequence variant 1

Structure

Experimental structures (PDB)

17 structures.

PDB	Method	Resolution (Å)
3H11	X-RAY DIFFRACTION	1.9
8YM5	X-RAY DIFFRACTION	2.09
3H13	X-RAY DIFFRACTION	2.2
8YM4	X-RAY DIFFRACTION	2.34
8YD8	X-RAY DIFFRACTION	3.11
8YM6	X-RAY DIFFRACTION	3.3
8YD7	X-RAY DIFFRACTION	3.32
8YNM	ELECTRON MICROSCOPY	3.49
8YNL	ELECTRON MICROSCOPY	3.55
8YNK	ELECTRON MICROSCOPY	3.62
8YNI	ELECTRON MICROSCOPY	3.66
8YBX	ELECTRON MICROSCOPY	3.68
8YNN	ELECTRON MICROSCOPY	3.97
2N5R	SOLUTION NMR
6M6O	SOLUTION NMR
7DEE	SOLUTION NMR
7LXC	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15519-F1	78.84	0.50

Functional residue map

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

Catalytic / active sites (2): 369–370 (cleavage; by casp8); 376–377 (cleavage; by casp8)

Mutagenesis-validated functional residues (2):

Position	Phenotype
360	decreases apoptosis-inducing activity. reduces interaction with caspase-3 and proteolytic processing.
376	abolishes proteolytic processing.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-75158	TRAIL signaling
R-HSA-3371378	Regulation by c-FLIP
R-HSA-5213460	RIPK1-mediated regulated necrosis
R-HSA-5218900	CASP8 activity is inhibited
R-HSA-5357905	Regulation of TNFR1 signaling
R-HSA-69416	Dimerization of procaspase-8

MSigDB gene sets: 619 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GSE45365_NK_CELL_VS_CD8_TCELL_UP, GOBP_REGULATION_OF_HEPATOCYTE_PROLIFERATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, MULLIGHAN_NPM1_SIGNATURE_3_UP, BROWNE_HCMV_INFECTION_6HR_DN, GOBP_REGULATION_OF_EPITHELIAL_CELL_APOPTOTIC_PROCESS, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_SKELETAL_MUSCLE_TISSUE_REGENERATION, GOBP_GLAND_MORPHOGENESIS, GOBP_RESPONSE_TO_ESTRADIOL, LU_IL4_SIGNALING

GO Biological Process (35): proteolysis (GO:0006508), apoptotic process (GO:0006915), skeletal muscle tissue development (GO:0007519), extrinsic apoptotic signaling pathway via death domain receptors (GO:0008625), negative regulation of cardiac muscle cell apoptotic process (GO:0010667), positive regulation of neuron projection development (GO:0010976), skeletal muscle atrophy (GO:0014732), regulation of skeletal muscle satellite cell proliferation (GO:0014842), skeletal myofibril assembly (GO:0014866), macrophage differentiation (GO:0030225), cellular response to insulin stimulus (GO:0032869), response to testosterone (GO:0033574), negative regulation of apoptotic process (GO:0043066), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), skeletal muscle tissue regeneration (GO:0043403), positive regulation of neuron apoptotic process (GO:0043525), regulation of necroptotic process (GO:0060544), positive regulation of ERK1 and ERK2 cascade (GO:0070374), cellular response to epidermal growth factor stimulus (GO:0071364), cellular response to estradiol stimulus (GO:0071392), cellular response to hypoxia (GO:0071456), cellular response to dexamethasone stimulus (GO:0071549), cellular response to nitric oxide (GO:0071732), positive regulation of glomerular mesangial cell proliferation (GO:0072126), negative regulation of myoblast fusion (GO:1901740), negative regulation of extrinsic apoptotic signaling pathway via death domain receptors (GO:1902042), positive regulation of extracellular matrix organization (GO:1903055), negative regulation of reactive oxygen species biosynthetic process (GO:1903427), negative regulation of cellular response to transforming growth factor beta stimulus (GO:1903845), negative regulation of hepatocyte apoptotic process (GO:1903944), positive regulation of hepatocyte proliferation (GO:2000347), negative regulation of extrinsic apoptotic signaling pathway (GO:2001237), response to hypoxia (GO:0001666), regulation of apoptotic process (GO:0042981), negative regulation of epithelial cell apoptotic process (GO:1904036)

GO Molecular Function (7): protease binding (GO:0002020), cysteine-type endopeptidase activity (GO:0004197), death receptor binding (GO:0005123), enzyme activator activity (GO:0008047), protein-containing complex binding (GO:0044877), protein binding (GO:0005515), cysteine-type peptidase activity (GO:0008234)

GO Cellular Component (5): cytoplasm (GO:0005737), cytosol (GO:0005829), death-inducing signaling complex (GO:0031264), CD95 death-inducing signaling complex (GO:0031265), ripoptosome (GO:0097342)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Caspase activation via Death Receptors in the presence of ligand	2
Death Receptor Signaling	1
Regulated Necrosis	1
Regulation of necroptotic cell death	1
TNF signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
cellular anatomical structure	2
protein metabolic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
striated muscle tissue development	1
skeletal muscle organ development	1
extrinsic apoptotic signaling pathway	1
cardiac muscle cell apoptotic process	1
negative regulation of striated muscle cell apoptotic process	1
regulation of cardiac muscle cell apoptotic process	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
striated muscle atrophy	1
skeletal muscle adaptation	1
skeletal muscle satellite cell proliferation	1
regulation of skeletal muscle cell proliferation	1
myofibril assembly	1
myeloid leukocyte differentiation	1
mononuclear cell differentiation	1
response to insulin	1
cellular response to peptide hormone stimulus	1
response to lipid	1
response to ketone	1
apoptotic process	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
tissue regeneration	1
positive regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
regulation of programmed necrotic cell death	1
necroptotic process	1
positive regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1

Protein interactions and networks

STRING

2404 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CFLAR	FADD	Q13158	999
CFLAR	RIPK1	Q13546	995
CFLAR	CASP8	Q14790	992
CFLAR	TRADD	Q15628	992
CFLAR	RIPK3	Q9Y572	987
CFLAR	ATG3	Q9NT62	942
CFLAR	BIRC2	Q13490	938
CFLAR	CASP1	P29466	936
CFLAR	TNFRSF10B	O14763	922
CFLAR	TNFRSF10A	O00220	913
CFLAR	FASLG	P48023	903
CFLAR	TRAF1	Q13077	902
CFLAR	CASP10	Q92851	900
CFLAR	XIAP	P98170	896
CFLAR	FAS	P25445	867

IntAct

63 interactions, top by confidence:

A	B	Type	Score
TNFSF10	TNFRSF10B	psi-mi:“MI:0914”(association)	0.950
CASP8	TNFRSF10A	psi-mi:“MI:0914”(association)	0.820
CASP8	CFLAR	psi-mi:“MI:0914”(association)	0.740
CFLAR	CASP8	psi-mi:“MI:0915”(physical association)	0.740
CFLAR	TRAF1	psi-mi:“MI:0915”(physical association)	0.720
CASP10	CFLAR	psi-mi:“MI:0914”(association)	0.650
CASP10	CFLAR	psi-mi:“MI:2364”(proximity)	0.650
CFLAR	CASP10	psi-mi:“MI:0915”(physical association)	0.650
CFLAR	PLIN5	psi-mi:“MI:0914”(association)	0.530
TNFRSF10A	TNFRSF10B	psi-mi:“MI:0914”(association)	0.530
PML-RAR	CFLAR	psi-mi:“MI:0915”(physical association)	0.400
HSP90AB1	CFLAR	psi-mi:“MI:0915”(physical association)	0.400
CFLAR		psi-mi:“MI:0915”(physical association)	0.400
CFLAR	NUDCD3	psi-mi:“MI:0915”(physical association)	0.400
	CFLAR	psi-mi:“MI:0915”(physical association)	0.400
PSMD2	CFLAR	psi-mi:“MI:0915”(physical association)	0.400
FKBPL	CFLAR	psi-mi:“MI:0915”(physical association)	0.400
STUB1	CFLAR	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (214): CFLAR (Affinity Capture-Western), GSN (Affinity Capture-Western), FADD (Reconstituted Complex), CFLAR (Biochemical Activity), CFLAR (Two-hybrid), CFLAR (Affinity Capture-Western), RIPK1 (Affinity Capture-Western), FADD (Affinity Capture-Western), CASP8 (Affinity Capture-Western), CASP10 (Affinity Capture-Western), TICAM1 (Affinity Capture-Western), PLIN5 (Affinity Capture-MS), CASP8 (Affinity Capture-MS), CFLAR (Synthetic Growth Defect), CASP10 (Co-localization)

