TREX1

Chr 3ADAR

three prime repair exonuclease 1

Also known as: AGS1, CRV, DRN3, HERNS, RVCLS

TREX1 encodes a 3'-to-5' DNA exonuclease that degrades cytosolic DNA fragments to prevent inappropriate activation of innate immune signaling pathways. Mutations cause Aicardi-Goutières syndrome (typically early-onset encephalopathy with calcifications and chronic CSF lymphocytosis), chilblain lupus, retinal vasculopathy with cerebral leukoencephalopathy, and systemic lupus erythematosus susceptibility. The gene shows both autosomal dominant and autosomal recessive inheritance patterns.

OMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismAD/ARLOEUF 0.694 OMIM phenotypes
Clinical SummaryTREX1
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Gene-Disease Validity (ClinGen)
TREX1-related type 1 interferonopathy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

3 total gene-disease associations curated

Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.58) — some intolerance to loss-of-function variants.
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Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Moderate LoF intolerance
LoF Constraint
0.69LOEUF
pLI 0.575
Z-score 2.07
OE 0.15 (0.050.69)
Moderately constrained

Typical tolerance to LoF variation

Missense Constraint
-0.82Z-score
OE missense 1.16 (1.041.29)
240 obs / 206.8 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.15 (0.050.69)
00.351.4
Missense OE1.16 (1.041.29)
00.61.4
Synonymous OE1.20
01.21.6
LoF obs/exp: 1 / 6.8Missense obs/exp: 240 / 206.8Syn Z: -1.46
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveTREX1-related Aicardi-Goutieres syndromeLOFAR

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

DN
0.5673th %ile
GOF
0.4875th %ile
LOF
0.4528th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Literature Evidence

GOFIt seems likely that D200N represents a gain-of-function mutation conferring altered substrate specificity, DNA binding, or protein-protein interactions; these would not be detected in the standard TREX1 exonuclease assay.PMID:17357087
LOFRecombinant mutant TREX1 homodimers are enzymatically inactive, while wild type/mutant heterodimers show residual exonucleolytic activity, suggesting a heterozygous loss of function.PMID:17440703

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

TREX1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold
Clinical Literature
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