Is TREX1 p.Leu134Phe (c.400C>T) pathogenic?

TREX1 p.Leu134Phe (c.400C>T) is classified Uncertain significance in TREX1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-25). AlphaMissense: likely benign (0.2714); Very rare (popmax 0.00769%, sas); Associated with Inborn genetic diseases.

What condition is associated with TREX1 p.Leu134Phe (c.400C>T)?

TREX1 p.Leu134Phe (c.400C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TREX1 p.Leu134Phe (c.400C>T) in the general population?

TREX1 p.Leu134Phe (c.400C>T) is very rare (popmax 0.00769%, sas) (gnomAD).

What do computational predictors say about TREX1 p.Leu134Phe (c.400C>T)?

AlphaMissense predicts likely benign (score 0.2714) — an in-silico prediction, not a clinical call.

TREX1 p.Leu134Phe

c.400C>T · rs878853087 · VCV235656

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2714 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00769%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2714	likely benign
REVEL	0.84	moderately pathogenic-leaning
SaProt	LLR -10.54	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 3.9	GERP 1.8, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 941 bp · p 0.82 · regional, not allelic
Overall
CADD	28.8	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00769% South Asian · 7/91,086 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.000434% 7/1,613,886 alleles · very rare

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.Leu134Phe
Coding: c.400C>T
MANE Select: NM_130384 · reported on NM_033629
dbSNP: rs878853087
Type: single nucleotide variant
Location: chr3:48467055 (GRCh38)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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-leu134phe (accessed [today's date]).

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