Is TREX1 p.Ala139fs (c.416del) pathogenic?

TREX1 p.Ala139fs (c.416del) is classified Pathogenic/Likely pathogenic in TREX1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-17). Very rare (popmax 0.00797%, nfe); Associated with TREX1-related disorder.

How common is TREX1 p.Ala139fs (c.416del) in the general population?

TREX1 p.Ala139fs (c.416del) is very rare (popmax 0.00797%, nfe) (gnomAD).

TREX1 p.Ala139fs

Q: What condition is associated with TREX1 p.Ala139fs (c.416del)?

TREX1 p.Ala139fs (c.416del) is associated with TREX1-related disorder, cerebral arteriopathy with subcortical infarcts and leukoencephalopathy, retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (ClinVar).

c.416del · rs763229085 · VCV843202

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00797%, nfe)

Conditions

TREX1-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 1.8	GERP -2.4, phastCons 1
Overall
CADD	28.8	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00797% European (non-Finnish) · 94/1,180,046 alleles

Filtering AF 0.00664% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00616%

Overall 0.00644% 104/1,613,870 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0144%	6,943
European (non-Finnish)grpmax	0.00797%	12,554
African / African-American	0.00133%	74,944

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.Ala139fs
Coding: c.416del
MANE Select: NM_130384 · reported on NM_033629
dbSNP: rs763229085
Type: Deletion
Location: chr3:48467071 (GRCh38)

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

Disease context

Also linked: cerebral arteriopathy with subcortical infarcts and leukoencephalopathy retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations Aicardi-Goutieres syndrome 1 chilblain lupus 1

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-ala139fs (accessed [today's date]).

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