Is TREX1 p.Lys66= (c.198G>A) pathogenic?

TREX1 p.Lys66= (c.198G>A) is classified Benign/Likely benign in TREX1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-03). Low-frequency (popmax 1.57%, afr); Associated with retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations.

How common is TREX1 p.Lys66= (c.198G>A) in the general population?

TREX1 p.Lys66= (c.198G>A) is low-frequency (popmax 1.57%, afr) (gnomAD).

TREX1 p.Lys66=

Q: What condition is associated with TREX1 p.Lys66= (c.198G>A)?

TREX1 p.Lys66= (c.198G>A) 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.198G>A · rs3135943 · VCV345774

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.57%, afr)

Conditions

retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 3.9	GERP -0.56, phastCons 1
Overall
CADD	7.928	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.57% African / African-American · 1,176/75,052 alleles

Filtering AF 1.49% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.46%

Overall 0.0823% 1,328/1,613,888 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.57%	64
Remaining individualsnot grpmax-eligible	0.117%	856
Admixed American	0.107%	938
Middle Eastern	0.0165%	6,062
South Asian	0.00549%	18,217
European (non-Finnish)	0.000763%	131,115

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.Lys66=
Coding: c.198G>A
MANE Select: NM_130384 · reported on NM_033629
dbSNP: rs3135943
Type: single nucleotide variant
Location: chr3:48466853 (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-lys66 (accessed [today's date]).

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