# NM_000030.3(AGXT):c.355A>G (p.Ile119Val)

https://sugi.bio/variant/agxt-p-ile119val

## Summary

**AGXT p.Ile119Val (c.355A>G)** is classified **Uncertain significance** in AGXT (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-31). AlphaMissense: likely benign (0.0964); Very rare (popmax 0.000429%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2106427685 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.000429%, nfe)

## 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.

*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 | [AGXT](https://sugi.bio/atlas/gene/AGXT/) |
| Protein change (HGVS p.) | p.Ile119Val |
| Coding change (HGVS c.) | c.355A>G |
| MANE Select transcript | [NM_000030](https://www.ncbi.nlm.nih.gov/nuccore/NM_000030) |
| dbSNP | [rs2106427685](https://www.ncbi.nlm.nih.gov/snp/rs2106427685/) |
| Variant type | single nucleotide variant |
| Location | chr2:240869359-240869359 (GRCh38) |
| ClinVar | [VCV1677853](https://www.ncbi.nlm.nih.gov/clinvar/variation/1677853/) |

**All HGVS expressions:** `NC_000002.11:g.241808776A>G`, `NC_000002.12:g.240869359A>G`, `NG_008005.1:g.5615A>G`, `NM_000030.3:c.355A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0964)
- REVEL 0.447 (indeterminate)
- SaProt LLR -5.948 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- SpliceAI predicts **donor gain** (Δ 0.25) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 0.741, GERP -2.55, phastCons 0.008 — weakly conserved position
- CADD: **PHRED 11.75**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.01**, acceptor gain **0.00**, donor gain **0.25**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.01**, acceptor gain **0.00**, donor gain **0.25**.
- Population frequency (gnomAD v4.1): grpmax **0.000429%** (nfe) · FAF95 0.000126% · FAF99 9.1e-05% · 5/1,166,820 in the highest group · 6/1,437,376 alleles overall — very rare (popmax 0.000429%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00162% | 61,628 |
| European (non-Finnish) (grpmax) | 0.000429% | 233,364 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-01-31.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| AiLife Diagnostics, AiLife Diagnostics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-01-31 |

**Reported phenotype names (ClinVar):** not provided, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

## Similar variants {#similar}

Related AGXT variant pages (same residue, condition, or type): [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), [AGXT c.525-2A>T](/variant/agxt-c-525-minus-2a-t), [AGXT c.595+1G>T](/variant/agxt-c-595-plus-1g-t), [AGXT c.596-2A>G](/variant/agxt-c-596-minus-2a-g).

### 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 1677853). 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.*