Is TREX1 p.Phe100Ser (c.299T>C) pathogenic?

TREX1 p.Phe100Ser (c.299T>C) is classified Uncertain significance in TREX1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-08). AlphaMissense: likely pathogenic (0.8967); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

How common is TREX1 p.Phe100Ser (c.299T>C) in the general population?

TREX1 p.Phe100Ser (c.299T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about TREX1 p.Phe100Ser (c.299T>C)?

AlphaMissense predicts likely pathogenic (score 0.8967) — an in-silico prediction, not a clinical call.

TREX1 p.Phe100Ser

Q: What condition is associated with TREX1 p.Phe100Ser (c.299T>C)?

TREX1 p.Phe100Ser (c.299T>C) is associated with Inborn genetic diseases, retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations, Aicardi-Goutieres syndrome 1 (ClinVar).

c.299T>C · rs757909936 · VCV593834

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8967 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

⚠ 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	0.8967	likely pathogenic
REVEL	0.753	pathogenic-leaning
SaProt	LLR -14.80	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.8	GERP 1.8, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 941 bp · p 0.82 · regional, not allelic
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00133% African / African-American · 1/74,932 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000744% 12/1,611,976 alleles · very rare exomes 11/1,459,794 · genomes 1/152,182 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,932
European (non-Finnish)	0.000932%	107,274

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.Phe100Ser
Coding: c.299T>C
MANE Select: NM_033629
dbSNP: rs757909936
Type: single nucleotide variant
Location: chr3:48466954 (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

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-phe100ser (accessed [today's date]).

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