TREX1
protein-codingthree prime repair exonuclease 1, the group of SET complex|Exonucleases
Gene summary
This gene encodes a nuclear protein with 3' exonuclease activity. The encoded protein may play a role in DNA repair and serve as a proofreading function for DNA polymerase. Mutations in this gene result in Aicardi-Goutieres syndrome, chilblain lupus, Cree encephalitis, and other diseases of the immune system. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2012]
- AGS1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~1.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009165
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0009165
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0012500
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0007915
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0009165
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0700256
Submitter: ClinGen
TREX1 was first reported in relation to autosomal recessive Aicardi-Goutières syndrome (AGS) in 2006 (Crow et al., PMID: 16845398). Other reports of TREX1 variants related to autosomal dominant disorders appeared in 2007 with systemic lupus erythematosus (SLE) (Kirsch et al., PMID 17660816), in 2007 with retinal vasculopathy (Richards et al., PMID 17660820), and in 2015 with chilblain lupus (Rice et al., PMID 25703219). These conditions are considered to be forms of type 1 interferonopathy, which is defined as a condition in which increased type 1 interferon signaling leads to autoimmune and neurological disorders (MONDO:0700260). These disorders are caused by variants in genes involved in nucleic acid metabolism, sensing, and the innate immune response. Individuals with biallelic variants in TREX1 can present with a range of symptoms of variable severity and age of onset, within the context of an autoimmune disease. TREX1-related type 1 interferonopathy can result from biallelic or monoallelic variants in the TREX1 gene. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we identified differences in inheritance patterns that necessitate separate curation of autosomal dominant and autosomal recessive disease entities. In this curation, the autosomal recessive TREX1-related type 1 interferonopathy is treated as a distinct entity due to its specific inheritance pattern and clinical manifestations, separate from the autosomal dominant forms. This curation of autosomal recessive TREX1-related type 1 interferonopathy included three missense, three frameshift, one nonsense, and one in-frame deletion variants reported in seven probands across three publications (PMIDs: 16845398, 31130681, 25138095). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is also supported by mouse models (PMID: 15254239). In summary, definitive evidence supports the relationship between TREX1 and autosomal recessive TREX1-related type 1 interferonopathy, with rigorous and reproducible evidence in research and clinical diagnostic settings. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Leukodystrophy and Leukoencephalopathy GCEP on the meeting date: June 3rd, 2024 SOP Version #10.
Inheritance Pattern: AD
Disease ID:MONDO:0009165
Submitter: PanelApp Australia
Inheritance Pattern: Unknown
Disease ID:MONDO:0007915
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0018866
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008641
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0009165
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0018827
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008641
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0700256
Submitter: ClinGen
TREX1 was first associated with disease in 2006 in autosomal recessive Aicardi-Goutières syndrome (AGS) (Crow et al., PMID: 16845398), a neuroinflammatory disorder characterized by early-onset encephalopathy, microcephaly, intracranial calcifications, and elevated interferon signaling. In 2007, heterozygous TREX1 variants were shown to cause an autosomal dominant form of AGS (PMID: 17660818). Additional heterozygous TREX1 variants have since been associated with other autosomal dominant autoimmune phenotypes, including systemic lupus erythematosus (SLE) (Kirsch et al., PMID: 17660816), familial chilblain lupus (FCL) (Rice et al., PMID: 25703219), and retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCLS) (Richards et al., PMID: 17660820). The TREX1 gene encodes for the major mammalian three prime repair exonuclease 1, a cytosolic 3’→5’ DNA exonuclease that degrades aberrant endogenous DNA derived from replication. TREX1 plays a critical role in preventing accumulation of intracellular DNA and inappropriate activation of the innate immune response. Loss or alteration of TREX1 function results in chronic activation of type I interferon signaling, leading to autoimmune and neuroinflammatory disease. TREX1-related autosomal dominant type I interferonopathy is characterized by immune-mediated neurological and systemic disease driven by chronic activation of interferon signaling. Clinical features vary depending on phenotype but commonly include neuroinflammation, vasculopathy, autoimmune manifestations, and variable neurologic impairment. Individuals with autosomal dominant TREX1 variants may present with chilblain skin lesions, lupus-like autoimmunity, cognitive decline, stroke-like episodes, retinal vasculopathy, and progressive leukoencephalopathy. Unlike classic AGS, autosomal dominant disease often has later onset and prominent vascular and autoimmune features. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, TREX1 disorders demonstrate differences in inheritance pattern, molecular mechanism, and phenotypic variability. TREX1 can cause disease through either biallelic or monoallelic variants, necessitating a separate curation of autosomal recessive and autosomal dominant entities. We elected to split retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCLS) due to its distinct molecular mechanism and phenotype. Aicardi-Goutières syndrome, familial chilblain lupus, and systemic lupus erythematosus are lumped as TREX1-related type I interferonopathies. In this curation, autosomal dominant TREX1-related type I interferonopathy is treated as a distinct disease entity due to its inheritance pattern and overlapping autoimmune-neuroinflammatory features, separately curated from the autosomal recessive TREX1-related type I interferonapathies. This curation of autosomal dominant TREX1-related type 1 interferonopathy included seven missense and two frameshift variants reported in eight probands across four publications (PMIDs: 21270825, 24300241, 32293470, 17660818). 10.5 points of genetic evidence was reached. This gene-disease relationship is also supported by a mouse model (PMID: 30872080) and biochemical function (PMID: 19442247) for a total of 1.5 points. The mouse model capitulates human disease but was downgraded due to the use of homozygous mice. In summary, definitive evidence supports the relationship between TREX1 and autosomal dominant TREX1-related type 1 interferonopathy, with rigorous and reproducible evidence in research and clinical diagnostic settings. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Leukodystrophy and Leukoencephalopathy GCEP on the meeting date: November 5, 2025 SOP Version #11. The Syndromic Disease GCEP contributed to this curation.
Inheritance Pattern: AD
Disease ID:MONDO:0008641
Submitter: ClinGen
Heterozygous variants in TREX1 were first associated with retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCLS) in 2007 (Richards et al., PMID: 17660820). RVCLS is an adult-onset disorder involving the microvessels of the brain and resulting in central nervous system degeneration with progressive loss of vision, stroke, motor impairment, and cognitive decline. TREX1 was first associated with disease in 2006 in autosomal recessive Aicardi-Goutières syndrome (AGS) (Crow et al., PMID: 16845398). In 2007, heterozygous TREX1 variants were shown to cause an autosomal dominant form of AGS (PMID: 17660818). Additional heterozygous TREX1 variants have since been associated with other autosomal dominant autoimmune phenotypes, including systemic lupus erythematosus (SLE) (Kirsch et al., PMID: 17660816) and familial chilblain lupus (FCL) (Rice et al., PMID: 25703219). RVCLS has been classified to be a distinct manifestation of TREX1 variants due to its unique molecular mechanism. The TREX1 gene encodes for the major mammalian three prime repair exonuclease 1, a cytosolic 3’→5’ DNA exonuclease that degrades aberrant endogenous DNA derived from replication. TREX1 plays a critical role in preventing accumulation of intracellular DNA and inappropriate activation of the innate immune response. Frameshift variants in TREX1 at the C terminus of the TREX1 gene are associated with RVCLS, causing protein truncation. Expression studies indicate the truncated proteins retained exonuclease activity but lost normal perinuclear localization. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, TREX1 disorders demonstrate differences in inheritance pattern, molecular mechanism, and phenotypic variability. TREX1 can cause disease through either biallelic or monoallelic variants, necessitating a separate curation of autosomal recessive and autosomal dominant entities. We elected to split retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCLS) due to its distinct molecular mechanism and phenotype. Aicardi-Goutières syndrome, familial chilblain lupus, and systemic lupus erythematosus are lumped as TREX1-related type I interferonopathies. This curation of retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCLS) included six frameshift variants reported in six probands across four publications (PMIDs: 27604306, 27604306, 39119967, 26691497). 11 points of genetic evidence was reached. This gene-disease relationship is also supported by a mouse model that accurately represented human RVCLS (PMID: 38834133) giving a total of 13 pts for genetic and experimental evidence. In summary, definitive evidence supports the relationship between TREX1 and autosomal dominant retinal Vasculopathy with cerebral leukoencephalopathy and systemic manifestations, with rigorous and reproducible evidence in research and clinical diagnostic settings. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Leukodystrophy and Leukoencephalopathy GCEP on the meeting date: November 5, 2025 SOP Version #11. The Syndromic Disease GCEP contributed to this curation.
Inheritance Pattern: AD
Disease ID:MONDO:0008641
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0012500
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008641
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009165
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0012500
Submitter: Genomics England PanelApp
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Dermatologic; Gastrointestinal; Hematologic; Neurologic; Ophthalmologic; Pulmonary
Intervention: Cardiovascular; Pulmonary
Rationale: The condition may include pulmonary hypertension, and awareness may allow surveillance, prompt diagnosis of disease, and management of this sequelae
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TREX1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_033629.6. 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 | 1 | 145 | 3 | 149 | ||
| missense | 4 | 10 | 319 | 10 | 343 | |
| nonsense | 7 | 5 | 3 | 15 | ||
| start loss | 1 | 3 | 4 | |||
| frameshift | 25 | 33 | 16 | 74 | ||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 36 | 50 | 342 | 155 | 3 | 586 |
Highest pathogenic variant AF is 0.0005095822
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_338599.1 | 1 | MANE Select | |
| Ensembl | ENSP00000486676.2 | 1 | MANE Select | |
| RefSeq | NP_009179.2 | 1 | Standard | |
| Ensembl | ENSP00000412404.1 | 1 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Cytosolic DNA-sensing pathway - Homo sapiens (human)
- role of brca1 brca2 and atr in cancer susceptibility
- regulation of cell cycle progression by plk3
- STING mediated induction of host immune responses
- Regulation by TREX1
Biological Process
- blood vessel development
- kidney development
- activation of immune response
- macrophage activation involved in immune response
- lymphoid progenitor cell differentiation
Molecular Function
- magnesium ion binding
- double-stranded DNA binding
- single-stranded DNA binding
- 3'-5'-exodeoxyribonuclease activity
- DNA binding, bending
Cellular Component
- nuclear envelope
- endoplasmic reticulum membrane
- cytosol
- oligosaccharyltransferase complex
- protein-DNA complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000422277
- Coding exons
- 1
- Length
- 2600
- 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 | -0.821 | 240 | 207 | 1.16 | 0.0000118 | 2327 |
| Missense (PolyPhen) | 70 | 66.762 | 1.0485 | 803 | ||
| Synonymous | -1.46 | 108 | 90.3 | 1.20 | 0.00000525 | 884 |
| Loss of Function | 2.07 | 1 | 6.84 | 0.146 | 3.85e-7 | 69 |
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:
- Function
- FUNCTION: Major cellular 3'-to-5' DNA exonuclease which digests single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) with mismatched 3' termini. Prevents cell-intrinsic initiation of autoimmunity. Acts by metabolizing DNA fragments from endogenous retroelements, including L1, LTR and SINE elements. Unless degraded, these DNA fragments accumulate in the cytosol and activate the IFN-stimulatory DNA (ISD) response and innate immune signaling. Prevents chronic ATM-dependent checkpoint activation, by processing ssDNA polynucleotide species arising from the processing of aberrant DNA replication intermediates. Inefficiently degrades oxidized DNA, such as that generated upon antimicrobial reactive oxygen production or upon absorption of UV light. During GZMA-mediated cell death, contributes to DNA damage in concert with NME1. NME1 nicks one strand of DNA and TREX1 removes bases from the free 3' end to enhance DNA damage and prevent DNA end reannealing and rapid repair. {ECO:0000269|PubMed:10391904, ECO:0000269|PubMed:10393201, ECO:0000269|PubMed:16818237, ECO:0000269|PubMed:17293595, ECO:0000269|PubMed:18045533, ECO:0000269|PubMed:23993650}.;
- Disease
- DISEASE: Aicardi-Goutieres syndrome 1 (AGS1) [MIM:225750]: A form of Aicardi-Goutieres syndrome, a genetically heterogeneous disease characterized by cerebral atrophy, leukoencephalopathy, intracranial calcifications, chronic cerebrospinal fluid (CSF) lymphocytosis, increased CSF alpha-interferon, and negative serologic investigations for common prenatal infection. Clinical features as thrombocytopenia, hepatosplenomegaly and elevated hepatic transaminases along with intermittent fever may erroneously suggest an infective process. Severe neurological dysfunctions manifest in infancy as progressive microcephaly, spasticity, dystonic posturing and profound psychomotor retardation. Death often occurs in early childhood. {ECO:0000269|PubMed:16845398, ECO:0000269|PubMed:17293595, ECO:0000269|PubMed:17357087, ECO:0000269|PubMed:17846997, ECO:0000269|PubMed:18045533, ECO:0000269|PubMed:20131292, ECO:0000269|PubMed:20799324, ECO:0000269|PubMed:23979357}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Systemic lupus erythematosus (SLE) [MIM:152700]: A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow. {ECO:0000269|PubMed:17660818, ECO:0000269|PubMed:20131292, ECO:0000269|PubMed:23979357}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Enhanced immune sensing of oxidized DNA may be involved in the phototoxicity experienced by SLE patients. Exposure to UV-light produces DNA oxidative damage. Oxidized DNA being a poor TREX1 substrate, it accumulates in skin, leading to enhanced auto-immune reactivity and eventually skin lesions (PubMed:23993650). {ECO:0000269|PubMed:23993650}.; DISEASE: Chilblain lupus 1 (CHBL1) [MIM:610448]: A rare cutaneous form of lupus erythematosus. Affected individuals present with painful bluish-red papular or nodular lesions of the skin in acral locations precipitated by cold and wet exposure at temperatures less than 10 degrees centigrade. {ECO:0000269|PubMed:17357087, ECO:0000269|PubMed:17440703}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Vasculopathy, retinal, with cerebral leukodystrophy (RVCL) [MIM:192315]: A microvascular endotheliopathy resulting in central nervous system degeneration and retinopathy, with progressive loss of vision, stroke, motor impairment, and cognitive decline. The ocular manifestations are characterized by telangiectasias, microaneurysms and retinal capillary obliteration starting in the macula. Diseased cerebral white matter has prominent small infarcts that often coalesce to pseudotumors. {ECO:0000269|PubMed:17660820}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.205
Intolerance Scores
- LoFtool
- 0.174
- RVIS EVS
- -0.67
- RVIS percentile EVS
- 15.76
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.908
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |