# NM_000030.3(AGXT):c.386_395del (p.Asp129fs)

https://sugi.bio/variant/agxt-p-asp129fs

## Summary

**AGXT p.Asp129fs (c.386_395del)** is classified **Likely pathogenic** in AGXT (ClinVar, Single submitter, 1 submitter). No gnomAD frequency available for this variant; Associated with primary hyperoxaluria type 1.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2528742910 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the AGXT gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to primary hyperoxaluria type 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 recessive |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-9 / 1 000 000 (Germany) |
| Clinical trials | 20 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | AGXT is a diagnostic-grade gene on 8 Genomics England panels |

**Commonly reported features of Primary hyperoxaluria** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hyperoxaluria — Very frequent (99-80%)
- Calcium oxalate nephrolithiasis — Very frequent (99-80%)
- Nephrocalcinosis — Frequent (79-30%)
- Abnormality of the dentition — Frequent (79-30%)
- Retinopathy — Frequent (79-30%)
- Optic disc pallor — Frequent (79-30%)
- Optic atrophy — Frequent (79-30%)
- Hematuria — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002835/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [AGXT](https://sugi.bio/atlas/gene/AGXT/) |
| Protein change (HGVS p.) | p.Asp129fs |
| Coding change (HGVS c.) | c.386_395del |
| MANE Select transcript | [NM_000030](https://www.ncbi.nlm.nih.gov/nuccore/NM_000030) |
| dbSNP | [rs2528742910](https://www.ncbi.nlm.nih.gov/snp/rs2528742910/) |
| Variant type | Deletion |
| Location | chr2:240870668-240870677 (GRCh38) |
| ClinVar | [VCV2584994](https://www.ncbi.nlm.nih.gov/clinvar/variation/2584994/) |

**All HGVS expressions:** `NC_000002.11:g.241810088_241810097del`, `NC_000002.12:g.240870671_240870680del`, `NG_008005.1:g.6927_6936del`, `NM_000030.3:c.386_395del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 10.644, GERP 1.07, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.251, pLI 2.0059e-14. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 11**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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.*

## Gene constraint & dosage {#gene-context}

**AGXT** population constraint: LOEUF 1.251, pLI 2.0059e-14, missense-Z -0.48001; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **alanine glyoxylate aminotransferase deficiency** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 98.30, 98% of residues very-high.

**17 experimental structure(s)** (PDB): [1H0C](https://www.rcsb.org/structure/1H0C), [1J04](https://www.rcsb.org/structure/1J04), [2YOB](https://www.rcsb.org/structure/2YOB), [3R9A](https://www.rcsb.org/structure/3R9A), [4CBR](https://www.rcsb.org/structure/4CBR), [4CBS](https://www.rcsb.org/structure/4CBS) — incl. mutant structure 4CBR.

## What this gene does {#gene-function}

*Describes the biological roles of AGXT (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** AGXT's established molecular role includes L-serine:pyruvate transaminase activity.


### Pathways affected {#pathways}

AGXT participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Glyoxylate metabolism and glycine degradation](https://reactome.org/content/detail/R-HSA-389661) | curated |
| [Peroxisomal protein import](https://reactome.org/content/detail/R-HSA-9033241) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** L-serine:pyruvate transaminase activity, L-alanine:glyoxylate transaminase activity, transaminase activity, amino acid binding, pyridoxal phosphate binding, identical protein binding.

**Biological process:** L-serine metabolic process, glyoxylate catabolic process, obsolete glycine biosynthetic process, by transamination of glyoxylate, L-cysteine catabolic process, L-alanine catabolic process, glyoxylate metabolic process.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Neuberg Centre For Genomic Medicine, NCGM | Likely pathogenic | criteria provided, single submitter | clinical testing |  |

## Associated conditions {#conditions}

[primary hyperoxaluria type 1](https://sugi.bio/atlas/disease/primary-hyperoxaluria-type-1/).

**Reported phenotype names (ClinVar):** Primary hyperoxaluria, type I, GLYCOLIC ACIDURIA, HEPATIC AGT DEFICIENCY, OXALOSIS I, Primary hyperoxaluria type 1.

## Similar variants {#similar}

Related AGXT variant pages (same residue, condition, or type): [AGXT p.Asp129His](/variant/agxt-p-asp129his), [AGXT c.359-1_382del](/variant/agxt-c-359-minus-1-382del), [AGXT c.424-66_425del](/variant/agxt-c-424-minus-66-425del), [AGXT c.679_680+2del](/variant/agxt-c-679-680-plus-2del), [AGXT p.Ala325fs](/variant/agxt-p-ala325fs), [AGXT p.Gln110fs](/variant/agxt-p-gln110fs), [AGXT p.Gln145fs](/variant/agxt-p-gln145fs), [AGXT p.Leu151fs](/variant/agxt-p-leu151fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 2584994). 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.*