FADD

Summary

FADD (Fas associated via death domain, HGNC:3573) is a protein-coding gene on chromosome 11q13.3, encoding FAS-associated death domain protein (Q13158). Apoptotic adapter molecule that recruits caspases CASP8 or CASP10 to the activated FAS/CD95 or TNFRSF1A/TNFR-1 receptors. It is a selective cancer dependency (DepMap: 14.9% of cell lines).

The protein encoded by this gene is an adaptor molecule that interacts with various cell surface receptors and mediates cell apoptotic signals. Through its C-terminal death domain, this protein can be recruited by TNFRSF6/Fas-receptor, tumor necrosis factor receptor, TNFRSF25, and TNFSF10/TRAIL-receptor, and thus it participates in the death signaling initiated by these receptors. Interaction of this protein with the receptors unmasks the N-terminal effector domain of this protein, which allows it to recruit caspase-8, and thereby activate the cysteine protease cascade. Knockout studies in mice also suggest the importance of this protein in early T cell development.

Source: NCBI Gene 8772 — RefSeq curated summary.

At a glance

• Gene–disease (curated): FADD-related immunodeficiency (Strong, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 154 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 17
• Cancer dependency (DepMap): dependent in 14.9% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_003824

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3573
Approved symbol	FADD
Name	Fas associated via death domain
Location	11q13.3
Locus type	gene with protein product
Status	Approved
Aliases	MORT1, GIG3
Ensembl gene	ENSG00000168040
Ensembl biotype	protein_coding
OMIM	602457
Entrez	8772

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000301838, ENST00000933048

RefSeq mRNA: 1 — MANE Select: NM_003824 NM_003824

CCDS: CCDS8196

Canonical transcript exons

ENST00000301838 — 2 exons

Exon	Start	End
ENSE00001119658	70206133	70207390
ENSE00001119659	70203296	70203745

Expression profiles

Bgee: expression breadth ubiquitous, 261 present calls, max score 90.25.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.7213 / max 189.6637, expressed in 1816 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
115646	19.6959	1812
115647	2.0598	1172
115645	0.9657	603

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endometrium epithelium	UBERON:0004811	90.25	gold quality
granulocyte	CL:0000094	88.41	gold quality
tendon of biceps brachii	UBERON:0008188	88.01	silver quality
stromal cell of endometrium	CL:0002255	87.94	gold quality
mucosa of transverse colon	UBERON:0004991	87.92	gold quality
tongue squamous epithelium	UBERON:0006919	87.39	silver quality
blood	UBERON:0000178	87.21	gold quality
parotid gland	UBERON:0001831	86.22	gold quality
right adrenal gland	UBERON:0001233	85.37	gold quality
right adrenal gland cortex	UBERON:0035827	84.95	gold quality
left adrenal gland	UBERON:0001234	84.88	gold quality
epithelium of esophagus	UBERON:0001976	84.80	gold quality
monocyte	CL:0000576	84.48	gold quality
leukocyte	CL:0000738	84.43	gold quality
mononuclear cell	CL:0000842	84.12	gold quality
left adrenal gland cortex	UBERON:0035825	84.07	gold quality
esophagus squamous epithelium	UBERON:0006920	83.95	gold quality
adrenal cortex	UBERON:0001235	83.74	gold quality
islet of Langerhans	UBERON:0000006	83.46	gold quality
colonic mucosa	UBERON:0000317	83.46	gold quality
transverse colon	UBERON:0001157	83.42	gold quality
adrenal gland	UBERON:0002369	83.21	gold quality
esophagus mucosa	UBERON:0002469	83.20	gold quality
corpus epididymis	UBERON:0004359	83.11	gold quality
descending thoracic aorta	UBERON:0002345	82.77	gold quality
placenta	UBERON:0001987	82.71	gold quality
mucosa of sigmoid colon	UBERON:0004993	82.15	gold quality
esophagus	UBERON:0001043	82.11	gold quality
spleen	UBERON:0002106	81.99	gold quality
apex of heart	UBERON:0002098	81.93	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.54

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CTNNB1, DEDD, JUN, RUNX3, TBX15, TP53

miRNA regulators (miRDB)

35 targeting FADD, 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-512-3P	99.97	67.35	1049
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-8062	99.88	68.43	995
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-1303	99.65	69.77	1662
HSA-MIR-6733-3P	99.54	67.80	1281
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-4652-3P	99.33	70.02	2742
HSA-MIR-145-3P	99.33	67.66	764
HSA-MIR-2115-3P	99.31	69.68	2026
HSA-MIR-4254	99.11	65.15	1315
HSA-MIR-4738-3P	98.98	67.98	1846
HSA-MIR-361-5P	98.95	70.16	1340
HSA-MIR-6737-3P	98.95	68.56	1577
HSA-MIR-7157-3P	98.95	68.70	1582
HSA-MIR-374A-3P	98.87	67.82	1531
HSA-MIR-589-5P	98.72	66.96	927
HSA-MIR-6868-3P	98.63	69.64	2259
HSA-MIR-4274	98.59	66.10	630
HSA-MIR-1237-3P	98.55	67.65	1423

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 14.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• binding of FADD and caspase-8 to molluscum contagiosum virus MC159 v-FLIP is not sufficient for its antiapoptotic function (PMID:11752160)
• study showed a significant decrease in the percentage of FADD-immunoreactive dopaminergic (DA) neurons in the substantia nigra pars compacta of patients with Parkinson’s disease (PMID:11805265)
• Apoptosis and NF-kappa B: the FADD connection. (PMID:11877464)
• HLA class II signals sensitize B lymphocytes to apoptosis, in part, by increasing FADD recruitment to activated Fas (PMID:11975981)
• alteration associated with nodal metastasis in non-small cell lung cancer (PMID:12037669)
• the death effector domain of FADD is involved in interaction with Fas. (PMID:12107169)
• dispensability for apoptotic function of Hid (PMID:12122017)
• dominant negative form inhibits cytochrome c release in response to TRAIL receptor 2 or CD95 (PMID:12196516)
• Caspase-10 is recruited to and activated at the native death-inducing signalling complexes in a FADD-dependent manner. (PMID:12198154)
• Functional assays using mutants of Fas-associated death domain revealed that this basic region influences binding and recruitment of caspase-8 and cellular FLICE inhibitor protein to the DISC. (PMID:12220669)
• The association of FADD with ABCA1 provides an unexpected link between high density lipoprotein metabolism and an adaptor molecule mainly described in death receptor signal transduction. (PMID:12235128)
• expression blocks keratinocyte apoptosis and vesication induced by sulfur mustard (PMID:12482751)
• TRAIL-R1 and TRAIL-R2 recruit FADD which then interacts with procaspase-8. This results in the assembly of FADD and procaspase-8 into DISC and initiates the cascacde to apoptosis. (PMID:12496482)
• evidence for caspase-8-ganglioside interaction in T cells (PMID:12499380)
• Regulation of FADD expression by UV may serve to enhance death receptor-mediated keratinocyte death. (PMID:12604344)
• caspase-8 and FADD are obligatory for TNF-mediated apoptosis but are not recruited to a TNF-induced membrane-bound receptor signaling complex; they must be activated elsewhere within the cell (PMID:12721308)
• FADD is present in both the cytoplasm and the nucleus of cells; its nuclear localization relies on strong nuclear localization and nuclear export signals (NLS and NES, respectively) that reside in the death-effector domain. (PMID:12815462)
• FADD may play a role in regulating genome surveillance (PMID:12851487)
• C-FADD may affect apoptosis sensitivity of cells by interfering with cell cycle progression and not only by binding to death receptors. (PMID:12954630)
• FADD death domain has an expanded binding surface responsible for interaction with CD95/Fas (PMID:14573612)
• Hypoxia-induced apoptosis was not affected by lack of caspase-8 or FADD. (PMID:15034549)
• binding of Fas-associated death domain (FADD) to the tumor necrosis factor-related apoptosis-inducing ligand receptor DR5 is regulated by the death effector domain of FADD (PMID:15173180)
• taxol induces FADD-dependent apoptosis primarily through activation of caspase-10 but independently of death receptors (PMID:15452117)
• absolute requirement for the C-terminal tail of TRAIL for FADD binding and signaling (PMID:15452120)
• c-FLIPL is recruited to death receptor 5 independent of Fas-associated protein with death domain (FADD) (PMID:15485835)
• This is the first report of FADD gene mutation in gastrointestinal cancers, and data suggest that the FADD gene is rarely mutated in human colon and stomach cancers. (PMID:15601308)
• FADD/caspase-8 pathway induces apoptosis through p53 in human pre-malignant and malignant cells (PMID:15645452)
• results suggest that autophagy 5-like Atg5 plays a crucial role in interferon-gamma-induced autophagic cell death by interacting with Fas-associated protein with death domain (FADD) (PMID:15778222)
• acid sphingomyelinase activation within rafts involves a Fas-mediated mechanism dependent upon caspase 8 and FADD (PMID:15849201)
• The mechanism controlling PEA-15 binding to ERK/MAPK or FADD, and its subsequent role in cell proliferation and apoptosis is reported. (PMID:15916534)
• The majority of Langerhans cell histiocytosis cells express FADD. (PMID:15956881)
• Extensive regions of the FADD death domain are required for binding to the TRAIL receptor DR5. (PMID:16003390)
• FADD uses a Tube-like surface in each of its death motifs to engage its binding partners, either CD95 or TRADD. (PMID:16006552)
• Phosphorylation of FADD by casein kinase Ialpha is a crucial event during mitosis. (PMID:16061179)
• induction of NF-kappaB activity and its effects on cell-cycle progression may represent a molecular basis underlying the aggressive tumor behavior associated with elevated p-FADD expression in lung adenocarcinoma (PMID:16109772)
• FADD dominant-negative transgenic mice are resistant to experimental autoimmune encephalomyelitis; FADD therefore serves as an enhancer of autoimmune encephalomyelitis. (PMID:16177127)
• This review suggests that levels of phosphorylated FADD may be used as a prognostic biomarker for predicting survival of lung cancer patients. (PMID:16258269)
• A deficiency in FADD sensitises Jurkat T cells to TNF-alpha-dependent necrosis during activation-induced cell death . (PMID:16289096)
• FADD does not play an essential role in NF-kappaB activation, suggesting an alternative route by which this adaptor promotes the clonal expansion of T cells (PMID:16339514)
• FADD self-associates through a conserved RXDLL motif in the death effector domain (PMID:16410793)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	fadd	ENSDARG00000103021
mus_musculus	Fadd	ENSMUSG00000031077
rattus_norvegicus	Fadd	ENSRNOG00000047035

Protein

Protein identifiers

FAS-associated death domain protein — Q13158 (reviewed: Q13158)

Alternative names: FAS-associating death domain-containing protein, Growth-inhibiting gene 3 protein, Mediator of receptor induced toxicity

All UniProt accessions (1): Q13158

UniProt curated annotations — full annotation on UniProt →

Function. Apoptotic adapter molecule that recruits caspases CASP8 or CASP10 to the activated FAS/CD95 or TNFRSF1A/TNFR-1 receptors. The resulting aggregate called the death-inducing signaling complex (DISC) performs CASP8 proteolytic activation. Active CASP8 initiates the subsequent cascade of caspases mediating apoptosis. Involved in interferon-mediated antiviral immune response, playing a role in the positive regulation of interferon signaling.

Subunit / interactions. Can self-associate. Component of the AIM2 PANoptosome complex, a multiprotein complex that drives inflammatory cell death (PANoptosis). Component of the death-induced signaling complex (DISC) composed of cell surface receptor FAS/CD95 or TNFRSF1A, adapter protein FADD and the CASP8 protease; recruitment of CASP8 to the complex is required for processing of CASP8 into the p18 and p10 subunits. Interacts (via death domain) with FAS (via death domain). Interacts directly (via DED domain) with NOL3 (via CARD domain); inhibits death-inducing signaling complex (DISC) assembly by inhibiting the increase in FAS-FADD binding induced by FAS activation. Interacts with CFLAR, PEA15 and MBD4. When phosphorylated, part of a complex containing HIPK3 and FAS. May interact with MAVS/IPS1. Interacts with MOCV v-CFLAR protein and PIDD1. Interacts with RIPK1 and TRADD. Interacts with stimulated TNFRSF10B. Interacts with DDX24. (Microbial infection) Interacts with human papillomavirus 16/HPV16 protein E6. (Microbial infection) Interacts with molluscum contagiosum virus proteins MC159L/v-CFLAR and MC160L.

Subcellular location. Cytoplasm.

Tissue specificity. Expressed in a wide variety of tissues, except for peripheral blood mononuclear leukocytes.

Post-translational modifications. (Microbial infection) Glycosylated at Arg-117 by enteropathogenic E.coli protein NleB1, C.rodentium protein NleB and S.typhimurium protein Ssek1: arginine GlcNAcylation prevents recruitment of caspase-8 or caspase-10 to the activated Fas (CD95) or TNFR-1 receptors.

Disease relevance. Infections, recurrent, associated with encephalopathy, hepatic dysfunction and cardiovascular malformations (IEHDCM) [MIM:613759] A condition with biological features of autoimmune lymphoproliferative syndrome such as high-circulating CD4(-)CD8(-)TCR-alpha-beta(+) T-cell counts, and elevated IL10 and FASL levels. Affected individuals suffer from recurrent, stereotypical episodes of fever, encephalopathy, and mild liver dysfunction sometimes accompanied by generalized seizures. The episodes can be triggered by varicella zoster virus (VZV), measles mumps rubella (MMR) attenuated vaccine, parainfluenza virus, and Epstein-Barr virus (EBV). The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Contains a death domain involved in the binding of the corresponding domain within Fas receptor. The interaction between the FAS and FADD death domains is crucial for the formation of the death-inducing signaling complex (DISC).

RefSeq proteins (1): NP_003815* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000488	Death_dom	Domain
IPR001875	DED_dom	Domain
IPR011029	DEATH-like_dom_sf	Homologous_superfamily
IPR016729	FADD	Family
IPR049634	FADD_vert	Family

Pfam: PF00531, PF01335

UniProt features (41 total): mutagenesis site 16, helix 13, strand 3, domain 2, chain 1, sequence conflict 1, region of interest 1, modified residue 1, turn 1, glycosylation site 1, sequence variant 1

Structure

Experimental structures (PDB)

18 structures.

PDB	Method	Resolution (Å)
6ACI	X-RAY DIFFRACTION	1.87
9U6E	ELECTRON MICROSCOPY	2.4
9L5W	ELECTRON MICROSCOPY	2.6
3EZQ	X-RAY DIFFRACTION	2.73
9U7A	ELECTRON MICROSCOPY	2.82
9N94	ELECTRON MICROSCOPY	3.07
8YD8	X-RAY DIFFRACTION	3.11
8YD7	X-RAY DIFFRACTION	3.32
9NCQ	ELECTRON MICROSCOPY	3.51
8YNI	ELECTRON MICROSCOPY	3.66
8YBX	ELECTRON MICROSCOPY	3.68
3OQ9	X-RAY DIFFRACTION	6.8
1A1W	SOLUTION NMR
1A1Z	SOLUTION NMR
1E3Y	SOLUTION NMR
1E41	SOLUTION NMR
2GF5	SOLUTION NMR
7LXC	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13158-F1	72.60	0.00

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): 194

Glycosylation sites (1): 117

Mutagenesis-validated functional residues (16):

Position	Phenotype
38	loss of interaction with casp8.
44	loss of interaction with casp8. abolishes induction of apoptosis. decreased interaction with fas.
51	loss of interaction with casp8.
117	abolished glcnacylation by e.coli nleb1.
117	loss of interaction with fas.
121	loss of interaction with fas.
123	strongly decreased interaction with fas.
135	strongly decreased interaction with fas.
142	decreased interaction with fas.
172	loss of interaction with fas.
172	strongly decreased interaction with fas.
175	strongly decreased interaction with fas.
176	decreased interaction with fas.
12	loss of interaction with casp8.
25	loss of interaction with fas. loss of self-association. abolishes induction of apoptosis.
33	loss of self-association.

Function

Pathways and Gene Ontology

Reactome pathways

14 pathways

ID	Pathway
R-HSA-140534	Caspase activation via Death Receptors in the presence of ligand
R-HSA-2562578	TRIF-mediated programmed cell death
R-HSA-3371378	Regulation by c-FLIP
R-HSA-5213460	RIPK1-mediated regulated necrosis
R-HSA-5218900	CASP8 activity is inhibited
R-HSA-5357786	TNFR1-induced proapoptotic signaling
R-HSA-5357905	Regulation of TNFR1 signaling
R-HSA-5675482	Regulation of necroptotic cell death
R-HSA-69416	Dimerization of procaspase-8
R-HSA-75157	FasL/ CD95L signaling
R-HSA-75158	TRAIL signaling
R-HSA-9013957	TLR3-mediated TICAM1-dependent programmed cell death
R-HSA-933543	NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10
R-HSA-9693928	Defective RIPK1-mediated regulated necrosis

MSigDB gene sets: 454 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, REACTOME_DDX58_IFIH1_MEDIATED_INDUCTION_OF_INTERFERON_ALPHA_BETA, GOBP_REGULATION_OF_CELL_ACTIVATION, BIOCARTA_RELA_PATHWAY, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, BROWNE_HCMV_INFECTION_6HR_DN, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_BEHAVIOR, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_RESPONSE_TO_COCAINE, GOBP_POSITIVE_REGULATION_OF_INTERLEUKIN_8_PRODUCTION, GOBP_RESPONSE_TO_PEPTIDE, GOBP_REGULATION_OF_LEUKOCYTE_APOPTOTIC_PROCESS

GO Biological Process (45): kidney development (GO:0001822), positive regulation of T cell mediated cytotoxicity (GO:0001916), positive regulation of adaptive immune response (GO:0002821), apoptotic process (GO:0006915), extrinsic apoptotic signaling pathway via death domain receptors (GO:0008625), positive regulation of type II interferon production (GO:0032729), positive regulation of interleukin-8 production (GO:0032757), positive regulation of tumor necrosis factor production (GO:0032760), T cell differentiation in thymus (GO:0033077), TRAIL-activated apoptotic signaling pathway (GO:0036462), positive regulation of activated T cell proliferation (GO:0042104), T cell homeostasis (GO:0043029), positive regulation of apoptotic process (GO:0043065), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), innate immune response (GO:0045087), positive regulation of innate immune response (GO:0045089), positive regulation of macrophage differentiation (GO:0045651), positive regulation of proteolysis (GO:0045862), positive regulation of transcription by RNA polymerase II (GO:0045944), behavioral response to cocaine (GO:0048148), lymph node development (GO:0048535), spleen development (GO:0048536), thymus development (GO:0048538), defense response to virus (GO:0051607), positive regulation of type I interferon-mediated signaling pathway (GO:0060340), negative regulation of necroptotic process (GO:0060546), negative regulation of activation-induced cell death of T cells (GO:0070236), cellular response to mechanical stimulus (GO:0071260), death-inducing signaling complex assembly (GO:0071550), motor neuron apoptotic process (GO:0097049), apoptotic signaling pathway (GO:0097190), extrinsic apoptotic signaling pathway (GO:0097191), extrinsic apoptotic signaling pathway in absence of ligand (GO:0097192), necroptotic signaling pathway (GO:0097527), positive regulation of execution phase of apoptosis (GO:1900119), positive regulation of CD8-positive, alpha-beta cytotoxic T cell extravasation (GO:2000454), positive regulation of extrinsic apoptotic signaling pathway (GO:2001238), positive regulation of cytokine production (GO:0001819), immune system process (GO:0002376), signal transduction (GO:0007165)

GO Molecular Function (12): protease binding (GO:0002020), death receptor binding (GO:0005123), tumor necrosis factor receptor binding (GO:0005164), protein-macromolecule adaptor activity (GO:0030674), tumor necrosis factor receptor superfamily binding (GO:0032813), receptor serine/threonine kinase binding (GO:0033612), signaling adaptor activity (GO:0035591), death effector domain binding (GO:0035877), identical protein binding (GO:0042802), protein-containing complex binding (GO:0044877), caspase binding (GO:0089720), protein binding (GO:0005515)

GO Cellular Component (9): cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), cytoplasmic side of plasma membrane (GO:0009898), death-inducing signaling complex (GO:0031264), CD95 death-inducing signaling complex (GO:0031265), cell body (GO:0044297), ripoptosome (GO:0097342), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
Caspase activation via Death Receptors in the presence of ligand	2
TNF signaling	2
Death Receptor Signaling	2
Caspase activation via extrinsic apoptotic signalling pathway	1
TRIF (TICAM1)-mediated TLR4 signaling	1
Regulated Necrosis	1
Regulation of necroptotic cell death	1
RIPK1-mediated regulated necrosis	1
Toll Like Receptor 3 (TLR3) Cascade	1
DDX58/IFIH1-mediated induction of interferon-alpha/beta	1
Diseases of programmed cell death	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
positive regulation of immune response	2
positive regulation of cytokine production	2
tumor necrosis factor receptor superfamily binding	2
protein binding	2
binding	2
animal organ development	1
renal system development	1
positive regulation of leukocyte mediated cytotoxicity	1
T cell mediated cytotoxicity	1
regulation of T cell mediated cytotoxicity	1
positive regulation of T cell mediated immunity	1
adaptive immune response	1
regulation of adaptive immune response	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
extrinsic apoptotic signaling pathway	1
type II interferon production	1
regulation of type II interferon production	1
interleukin-8 production	1
regulation of interleukin-8 production	1
tumor necrosis factor production	1
regulation of tumor necrosis factor production	1
positive regulation of tumor necrosis factor superfamily cytokine production	1
T cell differentiation	1
extrinsic apoptotic signaling pathway via death domain receptors	1
positive regulation of T cell proliferation	1
regulation of activated T cell proliferation	1
activated T cell proliferation	1
lymphocyte homeostasis	1
apoptotic process	1
regulation of apoptotic process	1
positive 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
immune response	1
defense response to symbiont	1
positive regulation of response to biotic stimulus	1

Protein interactions and networks

STRING

3372 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FADD	CFLAR	O15519	999
FADD	CASP8	Q14790	999
FADD	TRADD	Q15628	999
FADD	TNFRSF1A	P19438	998
FADD	TNFRSF10A	O00220	998
FADD	RIPK1	Q13546	998
FADD	TNFRSF10B	O14763	998
FADD	CASP10	Q92851	998
FADD	FAS	P25445	998
FADD	FASLG	P48023	998
FADD	RIPK3	Q9Y572	996
FADD	ATG5	Q9H1Y0	991
FADD	TRAF2	Q12933	982
FADD	ATG12	O94817	975
FADD	TNF	P01375	973

IntAct

281 interactions, top by confidence:

A	B	Type	Score
CASP8	FADD	psi-mi:“MI:0914”(association)	0.980
CASP8	FADD	psi-mi:“MI:0915”(physical association)	0.980
FADD	CASP8	psi-mi:“MI:0915”(physical association)	0.980
CASP8	FADD	psi-mi:“MI:0407”(direct interaction)	0.980
FADD	CASP8	psi-mi:“MI:0914”(association)	0.980
FAS	FADD	psi-mi:“MI:0915”(physical association)	0.960
FADD	FAS	psi-mi:“MI:0915”(physical association)	0.960
FAS	FADD	psi-mi:“MI:0914”(association)	0.960

BioGRID (344): FADD (Reconstituted Complex), ATG5 (Affinity Capture-Western), ATG12 (Affinity Capture-Western), ATG5 (Co-localization), FADD (Reconstituted Complex), CASP10 (Reconstituted Complex), CASP8 (Reconstituted Complex), FADD (Reconstituted Complex), FADD (Affinity Capture-Western), FADD (Affinity Capture-Western), NEFH (Affinity Capture-MS), IL37 (Affinity Capture-MS), RIPK1 (Affinity Capture-MS), PRKRIR (Affinity Capture-MS), FADD (Affinity Capture-MS)

ESM2 similar proteins: A2TF48, A5HNF6, A8QMS7, B3SRQ2, B3Y678, B3Y679, B3Y680, B3Y681, B3Y682, B3Y683, B6CJX2, C8BKC7, F1QWA8, I3L5V6, O02697, O88879, P0CI65, P22366, P42338, P48736, P52735, Q13158, Q28DJ2, Q3UR70, Q3V3E1, Q4LBC6, Q599T9, Q5FWM2, Q5XJ85, Q60992, Q61160, Q645M6, Q6AZT7, Q6Y1S1, Q7TNH6, Q7Z494, Q7ZYP6, Q803A6, Q8BGG7, Q8BTI9

Diamond homologs: A0A1D5PPP7, F1NV61, O01382, O02002, O08738, O35397, O89110, P29594, P42574, P42575, P55210, P55211, P55212, P55213, P55214, P55215, P55866, P70677, P89116, P97864, Q08DY9, Q13158, Q14790, Q2PFV2, Q3T0P5, Q5IS54, Q5IS99, Q60431, Q61160, Q645M6, Q8C3Q9, Q8MJC3, Q8MJU1, Q8MKI5, Q92851, Q95ND5, Q98943, Q9JHX4, Q13546, Q60855

SIGNOR signaling

17 interactions.

A	Effect	B	Mechanism
FADD	up-regulates	CASP10	binding
FADD	“up-regulates activity”	CASP8	binding
MAP2K7	“down-regulates activity”	FADD	phosphorylation
MAP3K1	“down-regulates activity”	FADD	phosphorylation
CSNK1A1	“down-regulates activity”	FADD	phosphorylation
PLK1	“down-regulates activity”	FADD	phosphorylation
FADD	“up-regulates activity”	RIPK1	binding
FAS	“up-regulates activity”	FADD	binding
AURKA	up-regulates	FADD	phosphorylation
TRADD	“up-regulates activity”	FADD	binding
DUSP26	“down-regulates activity”	FADD	dephosphorylation
RUNX3	“up-regulates quantity by expression”	FADD	“transcriptional regulation”
TNFRSF10A	up-regulates	FADD	binding
TNFRSF10B	up-regulates	FADD	binding
HIPK3	“down-regulates activity”	FADD	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 49 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	8	169.2×	2e-15
RIPK1-mediated regulated necrosis	11	139.6×	6e-20
RIP-mediated NFkB activation via ZBP1	5	93.3×	5e-08
TNFR1-induced proapoptotic signaling	5	61.0×	5e-07
Regulation of necroptotic cell death	5	61.0×	5e-07
TNF signaling	5	58.7×	5e-07
TNFR1-induced NF-kappa-B signaling pathway	6	56.0×	3e-08
Regulation of TNFR1 signaling	8	49.8×	1e-10

GO biological processes:

GO term	Partners	Fold	FDR
extrinsic apoptotic signaling pathway via death domain receptors	8	78.3×	2e-11
canonical NF-kappaB signal transduction	6	53.6×	1e-07
extrinsic apoptotic signaling pathway	7	52.3×	6e-09
positive regulation of neuron apoptotic process	6	39.8×	6e-07
obsolete positive regulation of NF-kappaB transcription factor activity	6	30.1×	3e-06
negative regulation of canonical NF-kappaB signal transduction	7	29.4×	3e-07
cellular response to mechanical stimulus	5	26.4×	6e-05
positive regulation of canonical NF-kappaB signal transduction	14	24.8×	1e-13

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	60
Likely benign	80
Benign	6

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
242497	NM_003824.4(FADD):c.52_58del (p.Ser17_Ser18insTer)	Pathogenic
30267	NM_003824.4(FADD):c.315T>G (p.Cys105Trp)	Likely pathogenic

SpliceAI

198 predictions. Top by Δscore:

Variant	Effect	Δscore
11:70206128:CCCA:C	acceptor_loss	1.0000
11:70206129:CCA:C	acceptor_loss	1.0000
11:70206131:A:AG	acceptor_gain	1.0000
11:70206131:A:C	acceptor_loss	1.0000
11:70206132:G:GT	acceptor_gain	1.0000
11:70206132:GA:G	acceptor_gain	1.0000
11:70206132:GAC:G	acceptor_gain	1.0000
11:70206132:GACC:G	acceptor_gain	1.0000
11:70206132:GACCT:G	acceptor_gain	1.0000
11:70203739:G:GT	donor_gain	0.9900
11:70203739:G:T	donor_gain	0.9900
11:70203741:AGAAG:A	donor_loss	0.9900
11:70203744:AGG:A	donor_loss	0.9900
11:70203745:GG:G	donor_loss	0.9900
11:70203746:G:T	donor_loss	0.9900
11:70203747:T:A	donor_loss	0.9900
11:70206128:CCCAG:C	acceptor_gain	0.9900
11:70206129:CCAG:C	acceptor_gain	0.9900
11:70206130:CAGAC:C	acceptor_gain	0.9900
11:70206131:A:T	acceptor_gain	0.9900
11:70203710:C:T	donor_gain	0.9800
11:70206127:TCCCA:T	acceptor_gain	0.9800
11:70206132:G:A	acceptor_gain	0.9800
11:70203742:GAAG:G	donor_gain	0.9700
11:70205777:G:GT	donor_gain	0.9200
11:70203743:A:T	donor_gain	0.8900
11:70203691:C:T	donor_gain	0.8700
11:70204011:A:G	donor_gain	0.8700
11:70203709:G:GT	donor_gain	0.8600
11:70204471:C:G	donor_gain	0.8200

AlphaMissense

1342 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:70203532:T:C	F25L	0.993
11:70203534:C:A	F25L	0.993
11:70203534:C:G	F25L	0.993
11:70206180:T:A	W112R	0.992
11:70206180:T:C	W112R	0.992
11:70206157:T:A	I104K	0.987
11:70206182:G:C	W112C	0.984
11:70206182:G:T	W112C	0.984
11:70206340:T:A	L165H	0.984
11:70206193:C:A	A116D	0.981
11:70203673:C:A	R72S	0.979
11:70203527:T:C	L23P	0.978
11:70206157:T:G	I104R	0.978
11:70206288:T:A	W148R	0.978
11:70206288:T:C	W148R	0.978
11:70203531:G:C	K24N	0.975
11:70203531:G:T	K24N	0.975
11:70206196:G:C	R117P	0.973
11:70206195:C:A	R117S	0.972
11:70206290:G:C	W148C	0.972
11:70206290:G:T	W148C	0.972
11:70206172:G:A	G109E	0.970
11:70206202:T:C	L119P	0.968
11:70203595:T:C	F46L	0.967
11:70203597:C:A	F46L	0.967
11:70203597:C:G	F46L	0.967
11:70206367:C:A	A174D	0.967
11:70206280:T:C	L145P	0.965
11:70203596:T:C	F46S	0.961
11:70206366:G:C	A174P	0.961

dbSNP variants (sampled 300 via entrez): RS1000170791 (11:70203658 C>T), RS1000441004 (11:70205982 G>A), RS1000710410 (11:70204512 C>T), RS1001173488 (11:70202595 C>T), RS1001392353 (11:70202292 C>G), RS1001501499 (11:70207854 C>T), RS1002222046 (11:70201323 T>A), RS1003134990 (11:70203716 C>A,G,T), RS1003228366 (11:70207575 C>T), RS1003301896 (11:70207757 C>CCA), RS1003488819 (11:70202707 T>G), RS1003722300 (11:70206535 C>A,G), RS1003862504 (11:70202444 G>A,C), RS1003933207 (11:70206742 T>C), RS1004239983 (11:70206702 C>T)

Disease associations

OMIM: gene MIM:602457 | disease phenotypes: MIM:613759

GenCC curated gene-disease

Disease	Classification	Inheritance
FADD-related immunodeficiency	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
FADD-related immunodeficiency	Moderate	AR

Mondo (1): FADD-related immunodeficiency (MONDO:0013408)

Orphanet (1): FADD-related immunodeficiency (Orphanet:306550)

HPO phenotypes

17 total (17 of 17 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001250	Seizure
HP:0001298	Encephalopathy
HP:0001395	Hepatic fibrosis
HP:0001410	Decreased liver function
HP:0001629	Ventricular septal defect
HP:0002059	Cerebral atrophy
HP:0002719	Recurrent infections
HP:0003819	Death in childhood
HP:0004935	Pulmonary artery atresia
HP:0011669	Left superior vena cava draining directly to the left atrium
HP:0012852	Hepatic bridging fibrosis
HP:0030057	Autoimmune antibody positivity
HP:0031964	Elevated circulating alanine aminotransferase concentration
HP:0032550	Howell-Jolly bodies
HP:0033196	Portal inflammation
HP:0033199	Increased circulating interleukin 10 concentration

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006479_130	Diverticular disease	2.000000e-09
GCST006479_131	Diverticular disease	6.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009959	diverticular disease

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Quercetin	affects localization, increases reaction, decreases expression, increases expression	5
bisphenol A	decreases expression, increases expression, affects cotreatment	4
Resveratrol	increases response to substance, affects localization, decreases reaction, increases expression, affects binding (+2 more)	4
sodium arsenite	increases expression, affects binding, increases reaction, decreases expression	3
dioscin	increases expression	3
pyrazolanthrone	decreases reaction, increases phosphorylation, decreases phosphorylation	3
Doxorubicin	affects expression, affects binding, affects cotreatment, increases reaction, increases expression	3
titanium dioxide	affects binding, decreases expression	2
ochratoxin A	decreases expression	2
hydroquinone	affects reaction, increases cleavage, decreases expression	2
casticin	increases expression	2
Celecoxib	affects binding, increases reaction, affects response to substance, decreases reaction, increases activity (+1 more)	2
Estradiol	affects expression, increases expression	2
Mustard Gas	affects reaction, increases cleavage, increases reaction, increases expression	2
Plant Extracts	decreases reaction, increases expression	2
Selenium	decreases expression, decreases reaction, increases expression, affects binding, affects cotreatment (+1 more)	2
Tamoxifen	affects cotreatment, decreases expression, increases phosphorylation	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
Paclitaxel	decreases reaction, increases expression, increases phosphorylation	2
Cadmium Chloride	decreases expression	2
Genistein	decreases reaction, increases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
GSK-J4	decreases expression	1
ON123300	decreases expression	1
picrasidine I	decreases expression	1
ZH-2 compound	increases expression	1
syringic acid	decreases reaction, increases secretion	1
2-anisidine	affects expression	1
naringenin	affects cotreatment, increases expression	1
naringin	increases expression	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1RT	Abcam HeLa FADD KO	Cancer cell line	Female
CVCL_KT55	HeLa SilenciX FADD	Cancer cell line	Female
CVCL_SM74	HAP1 FADD (-) 1	Cancer cell line	Male
CVCL_SM75	HAP1 FADD (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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