# NM_000030.3(AGXT):c.353G>C (p.Arg118Pro)

https://sugi.bio/variant/agxt-p-arg118pro

## Summary

**AGXT p.Arg118Pro (c.353G>C)** is classified **Uncertain significance** in AGXT (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-27). AlphaMissense: likely pathogenic (0.9694); Absent from gnomAD v4.1; Associated with primary hyperoxaluria type 1.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs138025751 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the AGXT gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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.Arg118Pro |
| Coding change (HGVS c.) | c.353G>C |
| MANE Select transcript | [NM_000030](https://www.ncbi.nlm.nih.gov/nuccore/NM_000030) |
| dbSNP | [rs138025751](https://www.ncbi.nlm.nih.gov/snp/rs138025751/) |
| Variant type | single nucleotide variant |
| Location | chr2:240869357-240869357 (GRCh38) |
| ClinVar | [VCV2664122](https://www.ncbi.nlm.nih.gov/clinvar/variation/2664122/) |

**All HGVS expressions:** `NC_000002.11:g.241808774G>C`, `NC_000002.12:g.240869357G>C`, `NG_008005.1:g.5613G>C`, `NM_000030.3:c.353G>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** (0.9694)
- REVEL 0.905 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -16.399 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.314, GERP 1.27, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 1%** most-pathogenic-predicted substitutions in AGXT (of 2,301 modeled).
- CADD: **PHRED 29.1**. 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 1.00** across the covering region of the MANE Select transcript (240,868,866–240,878,818), spanning 9,952 bp. Chi-square p 0.92. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **118** 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}

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

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Rare Kidney Stone Consortium and the Mayo Clinic Hyperoxaluria Center, Mayo Clinic | Uncertain significance | criteria provided, single submitter | curation | 2023-10-27 |

## 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 **118** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [AGXT p.Arg118His](/variant/agxt-p-arg118his), [AGXT p.Arg118Ser](/variant/agxt-p-arg118ser). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related AGXT variant pages (same residue, condition, or type): [AGXT p.Arg118His](/variant/agxt-p-arg118his), [AGXT p.Arg118Ser](/variant/agxt-p-arg118ser), [AGXT p.Arg118Cys](/variant/agxt-p-arg118cys), [AGXT c.358+1G>A](/variant/agxt-c-358-plus-1g-a), [AGXT c.359-2A>G](/variant/agxt-c-359-minus-2a-g), [AGXT c.423+1G>A](/variant/agxt-c-423-plus-1g-a), [AGXT c.524+2T>A](/variant/agxt-c-524-plus-2t-a), [AGXT c.525-1G>A](/variant/agxt-c-525-minus-1g-a).

### 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 2664122). 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.*