FAS
protein-codingFas cell surface death receptor, the group of CD molecules|Tumor necrosis factor receptor superfamily|Death inducing signaling complex
Gene summary
The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor contains a death domain. It has been shown to play a central role in the physiological regulation of programmed cell death, and has been implicated in the pathogenesis of various malignancies and diseases of the immune system. The interaction of this receptor with its ligand allows the formation of a death-inducing signaling complex that includes Fas-associated death domain protein (FADD), caspase 8, and caspase 10. The autoproteolytic processing of the caspases in the complex triggers a downstream caspase cascade, and leads to apoptosis. This receptor has been also shown to activate NF-kappaB, MAPK3/ERK1, and MAPK8/JNK, and is found to be involved in transducing the proliferating signals in normal diploid fibroblast and T cells. Several alternatively spliced transcript variants have been described, some of which are candidates for nonsense-mediated mRNA decay (NMD). The isoforms lacking the transmembrane domain may negatively regulate the apoptosis mediated by the full length isoform. [provided by RefSeq, Mar 2011]
- FAS1
- APT1
- TNFRSF6
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~75.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0011158
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0011158
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0017979
Submitter: Orphanet
Inheritance Pattern: SD
Disease ID:MONDO:1060194
Submitter: ClinGen
FAS was first reported in relation to semidominant autoimmune lymphoproliferative syndrome (ALPS) in 1995 (Fisher et al., PMID: 7540117). ALPS is an immune dysregulation disorder caused by defective lymphocyte homeostasis and characterized by the following: 1) non-malignant lymphoproliferation (lymphadenopathy, hepatosplenomegaly with or without hypersplenism) that often improves with age; 2) Autoimmune disease, mostly directed toward blood cells; 3) lifelong increased risk for both Hodgkin and non-Hodgkin lymphoma. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found distinct but complementary molecular mechanisms, haploinsufficiency and dominant negativity, in a semidominant inheritance pattern with incomplete penetrance, where monoallelic cases consistently show less severe presentations compared to biallelic cases. Additionally, loss-of-function variants affecting the extracellular domain of FAS shown reduced penetrance (~30%), appearing to require a second somatic hit or loss-of-heterozygosity to cause clinical disease, while missense variants that disrupt the FAS-FADD interaction act in a dominant negative manner and show high penetrance (~80%). Therefore, a single disease entity has been curated: autoimmune lymphoproliferative syndrome (OMIM: 601859). More than 100 distinct variants (missense, nonsense, frameshift, splice site, and large deletions) have been reported in more than 200 probands in several publications (PMIDs: 21490157, 34171534, 7540117, 15459303, 9028321, 9821419, 23524443) are included in this curation. For example, Hauck et al., 2011 reports on a four generation kindred with 12 heterozygous carriers of a start loss variant (c.3G>T) that presents as ALPS in a daughter and father. The proband was shown to have a loss of heterozygosity in their double-negative T-cells (PMID: 23524443). The other heterozygous carriers are affected by milder, mostly sub-clinical phenotypes, though all show impaired apoptosis cellularly. There is a failure of peripheral tolerance in FAS-ALPS resulting in an accumulation of autoreactive T cells that become double negative T cells. Impaired apoptosis also affects B cells resulting in hypergammaglobulinemia (PMID: 31309545) and production of autoantibodies observed in the autoimmune cytopenias. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be both loss-of-function or dominant negativity depending on where the FAS variant falls in the gene. This gene-disease relationship is also supported by extensive animal modeling (PMID:1910678, 7930845, 7533326, 8700897). There is a natural partial knockout allele on the MRL murine background caused by a retrotransposon insertion in intron 2 which presents as lymphadenopathy and splenomegaly when in a homozygous state (PMID: 1910678). Complete Fas KO mice have also been engineered and exhibit more severe and earlier symptoms than the natural models [PMID: 8700897]. In summary, there is definitive evidence supporting the relationship between FAS and semidominant autoimmune lymphoproliferative syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over three decades of research. This classification was approved by the ClinGen Childhood, Adolescent, and Young Adult Cancer Predisposition GCEP on the meeting date October 14, 2025 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0011158
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0017979
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0017979
Submitter: G2P
Inheritance Pattern: SD
Disease ID:MONDO:0017979
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Hematologic; Oncologic; Renal
Intervention: Allergy/Immunology/Infectious; Oncologic
Rationale: Lymphoproliferation can be suppressed with medications such as corticosteroids, cyclosporine, tacrolimus, sirolimus, and mycophenolate mofetil; BMT/HSCT the only curative treatment for ALPS, has to date mostly been reported in patients with severe clinical findings; Surveillance for manifestations of lymphoproliferation and autoimmunity, and specialized imaging studies to detect malignant transformation may be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to FAS variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000043.6. 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 | 2 | 59 | 1 | 62 | ||
| missense | 17 | 26 | 192 | 17 | 252 | |
| nonsense | 10 | 6 | 2 | 18 | ||
| start loss | 0 | |||||
| frameshift | 27 | 15 | 2 | 44 | ||
| splice donor/acceptor (+/-2bp) | 14 | 11 | 6 | 31 | ||
| Total | 68 | 58 | 204 | 76 | 1 | 407 |
Highest pathogenic variant AF is 0.000016731838
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000034.1 | 9 | MANE Select | |
| Ensembl | ENSP00000498466.1 | 9 | MANE Select | |
| RefSeq | NP_001307548.1 | 8 | Standard | |
| RefSeq | NP_001397885.1 | 9 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| fas | Danio rerio | Structure: post-vent region Quality: increased curvature abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Type I diabetes mellitus - Homo sapiens (human)
- Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human)
- Allograft rejection - Homo sapiens (human)
- Graft-versus-host disease - Homo sapiens (human)
- Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human)
Biological Process
- positive regulation of protein phosphorylation
- apoptotic process
- activation of cysteine-type endopeptidase activity involved in apoptotic process
- immune response
- signal transduction
Molecular Function
- transmembrane signaling receptor activity
- protein binding
- calmodulin binding
- kinase binding
- signaling receptor activity
Cellular Component
- cytosol
- plasma membrane
- cell surface
- integral component of membrane
- nuclear body
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000355740
- Coding exons
- 9
- Length
- 25129
- Individuals with no LoFs
- 125734
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 2
- Defined
- 125736
- p
- 0.00000795
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.23 | 121 | 166 | 0.731 | 0.00000803 | 2214 |
| Missense (PolyPhen) | 22 | 53.688 | 0.40977 | 746 | ||
| Synonymous | 0.399 | 55 | 58.9 | 0.934 | 0.00000300 | 591 |
| Loss of Function | 3.01 | 2 | 14.3 | 0.140 | 6.14e-7 | 189 |
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) | 0.000018 | 0.000018 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Receptor for TNFSF6/FASLG. The adapter molecule FADD recruits caspase-8 to the activated receptor. The resulting death- inducing signaling complex (DISC) performs caspase-8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. FAS- mediated apoptosis may have a role in the induction of peripheral tolerance, in the antigen-stimulated suicide of mature T-cells, or both. The secreted isoforms 2 to 6 block apoptosis (in vitro). {ECO:0000269|PubMed:19118384, ECO:0000269|PubMed:7533181}.;
- Disease
- DISEASE: Autoimmune lymphoproliferative syndrome 1A (ALPS1A) [MIM:601859]: A disorder of apoptosis that manifests in early childhood and results in the accumulation of autoreactive lymphocytes. It is characterized by non-malignant lymphadenopathy with hepatosplenomegaly, and autoimmune hemolytic anemia, thrombocytopenia and neutropenia. {ECO:0000269|PubMed:10090885, ECO:0000269|PubMed:10340403, ECO:0000269|PubMed:10515860, ECO:0000269|PubMed:11418480, ECO:0000269|PubMed:17336828, ECO:0000269|PubMed:20935634, ECO:0000269|PubMed:7540117, ECO:0000269|PubMed:8929361, ECO:0000269|PubMed:9028321, ECO:0000269|PubMed:9028957, ECO:0000269|PubMed:9322534, ECO:0000269|PubMed:9821419, ECO:0000269|PubMed:9927496}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.872
Intolerance Scores
- LoFtool
- 0.0628
- RVIS EVS
- 0.46
- RVIS percentile EVS
- 78.46
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.597
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |