Is TREX1 p.Ser27Phe (c.80C>T) pathogenic?

TREX1 p.Ser27Phe (c.80C>T) is classified Uncertain significance in TREX1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-29). AlphaMissense: ambiguous (0.3622); Very rare (popmax 0.00329%, sas); Associated with TREX1-related disorder.

How common is TREX1 p.Ser27Phe (c.80C>T) in the general population?

TREX1 p.Ser27Phe (c.80C>T) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about TREX1 p.Ser27Phe (c.80C>T)?

AlphaMissense predicts ambiguous (score 0.3622) — an in-silico prediction, not a clinical call.

TREX1 p.Ser27Phe

Q: What condition is associated with TREX1 p.Ser27Phe (c.80C>T)?

TREX1 p.Ser27Phe (c.80C>T) is associated with TREX1-related disorder, retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations, Aicardi-Goutieres syndrome 1 (ClinVar).

c.80C>T · rs11548268 · VCV1423215

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3622 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Conditions

TREX1-related disorder

Computational evidence

Protein change
AlphaMissense	0.3622	ambiguous
REVEL	0.488	indeterminate
SaProt	LLR -9.97	tolerated
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 5.9	GERP -1.8, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 941 bp · p 0.82 · regional, not allelic
Overall
CADD	30.0	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 0.00329% South Asian · 3/91,084 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000274% 4/1,461,766 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,361
European (non-Finnish)	8.47e-05%	1,180,030

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.Ser27Phe
Coding: c.80C>T
MANE Select: NM_130384 · reported on NM_033629
dbSNP: rs11548268
Type: single nucleotide variant
Location: chr3:48466735 (GRCh38)

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

Disease context

Also linked: 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-ser27phe (accessed [today's date]).

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