FADD

protein-coding

Fas associated via death domain, the group of Death inducing signaling complex |Death effector domain containing|Ripoptosome

Gene summary

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. [provided by RefSeq, Jul 2008]

MANE transcript

NM_003824.4

Inheritance

ClinVar variants

P:4U:64B:72

Top phenotype

Immunodeficiency 90 with encephalopathy, functional hyposplenia, and hepatic dysfunction

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr11:70,203,296-70,207,390

External References & Databases

Ensembl (ENSG00000168040)

Transcript & Mutation Effects

hg38 • Region Span ~4.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

FADD-related immunodeficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013408

Submitter: PanelApp Australia

FADD-related immunodeficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013408

Submitter: ClinGen

The first report indicating a relationship of the FADD gene with autosomal recessive FADD-related autoimmune lymphoproliferative immune disorder (also called immunodeficiency 90 with encephalopathy, functional hyposplenia, and hepatic dysfunction) was made by Bolze et al., 2010 (PMID 21109225). This report featured a single consanguineous Pakistani family with several affected family members who carried the same homozygous variant in the FADD gene, with each affected individual displaying a heterogeneous number of symptoms including increased infections, recurrent liver inflammation, febrile seizures with encephalopathy, variable cardiac malformations and variable autoimmune features. Since that publication, there have been five other publications that were discovered in these curation efforts, featuring a total of five different ITCH variants. The proposed mechanism for the gene-disease relationship is protein loss of function leading to impaired FADD-mediated apoptosis in affected cells. In summary, FADD is MODERATELY associated with autosomal recessive FADD-related autoimmune lymphoproliferative immune disorder. Evidence supporting this gene-disease relationship includes case-level data, functional data and model organisms. This classification was presented to the ClinGen Primary Immunodeficiencies Gene Curation Expert Panel on February 17, 2026, and approved thereafter.

FADD-related immunodeficiencyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013408

Submitter: Ambry Genetics

FADD-related immunodeficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013408

Submitter: Labcorp Genetics (formerly Invitae)

FADD-related immunodeficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013408

Submitter: Orphanet

Clinical Genomic Database (CGD)

Immunodeficiency 90 with encephalopathy, functional hyposplenia, and hepatic dysfunctionAR

Manifestation: Allergy/Immunology/Infectious; Cardiovascular; Gastrointestinal; Neurologic

Intervention: Allergy/Immunology/Infectious; Cardiovascular

Rationale: Antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; Patients suffer from stereotypical episodes of fever, liver dyfunction, and encephalopathy, which may be severe and precipitated by viral infections; Other findings, such as cardiovascular malformations, and functional hyposplenism, have been described, and awareness may enable management

Refs: 21109225

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FADD variants in ClinVar

5 Conditions Cataloged

FADD-related immunodeficiencyTotal: 134

not providedTotal: 16

Inborn genetic diseasesTotal: 16

not specifiedTotal: 8

FADD-related disorderTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003824.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				67 clinvar	1 clinvar	68
missense		3 clinvar	64 clinvar	4 clinvar		71
nonsense						0
start loss						0
frameshift	1 clinvar					1
splice donor/acceptor (+/-2bp)						0
Total	1	3	64	71	1	140

Highest pathogenic variant AF is 0.00010099458

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 6 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003824.4	RefSeq	NP_003815.1	2	MANE Select
ENST00000301838.5	Ensembl	ENSP00000301838.5	2	MANE Select
ENST00000933048.1	Ensembl	ENSP00000603107.1	2	Standard
ENST00000933048.2	Ensembl	ENSP00000603107.1	2	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
fadd	Danio rerio	Structure: whole organism Quality: morphology abnormal

Gene / Model

Organism

Observed Phenotype

fadd

Danio rerio

Structure: whole organism

Quality: morphology

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human)
Apoptosis - multiple species - Homo sapiens (human)
Alzheimer,s disease - Homo sapiens (human)
TNF signaling pathway - Homo sapiens (human)
Chagas disease (American trypanosomiasis) - Homo sapiens (human)

Biological Process

kidney development
positive regulation of T cell mediated cytotoxicity
positive regulation of adaptive immune response
apoptotic process
activation of cysteine-type endopeptidase activity involved in apoptotic process

Molecular Function

protease binding
death receptor binding
tumor necrosis factor receptor binding
protein binding
tumor necrosis factor receptor superfamily binding

Cellular Component

nucleus
cytoplasm
cytosol
plasma membrane
death-inducing signaling complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000301838
Coding exons: 2
Length: 4228
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.837	101	128	0.791	0.00000707	1333
Missense (PolyPhen)		39	48.257	0.80818		468
Synonymous	-1.10	70	59.3	1.18	0.00000332	450
Loss of Function	1.37	0	2.17	0.00	9.29e-8	28

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Apoptotic adaptor molecule that recruits caspase-8 or caspase-10 to the activated Fas (CD95) or TNFR-1 receptors. The resulting aggregate called the death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation. Active caspase-8 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. {ECO:0000269|PubMed:16762833, ECO:0000269|PubMed:19118384, ECO:0000269|PubMed:20935634, ECO:0000269|PubMed:21109225}.;
Disease: DISEASE: 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). {ECO:0000269|PubMed:21109225}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.501

Intolerance Scores

LoFtool: 0.0618
RVIS EVS: 0.06
RVIS percentile EVS: 58.26

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.582

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Low	Medium
Primary Immunodeficiency	Medium	Low	Medium
Cancer	Medium	Medium	Medium