XIAP
protein-codingX-linked inhibitor of apoptosis, the group of Ring finger proteins|Baculoviral IAP repeat containing
Gene summary
This gene encodes a protein that belongs to a family of apoptotic suppressor proteins. Members of this family share a conserved motif termed, baculovirus IAP repeat, which is necessary for their anti-apoptotic function. This protein functions through binding to tumor necrosis factor receptor-associated factors TRAF1 and TRAF2 and inhibits apoptosis induced by menadione, a potent inducer of free radicals, and interleukin 1-beta converting enzyme. This protein also inhibits at least two members of the caspase family of cell-death proteases, caspase-3 and caspase-7. Mutations in this gene are the cause of X-linked lymphoproliferative syndrome. Alternate splicing results in multiple transcript variants. Pseudogenes of this gene are found on chromosomes 2 and 11.[provided by RefSeq, Feb 2011]
- API3
- BIRC4
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~54.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: XL
Disease ID:MONDO:0010385
Submitter: ClinGen
*XIAP*, also known as *BIRC4*, was first reported in relation to X-linked lymphoproliferative disease due to *XIAP* deficiency in 2006 (Rigaud S, et al., 2006, PMID: 17080092). X-linked lymphoproliferative disease due to XIAP deficiency is a variable immune dysregulation disorder that often presents with hemophagocytic lymphohistiocytosis, splenomegaly, hypogammaglobulinemia, inflammatory bowel disease, cytopenia, and recurrent and/or complicated infections (PMID: 34222142). Nine variants (missense, nonsense, frameshift, and intragenic deletion) that have been reported in 9 probands in 3 publications (PMIDs: 17080092, 23973892, 40296086) are included in this curation. Segregation of a *XIAP* variant with this disorder in a single family was included as evidence (PMID: 17080092). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function (PMIDs: 17080092, 18055022, 18769721, 23973892, 24611904, 40296086, 42039706). This gene-disease relationship is also supported by animal models, expression studies, and in vitro functional (PMIDs: 17080092, 18055022, 18769721, 24611904, 42039706). *XIAP*-/- mice recapitulate aspects of human disease (PMID: 18769721, 42039706). Patient-derived T- cells display increased susceptibility to apoptosis following stimulation that can be rescued by expression of WT XIAP (PMID: 17080092). Allogeneic hematopoietic stem cell transplant is currently the only curative option for patients with X-linked lymphoproliferative disease due to *XIAP* deficiency (PMIDs: 23131490, 23766462 , 24084330, 24942029, 25412586, 27815752). In summary, there is definitive evidence supporting the relationship between *XIAP* and X-linked lymphoproliferative disease due to XIAP deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time (need to change to other wording if not definitive, according to the ClinGen template). This classification was approved by the ClinGen Primary Immune Regulatory Disorders GCEP on the meeting date July 21, 2026 (SOP Version 12)].
Inheritance Pattern: XL
Disease ID:MONDO:0010385
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0010385
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010385
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Hematologic; Oncologic
Intervention: Allergy/Immunology/Infectious; Hematologic; Oncologic
Rationale: Surveillance for EBV infections is indicated; Prompt recognition and treatment of hemophagocytic lymphohistiocytosis (with immunologic agents or rituximab in the case of EBV infection); Treatment for individuals with hypogammaglobulinemia (with IVIG) may be beneficial; Awareness of the increased risk of lymphoma may allow prompt recognition and treatment; HSCT has been described, and is indicated in many individuals
Comments: Digenic disease (with CD40LG) have been reported
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to XIAP variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001167.4. 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 | 10 | 60 | 3 | 73 | ||
| missense | 2 | 5 | 168 | 22 | 9 | 206 |
| nonsense | 21 | 6 | 9 | 36 | ||
| start loss | 1 | 1 | ||||
| frameshift | 30 | 4 | 1 | 35 | ||
| splice donor/acceptor (+/-2bp) | 4 | 8 | 13 | 25 | ||
| Total | 58 | 23 | 201 | 82 | 12 | 376 |
Highest pathogenic variant AF is 0.000014984929
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001158.2 | 6 | MANE Select | |
| Ensembl | ENSP00000360242.3 | 6 | MANE Select | |
| RefSeq | NP_001191330.1 | 6 | Standard | |
| RefSeq | NP_001365519.1 | 6 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Focal adhesion - Homo sapiens (human)
- Small cell lung cancer - Homo sapiens (human)
- Apoptosis - multiple species - Homo sapiens (human)
- Ubiquitin mediated proteolysis - Homo sapiens (human)
- HTLV-I infection - Homo sapiens (human)
Biological Process
- apoptotic process
- cellular response to DNA damage stimulus
- Wnt signaling pathway
- protein ubiquitination
- regulation of BMP signaling pathway
Molecular Function
- ubiquitin-protein transferase activity
- protein binding
- identical protein binding
- cysteine-type endopeptidase inhibitor activity involved in apoptotic process
- metal ion binding
Cellular Component
- nucleus
- nucleoplasm
- cytoplasm
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000371199
- Coding exons
- 6
- Length
- 54256
- Individuals with no LoFs
- 125724
- Homozygous LoFs
- 1
- Heterozygous LoFs
- 2
- Defined
- 125727
- p
- 0.0000119
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.49 | 123 | 179 | 0.686 | 0.0000127 | 3291 |
| Missense (PolyPhen) | 17 | 53.414 | 0.31827 | 1000 | ||
| Synonymous | 0.912 | 51 | 60.0 | 0.850 | 0.00000417 | 908 |
| Loss of Function | 3.35 | 2 | 16.8 | 0.119 | 0.00000136 | 289 |
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) | 0.000025 | 0.000018 | rare |
| South Asian | 0.000054 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, copper homeostasis, mitogenic kinase signaling, cell proliferation, as well as cell invasion and metastasis. Acts as a direct caspase inhibitor. Directly bind to the active site pocket of CASP3 and CASP7 and obstructs substrate entry. Inactivates CASP9 by keeping it in a monomeric, inactive state. Acts as an E3 ubiquitin-protein ligase regulating NF-kappa-B signaling and the target proteins for its E3 ubiquitin-protein ligase activity include: RIPK1, CASP3, CASP7, CASP8, CASP9, MAP3K2/MEKK2, DIABLO/SMAC, AIFM1, CCS and BIRC5/survivin. Ubiquitinion of CCS leads to enhancement of its chaperone activity toward its physiologic target, SOD1, rather than proteasomal degradation. Ubiquitinion of MAP3K2/MEKK2 and AIFM1 does not lead to proteasomal degradation. Plays a role in copper homeostasis by ubiquitinationg COMMD1 and promoting its proteasomal degradation. Can also function as E3 ubiquitin-protein ligase of the NEDD8 conjugation pathway, targeting effector caspases for neddylation and inactivation. Regulates the BMP signaling pathway and the SMAD and MAP3K7/TAK1 dependent pathways leading to NF-kappa-B and JNK activation. Acts as an important regulator of innate immune signaling via regulation of Nodlike receptors (NLRs). Protects cells from spontaneous formation of the ripoptosome, a large multi-protein complex that has the capability to kill cancer cells in a caspase-dependent and caspase-independent manner. Suppresses ripoptosome formation by ubiquitinating RIPK1 and CASP8. Acts as a positive regulator of Wnt signaling and ubiquitinates TLE1, TLE2, TLE3, TLE4 and AES. Ubiquitination of TLE3 results in inhibition of its interaction with TCF7L2/TCF4 thereby allowing efficient recruitment and binding of the transcriptional coactivator beta- catenin to TCF7L2/TCF4 that is required to initiate a Wnt-specific transcriptional program. {ECO:0000269|PubMed:11447297, ECO:0000269|PubMed:12121969, ECO:0000269|PubMed:14645242, ECO:0000269|PubMed:14685266, ECO:0000269|PubMed:17560374, ECO:0000269|PubMed:17967870, ECO:0000269|PubMed:19473982, ECO:0000269|PubMed:20154138, ECO:0000269|PubMed:21145488, ECO:0000269|PubMed:22103349, ECO:0000269|PubMed:22304967, ECO:0000269|PubMed:9230442}.;
- Disease
- DISEASE: Lymphoproliferative syndrome, X-linked, 2 (XLP2) [MIM:300635]: A rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus (EBV). Symptoms include severe or fatal mononucleosis, acquired hypogammaglobulinemia, pancytopenia and malignant lymphoma. {ECO:0000269|PubMed:17080092}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.245
- RVIS EVS
- 0.02
- RVIS percentile EVS
- 55.22
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.834
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |