TREX1

Chr 3ADAR

three prime repair exonuclease 1

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

NCBI Gene: 11277 ENSG00000213689 UniProt: Q9NSU2 OMIM: 606609

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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 0.694 OMIM phenotypes

Clinical Summary— TREX1

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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

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.58) — some intolerance to loss-of-function variants.

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ClinVar Variants

80 unique Pathogenic / Likely Pathogenic· 353 VUS of 618 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — TREX1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.69LOEUF

pLI 0.575

Z-score 2.07

OE 0.15 (0.05–0.69)

Moderately constrained

Typical tolerance to LoF variation

Missense Constraint?

-0.82Z-score

OE missense 1.16 (1.04–1.29)

240 obs / 206.8 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.15 (0.05–0.69)

0≤0.351.4

Missense OE?1.16 (1.04–1.29)

0≤0.61.4

Synonymous OE?1.20

0≤1.21.6

LoF obs/exp: 1 / 6.8Missense obs/exp: 240 / 206.8Syn Z: -1.46

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveTREX1-related Aicardi-Goutieres syndromeLOFAR

This gene — mechanism propensity

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

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.1

LOFRecombinant mutant TREX1 homodimers are enzymatically inactive, while wild type/mutant heterodimers show residual exonucleolytic activity, suggesting a heterozygous loss of function.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

618 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic36

Likely Pathogenic44

VUS353

Likely Benign145

Benign8

Conflicting29

Pathogenic

Likely Pathogenic

353

VUS

145

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	32	4	0	0	36
Likely Pathogenic	34	9	1	0	44
VUS	18	325	9	1	353
Likely Benign	0	2	5	138	145
Benign	0	0	4	4	8
Conflicting	—				29
Total	84	340	19	143	615

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

9 pathogenic / likely-pathogenic (of 13) ClinVar copy-number / structural variants overlap TREX1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →