Is TREX1 p.Pro48Arg (c.143C>G) pathogenic?

TREX1 p.Pro48Arg (c.143C>G) is classified Uncertain significance in TREX1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-22). AlphaMissense: likely benign (0.0804); Absent from gnomAD v4.1; Associated with Aicardi-Goutieres syndrome 1.

What condition is associated with TREX1 p.Pro48Arg (c.143C>G)?

TREX1 p.Pro48Arg (c.143C>G) is associated with Aicardi-Goutieres syndrome 1, retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations, chilblain lupus 1 (ClinVar).

How common is TREX1 p.Pro48Arg (c.143C>G) in the general population?

TREX1 p.Pro48Arg (c.143C>G) is absent from gnomAD v4.1 (gnomAD).

How is Aicardi-Goutières syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TREX1 p.Pro48Arg (c.143C>G)?

AlphaMissense predicts likely benign (score 0.0804) — an in-silico prediction, not a clinical call.

TREX1 p.Pro48Arg

c.143C>G · rs2040328677 · VCV2936701

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0804 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Aicardi-Goutieres syndrome 1

Computational evidence

Protein change
AlphaMissense	0.0804	likely benign
REVEL	0.23	benign-leaning
SaProt	LLR -8.38	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -2.2, phastCons 0.027
Regional constraint	o/e 1.01	unconstrained · MANE · 941 bp · p 0.82 · regional, not allelic
Overall
CADD	15.04	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TREX1
Protein: p.Pro48Arg
Coding: c.143C>G
MANE Select: NM_033629
dbSNP: rs2040328677
Type: single nucleotide variant
Location: chr3:48466798 (GRCh38)
Gene constraint: LOEUF 1.265 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.03 · 12 PDB
Residue 48: an α-helix

Full TREX1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Aicardi-Goutieres syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations chilblain lupus 1

For Aicardi-Goutières syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Antenatal, Infancy, Neonatal
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

TREX1 p.Pro48Leu Uncertain significance ★ ⚠ same residue
TREX1 p.Ala150Thr Uncertain significance ★★ ⚠ same condition
TREX1 p.Ala43Thr Uncertain significance ★★ ⚠ same condition
TREX1 p.Asp130Asn Uncertain significance ★★ ⚠ same condition
TREX1 p.Gln209His Uncertain significance ★★ same condition
TREX1 p.Gln28His Uncertain significance ★★ ⚠ same condition
TREX1 p.Ile84Val Uncertain significance ★★ same condition
TREX1 p.Leu69Pro Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/trex1-p-pro48arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown