Is TREX1 p.Ser169Pro (c.505T>C) pathogenic?

TREX1 p.Ser169Pro (c.505T>C) is classified Uncertain significance in TREX1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-15). AlphaMissense: likely benign (0.0682); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

How common is TREX1 p.Ser169Pro (c.505T>C) in the general population?

TREX1 p.Ser169Pro (c.505T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about TREX1 p.Ser169Pro (c.505T>C)?

AlphaMissense predicts likely benign (score 0.0682) — an in-silico prediction, not a clinical call.

TREX1 p.Ser169Pro

Q: What condition is associated with TREX1 p.Ser169Pro (c.505T>C)?

TREX1 p.Ser169Pro (c.505T>C) is associated with Inborn genetic diseases, retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations, Aicardi-Goutieres syndrome 1 (ClinVar).

c.505T>C · rs2040355618 · VCV2937830

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0682 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0682	likely benign
REVEL	0.263	benign-leaning
SaProt	LLR -10.10	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -0.18	GERP -0.76
Regional constraint	o/e 1.01	unconstrained · MANE · 941 bp · p 0.82 · regional, not allelic
Overall
CADD	8.469	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 0.00167% Admixed American · 1/60,020 alleles

Overall 0.000137% 2/1,461,724 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,020
Remaining individualsnot grpmax-eligible	0.0016%	62,510

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.Ser169Pro
Coding: c.505T>C
MANE Select: NM_130384 · reported on NM_033629
dbSNP: rs2040355618
Type: single nucleotide variant
Location: chr3:48467160 (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-ser169pro (accessed [today's date]).

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