Is TREX1 p.Pro7Arg (c.20C>G) pathogenic?

TREX1 p.Pro7Arg (c.20C>G) is classified Uncertain significance in TREX1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-13). AlphaMissense: likely benign (0.0837); Very rare (popmax 8.47e-05%, nfe); Associated with retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations.

How common is TREX1 p.Pro7Arg (c.20C>G) in the general population?

TREX1 p.Pro7Arg (c.20C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about TREX1 p.Pro7Arg (c.20C>G)?

AlphaMissense predicts likely benign (score 0.0837) — an in-silico prediction, not a clinical call.

TREX1 p.Pro7Arg

Q: What condition is associated with TREX1 p.Pro7Arg (c.20C>G)?

TREX1 p.Pro7Arg (c.20C>G) is associated with retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations, Aicardi-Goutieres syndrome 1, chilblain lupus 1 (ClinVar).

Q: How is Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations inherited?

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

c.20C>G · rs753028146 · VCV1949577

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0837 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.0837	likely benign
REVEL	0.05	moderately benign-leaning
SaProt	LLR -6.42	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 2	GERP -3.6, phastCons 0.007
Regional constraint	o/e 1.01	unconstrained · MANE · 941 bp · p 0.82 · regional, not allelic
Overall
CADD	19.4	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,990 alleles

Overall 0.000186% 3/1,614,032 alleles · very rare exomes 3/1,461,794 · genomes 0/152,238 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,253
European (non-Finnish)grpmax	8.47e-05%	1,179,990

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: TREX1
Protein: p.Pro7Arg
Coding: c.20C>G
MANE Select: NM_033629
dbSNP: rs753028146
Type: single nucleotide variant
Location: chr3:48466675 (GRCh38)

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

Disease context

retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Aicardi-Goutieres syndrome 1 chilblain lupus 1

For Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

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-pro7arg (accessed [today's date]).

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