ESM2 similar proteins: A0A0B4J1F4, A6NEK1, G3X9X1, O14972, O15344, O15519, O35075, O70263, O70583, O94955, P82457, P82458, Q2HY40, Q2TBA3, Q32KX1, Q32NJ2, Q497K5, Q4VX76, Q54DI8, Q568M3, Q5M7W1, Q5R5L7, Q5R811, Q5R8Q5, Q5RD56, Q5RDY3, Q5RF33, Q60584, Q62807, Q6TXF1, Q6ZWE6, Q7TP90, Q7TPQ9, Q7ZX59, Q80WG7, Q8BG60, Q8BM47, Q8IY47, Q8NCT1, Q8W4D4

Diamond homologs: A0A1D5PPP7, F1NV61, G5EBM1, G5ECW5, O01382, O02002, O08738, O15519, O35397, O89094, O89110, P31944, P42573, P42574, P42575, P45436, P55210, P55211, P55212, P55213, P55214, P55866, P70677, P89116, P97864, Q08DY9, Q14790, Q29IM7, Q2PFV2, Q3T0P5, Q5IS54, Q5IS99, Q5RD56, Q60431, Q8C3Q9, Q8MJC3, Q8MJU1, Q8MKI5, Q92851, Q95ND5

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
CBL	“down-regulates quantity by destabilization”	CFLAR	ubiquitination
MAPK14	up-regulates	CFLAR	phosphorylation
AKT	“down-regulates quantity”	CFLAR	phosphorylation
AKT1	“down-regulates quantity”	CFLAR	phosphorylation
RUNX3	“down-regulates quantity by repression”	CFLAR	“transcriptional regulation”
PRKCB	“up-regulates quantity by stabilization”	CFLAR	phosphorylation
PRKCA	“up-regulates quantity by stabilization”	CFLAR	phosphorylation
BIRC2	“down-regulates quantity”	CFLAR	ubiquitination
STUB1	“down-regulates quantity by destabilization”	CFLAR	ubiquitination
CFLAR	“down-regulates activity”	CASP8	binding
ITCH	“down-regulates quantity”	CFLAR	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 39 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Caspase activation via Death Receptors in the presence of ligand	7	177.6×	2e-13
RIPK1-mediated regulated necrosis	9	137.0×	1e-15

GO biological processes:

GO term	Partners	Fold	FDR
extrinsic apoptotic signaling pathway via death domain receptors	7	75.9×	1e-09
extrinsic apoptotic signaling pathway	6	49.7×	3e-07
cellular response to mechanical stimulus	5	29.2×	5e-05
positive regulation of canonical NF-kappaB signal transduction	7	13.7×	5e-05
positive regulation of apoptotic process	7	10.7×	2e-04
cell surface receptor signaling pathway	5	8.7×	7e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	32
Likely benign	3
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

2286 predictions. Top by Δscore:

Variant	Effect	Δscore
2:201133019:T:TA	acceptor_gain	1.0000
2:201133020:G:A	acceptor_gain	1.0000
2:201133023:TTGCA:T	acceptor_loss	1.0000
2:201133024:TGCA:T	acceptor_loss	1.0000
2:201133026:CA:C	acceptor_loss	1.0000
2:201133026:CAG:C	acceptor_gain	1.0000
2:201133027:A:AG	acceptor_gain	1.0000
2:201133027:A:C	acceptor_loss	1.0000
2:201133027:AGA:A	acceptor_gain	1.0000
2:201133027:AGAGT:A	acceptor_gain	1.0000
2:201133028:G:GG	acceptor_gain	1.0000
2:201133028:GA:G	acceptor_gain	1.0000
2:201133028:GAG:G	acceptor_gain	1.0000
2:201133028:GAGT:G	acceptor_gain	1.0000
2:201133028:GAGTG:G	acceptor_gain	1.0000
2:201133131:GAAG:G	donor_gain	1.0000
2:201133132:AAGGT:A	donor_loss	1.0000
2:201133133:AGGT:A	donor_loss	1.0000
2:201133134:GGT:G	donor_loss	1.0000
2:201133135:G:GG	donor_gain	1.0000
2:201133136:T:A	donor_loss	1.0000
2:201135960:T:TA	acceptor_gain	1.0000
2:201135970:A:AG	acceptor_gain	1.0000
2:201135971:G:GG	acceptor_gain	1.0000
2:201135971:GA:G	acceptor_gain	1.0000
2:201136103:GTCTG:G	donor_gain	1.0000
2:201149001:A:AG	acceptor_gain	1.0000
2:201149002:G:GG	acceptor_gain	1.0000
2:201149002:GAA:G	acceptor_gain	1.0000
2:201149748:TTCCA:T	acceptor_loss	1.0000

AlphaMissense

3171 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:201149804:C:G	C254W	0.996
2:201160557:A:C	S307R	0.994
2:201160559:C:A	S307R	0.994
2:201160559:C:G	S307R	0.994
2:201160848:A:C	S404R	0.994
2:201160850:C:A	S404R	0.994
2:201160850:C:G	S404R	0.994
2:201130056:G:C	R64P	0.991
2:201149802:T:C	C254R	0.991
2:201160578:A:C	S314R	0.991
2:201160580:C:A	S314R	0.991
2:201160580:C:G	S314R	0.991
2:201136066:G:C	R161T	0.990
2:201136067:A:C	R161S	0.989
2:201136067:A:T	R161S	0.989
2:201160697:G:C	K353N	0.989
2:201160697:G:T	K353N	0.989
2:201149803:G:A	C254Y	0.988
2:201160566:T:C	C310R	0.988
2:201130038:T:C	L58P	0.987
2:201136051:T:C	L156P	0.984
2:201160702:T:C	F355S	0.983
2:201160836:G:C	D400H	0.983
2:201149806:T:C	L255P	0.982
2:201160450:T:C	F271S	0.982
2:201160657:T:C	F340S	0.982
2:201160845:T:A	W403R	0.982
2:201160845:T:C	W403R	0.982
2:201133087:T:C	F114L	0.981
2:201133089:C:A	F114L	0.981

dbSNP variants (sampled 300 via entrez): RS1000008921 (2:201142013 C>T), RS1000084562 (2:201133508 C>G,T), RS1000192673 (2:201144623 C>G), RS1000277347 (2:201161999 C>T), RS1000363173 (2:201141970 A>T), RS1000649752 (2:201160180 G>T), RS1000677745 (2:201153651 A>G), RS1000735229 (2:201143417 A>G), RS1000765718 (2:201154217 G>A,C), RS1000802997 (2:201143220 A>G), RS1000830424 (2:201167743 C>T), RS1000834023 (2:201123491 T>A), RS1000928836 (2:201173487 G>A), RS1000929376 (2:201126364 C>T), RS1001040895 (2:201167366 G>A)

Disease associations

OMIM: gene MIM:603599 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST002318_138	Rheumatoid arthritis	3.000000e-09
GCST002318_177	Rheumatoid arthritis	2.000000e-09
GCST003008_11	Triptolide cytotoxicity	3.000000e-07
GCST006959_113	Rheumatoid arthritis	5.000000e-07
GCST006959_72	Rheumatoid arthritis	3.000000e-07
GCST90000025_863	Appendicular lean mass	6.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0006952	cytotoxicity measurement
EFO:0004980	appendicular lean mass

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1955713 (SINGLE PROTEIN)

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
CFLAR EXPRESSION	Bicalutamide	Prostate Cancer	Resistance	CIViC D	EID925

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1594	CFLAR		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Bortezomib	increases reaction, affects expression, affects cotreatment, decreases expression, increases expression (+1 more)	10
Arsenic Trioxide	decreases reaction, decreases response to substance, affects cotreatment, decreases expression, increases reaction (+1 more)	6
Fluorouracil	increases activity, increases response to substance, affects cotreatment, decreases expression, increases expression (+3 more)	6
Valproic Acid	affects cotreatment, decreases expression, affects expression	6
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	decreases reaction, affects expression, decreases expression	5
Vorinostat	affects cotreatment, affects localization, decreases reaction, decreases expression, increases expression	5
Cycloheximide	increases reaction, decreases expression	5
Tretinoin	affects cotreatment, increases expression, decreases expression, increases reaction	5
(+)-JQ1 compound	decreases response to substance, decreases expression, decreases reaction, affects cotreatment	4
Resveratrol	affects cotreatment, decreases expression, decreases reaction, increases expression, decreases cleavage (+1 more)	4
Acetylcysteine	decreases expression, decreases reaction, increases reaction	4
bisphenol A	affects expression, decreases expression	3
sodium arsenite	increases expression	3
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	decreases expression	3
3-(4-methylphenylsulfonyl)-2-propenenitrile	decreases expression	3
Rosiglitazone	decreases expression, increases reaction	3
Cisplatin	decreases expression, increases response to substance, decreases response to substance, increases expression	3
Curcumin	decreases reaction, increases expression, decreases expression	3
Dexamethasone	decreases expression, decreases reaction, increases expression, affects cotreatment	3
Simvastatin	decreases expression, decreases reaction, increases expression	3
indole-3-carbinol	decreases reaction, increases expression, decreases expression	2
diallyl trisulfide	decreases expression, increases expression	2
alvocidib	affects expression, decreases expression, decreases reaction	2
entinostat	affects cotreatment, decreases expression	2
monomethylarsonous acid	decreases expression, increases expression	2
Sorafenib	affects cotreatment, decreases expression, increases response to substance, increases degradation	2
Acetaminophen	decreases expression	2
Air Pollutants	affects expression, increases abundance, increases expression	2
Cannabidiol	affects expression, affects response to substance, affects cotreatment, decreases expression	2
Capsaicin	decreases expression, increases expression	2

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1961026	Binding	Inhibition of cFLIP-L in human SKOV3 cells assessed as restoration of death receptor signaling-mediated apoptosis	Synthesis and biological evaluation of sulfonyl acrylonitriles as novel inhibitors to peritoneal carcinomatosis. — Bioorg Med Chem Lett

Cellosaurus cell lines

7 cell lines: 6 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_9U01	HeLa ICRP FLIP-L-mCherry	Cancer cell line	Female
CVCL_9U02	HeLa ICRP FLIP-S-mCherry	Cancer cell line	Female
CVCL_D8IV	Ubigene HCT 116 CFLAR KO	Cancer cell line	Male
CVCL_D9BW	Ubigene HEK293 CFLAR KO	Transformed cell line	Female
CVCL_E0A2	Ubigene HeLa CFLAR KO	Cancer cell line	Female
CVCL_SI72	HAP1 CFLAR (-) 1	Cancer cell line	Male
CVCL_XM75	HAP1 CFLAR (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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