# NM_031900.4(AGXT2):c.101G>A (p.Arg34Gln)

https://sugi.bio/variant/agxt2-p-arg34gln

## Summary

**AGXT2 p.Arg34Gln (c.101G>A)** is classified **Uncertain significance** in AGXT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-04). AlphaMissense: likely benign (0.074); Very rare (popmax 0.00401%, afr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00401%, afr)

## For patients & families {#patients}

This is a change in the AGXT2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [AGXT2](https://sugi.bio/atlas/gene/AGXT2/) |
| Protein change (HGVS p.) | p.Arg34Gln |
| Coding change (HGVS c.) | c.101G>A |
| MANE Select transcript | [NM_031900](https://www.ncbi.nlm.nih.gov/nuccore/NM_031900) |
| Variant type | single nucleotide variant |
| Location | chr5:35040651-35040651 (GRCh38) |
| ClinVar | [VCV4253724](https://www.ncbi.nlm.nih.gov/clinvar/variation/4253724/) |

**All HGVS expressions:** `NC_000005.10:g.35040651C>T`, `NC_000005.9:g.35040756C>T`, `NM_001306173.2:c.101G>A`, `NM_001438050.1:c.101G>A`, `NM_001438583.1:c.98G>A`, `NM_001438584.1:c.101G>A`, `NM_001438585.1:c.-99-1143G>A`, `NM_031900.4:c.101G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.074)
- REVEL 0.181 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.07 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor loss** (Δ 0.28) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 2.199, GERP 0.79, phastCons 0.997 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 18.76**. 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 1.04** across the covering region of the MANE Select transcript (34,998,722–35,047,892), spanning 49,170 bp. Chi-square p 0.33. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.28**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.28**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.29** (loss), gain 0.01 / loss 0.29. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00401%** (afr) · FAF95 0.00256% · FAF99 0.00225% · 3/74,868 in the highest group · 47/1,613,532 alleles overall — very rare (popmax 0.00401%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00401% | 24,956 |
| European (non-Finnish) | 0.00339% | 29,491 |
| Admixed American | 0.00333% | 30,002 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,234 |

*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}

**AGXT2** population constraint: LOEUF 1.185, pLI 1.3802e-18, missense-Z 0.075848. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 91.02, 87% of residues very-high.

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

*Describes the biological roles of AGXT2 (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:** AGXT2's established molecular role includes L-alanine:glyoxylate transaminase activity.


### Pathways affected {#pathways}

AGXT2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Glyoxylate metabolism and glycine degradation](https://reactome.org/content/detail/R-HSA-389661) | curated |
| [Pyrimidine catabolism](https://reactome.org/content/detail/R-HSA-73621) | electronic |

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

**Molecular function:** L-alanine:glyoxylate transaminase activity, (R)-3-amino-2-methylpropionate:pyruvate transaminase activity.

**Biological process:** glyoxylate catabolic process, obsolete glycine biosynthetic process, by transamination of glyoxylate, obsolete L-alanine catabolic process, by transamination, positive regulation of nitric oxide biosynthetic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-04.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-04 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related AGXT2 variant pages (same residue, condition, or type): [AGXT2 p.Arg34Leu](/variant/agxt2-p-arg34leu), [AGXT2 c.1188+1G>A](/variant/agxt2-c-1188-plus-1g-a), [AGXT2 p.Arg133Cys](/variant/agxt2-p-arg133cys), [AGXT2 p.Arg242Gln](/variant/agxt2-p-arg242gln), [AGXT2 p.Tyr203=](/variant/agxt2-p-tyr203), [AGXT2 p.Val116=](/variant/agxt2-p-val116), [AGXT2 p.Ala183Val](/variant/agxt2-p-ala183val), [AGXT2 p.Ala306Gly](/variant/agxt2-p-ala306gly).

### 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 4253724). 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.*