# NM_000030.3(AGXT):c.243G>A (p.Ser81=)

https://sugi.bio/variant/agxt-p-ser81

## Summary

**AGXT p.Ser81= (c.243G>A)** is classified **Conflicting classifications of pathogenicity** in AGXT (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-31). Rare (popmax 0.132%, mid); Associated with primary hyperoxaluria type 1.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs145135990 · 4 submitters · 1 linked condition · rare (popmax 0.132%, mid)

## For patients & families {#patients}

This is a change in the AGXT gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 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.Ser81= |
| Coding change (HGVS c.) | c.243G>A |
| MANE Select transcript | [NM_000030](https://www.ncbi.nlm.nih.gov/nuccore/NM_000030) |
| dbSNP | [rs145135990](https://www.ncbi.nlm.nih.gov/snp/rs145135990/) |
| Variant type | single nucleotide variant |
| Location | chr2:240869247-240869247 (GRCh38) |
| ClinVar | [VCV1117136](https://www.ncbi.nlm.nih.gov/clinvar/variation/1117136/) |

**All HGVS expressions:** `NC_000002.11:g.241808664G>A`, `NC_000002.12:g.240869247G>A`, `NG_008005.1:g.5503G>A`, `NM_000030.3:c.243G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.42) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -20, GERP -2.55 — fast-evolving / accelerated position
- CADD: **PHRED 0.409**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.42**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.42**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.132%** (mid) · FAF95 0.0656% · FAF99 0.0478% · 8/6,062 in the highest group · 102/1,613,796 alleles overall — rare (popmax 0.132%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.132% | 758 |
| African / African-American | 0.0666% | 1,501 |
| South Asian | 0.0121% | 8,280 |
| Remaining individuals (not grpmax-eligible) | 0.0112% | 8,929 |
| Admixed American | 0.00333% | 30,006 |
| European (non-Finnish) | 0.00203% | 49,166 |

*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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-31.

**Submitter consensus:** conflicting (3 Likely benign, 1 Uncertain significance).

**Submission history:** 4 submissions (2024–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-05-16 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-31 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-06-25 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Primary hyperoxaluria, type I, not provided, HEPATIC AGT DEFICIENCY, OXALOSIS I, Primary hyperoxaluria type 1, GLYCOLIC ACIDURIA, none provided.

## Same-residue context {#hotspot}

Residue **81** carries **3 other pathogenic ClinVar variants** — a recurrently-mutated position: [AGXT p.Ser81Ter](/variant/agxt-p-ser81ter), [AGXT p.Ser81Leu](/variant/agxt-p-ser81leu), [AGXT p.Ser81Trp](/variant/agxt-p-ser81trp). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related AGXT variant pages (same residue, condition, or type): [AGXT p.Ser81Leu](/variant/agxt-p-ser81leu), [AGXT p.Ser81Trp](/variant/agxt-p-ser81trp), [AGXT p.Ser81Ter](/variant/agxt-p-ser81ter), [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 1117136). 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.*