# NM_033629.6(TREX1):c.50T>C (p.Phe17Ser)

https://sugi.bio/variant/trex1-p-phe17ser

## Summary

**TREX1 p.Phe17Ser (c.50T>C)** is classified **Uncertain significance** in TREX1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-18). AlphaMissense: likely pathogenic (0.6704); Ultra-rare (popmax 0.0209%, sas); Associated with Aicardi-Goutieres syndrome 1.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs531498263 · 3 submitters · 3 linked conditions · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0209%, sas)

> **Built without this gene's context.** ClinVar files this variant under an overlapping gene, so its own gene's record set does not contain it and this page is assembled from the variant alone. Gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up — absent from this page, not from the data.

## For patients & families {#patients}

This is a change in the TREX1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 submitters, and is linked to Aicardi-Goutieres syndrome 1.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive |
| Age of onset (of this condition) | Antenatal, Infancy, Neonatal |
| Prevalence | 1-5 / 10 000 (Europe) |

**Commonly reported features of Aicardi-Goutières syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Spasticity — Very frequent (99-80%)
- Global developmental delay — Very frequent (99-80%)
- Hypertonia — Very frequent (99-80%)
- Porencephaly — Very frequent (99-80%)
- Arrhinencephaly — Very frequent (99-80%)
- Intellectual disability, profound — Very frequent (99-80%)
- Multifocal cerebral white matter abnormalities — Very frequent (99-80%)
- Convex nasal ridge — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015167/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TREX1](https://sugi.bio/atlas/gene/TREX1/) |
| Protein change (HGVS p.) | p.Phe17Ser |
| Coding change (HGVS c.) | c.50T>C |
| MANE Select transcript | [NM_033629](https://www.ncbi.nlm.nih.gov/nuccore/NM_033629) |
| dbSNP | [rs531498263](https://www.ncbi.nlm.nih.gov/snp/rs531498263/) |
| Variant type | single nucleotide variant |
| Location | chr3:48466705-48466705 (GRCh38) |
| ClinVar | [VCV3029694](https://www.ncbi.nlm.nih.gov/clinvar/variation/3029694/) |

**All HGVS expressions:** `LRG_282:g.5876T>C`, `LRG_282t1:c.50T>C`, `NC_000003.11:g.48508104T>C`, `NC_000003.12:g.48466705T>C`, `NG_009820.2:g.5876T>C`, `NG_033100.1:g.39156A>G`, `NG_033100.2:g.43105A>G`, `NG_041782.1:g.24996T>C`, `NG_099339.1:g.648T>C`, `NM_001271022.2:c.*1151T>C`, `NM_001271023.2:c.*1151T>C`, `NM_007248.5:c.20T>C`, `NM_032166.4:c.*1151T>C`, `NM_033629.6:c.50T>C`, `NM_130384.3:c.*1151T>C`, `NR_153405.1:n.3359T>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.6704)
- REVEL 0.741 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.552 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.782, GERP 1.78, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 25.9**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 1.01** across the covering region of the MANE Select transcript (48,466,656–48,467,597), spanning 941 bp. Chi-square p 0.82. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency (gnomAD v4.1): grpmax **0.0209%** (sas) · FAF95 0.0136% · FAF99 0.0114% · 19/91,080 in the highest group · 21/1,614,082 alleles overall — ultra-rare (popmax 0.0209%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0209% | 4,794 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,253 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-12-18.

**Submitter consensus:** unanimous (3/3 Uncertain significance).

**Submission history:** 3 submissions (2023–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-04-02 |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | no assertion criteria provided | clinical testing | 2023-11-11 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-12-18 |

## Associated conditions {#conditions}

[Aicardi-Goutieres syndrome 1](https://sugi.bio/atlas/disease/aicardi-goutieres-syndrome-1/), [retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations](https://sugi.bio/atlas/disease/retinal-vasculopathy-with-cerebral-leukoencephalopathy-and-systemic-manifestations/), [chilblain lupus 1](https://sugi.bio/atlas/disease/chilblain-lupus-1/).

**Reported phenotype names (ClinVar):** Aicardi-Goutieres syndrome 1, TREX1-related disorder, not specified, Chilblain lupus 1, Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations, TREX1-related condition, TREX1-related disorders, CREE ENCEPHALITIS, ENCEPHALOPATHY, FAMILIAL INFANTILE, WITH INTRACRANIAL CALCIFICATION AND CHRONIC CEREBROSPINAL FLUID LYMPHOCYTOSIS, PSEUDOTOXOPLASMOSIS SYNDROME.

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 3029694). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*