# NM_000030.3(AGXT):c.28_29delinsA (p.Pro10fs)

https://sugi.bio/variant/agxt-p-pro10fs

## Summary

**AGXT p.Pro10fs (c.28_29delinsA)** is classified **Pathogenic** in AGXT (ClinVar, Single submitter, 2 submitters; last evaluated 2023-10-27). No gnomAD frequency available for this variant; Associated with primary hyperoxaluria type 1.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2528738902 · 2 submitters · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the AGXT gene that is reported as disease-causing, but on limited review, submitted by 2 submitters, 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.Pro10fs |
| Coding change (HGVS c.) | c.28_29delinsA |
| MANE Select transcript | [NM_000030](https://www.ncbi.nlm.nih.gov/nuccore/NM_000030) |
| dbSNP | [rs2528738902](https://www.ncbi.nlm.nih.gov/snp/rs2528738902/) |
| Variant type | Indel |
| Location | chr2:240868893-240868894 (GRCh38) |
| ClinVar | [VCV2681160](https://www.ncbi.nlm.nih.gov/clinvar/variation/2681160/) |

**All HGVS expressions:** `NC_000002.11:g.241808310_241808311delinsA`, `NC_000002.12:g.240868893_240868894delinsA`, `NG_008005.1:g.5149_5150delinsA`, `NG_098313.1:g.651_652delinsA`, `NM_000030.3:c.28_29delCCinsA`, `NM_000030.3:c.28_29delinsA`

## 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 3.753, GERP 1.27, phastCons 0.999 — 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 1 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 indel 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}

Residue **10** lies in an α-helix.

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}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-10-27.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2023–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Clinical Biochemistry Laboratory, Health Services Laboratory | Pathogenic | criteria provided, single submitter | curation | 2023-10-27 |
| Chinese Inherited Urolithiasis Consortium, The Affiliated Yantai Yuhuangding Hospital of Qingdao University | Pathogenic | no assertion criteria provided | clinical testing | 2024-08-26 |

## Associated conditions {#conditions}

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

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

## Same-residue context {#hotspot}

Residue **10** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [AGXT p.Pro10Ser](/variant/agxt-p-pro10ser). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related AGXT variant pages (same residue, condition, or type): [AGXT p.Pro10Ala](/variant/agxt-p-pro10ala), [AGXT p.Pro10Thr](/variant/agxt-p-pro10thr), [AGXT p.Pro10Ser](/variant/agxt-p-pro10ser), [AGXT p.Cys173_His174delinsTrpAsn](/variant/agxt-p-cys173-his174delinstrpasn), [AGXT p.Met1Asn](/variant/agxt-p-met1asn), [AGXT c.166-11_166-8delinsTGCATGCAAGAT](/variant/agxt-c-166-minus-11-166-minus-8delinstgcatgcaagat), [AGXT c.680+480_776+69delinsTGAGA](/variant/agxt-c-680-plus-480-776-plus-69delinstgaga), [AGXT p.Ala277fs](/variant/agxt-p-ala277fs).

### 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 2681160). 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.*