# NM_000274.4(OAT):c.1112dup (p.Arg372fs)

https://sugi.bio/variant/oat-p-arg372fs

## Summary

**OAT p.Arg372fs (c.1112dup)** is classified **Pathogenic/Likely pathogenic** in OAT (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-01-18). Very rare (popmax 0.00017%, nfe); Associated with OAT-related disorder.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs750535638 · 5 submitters · 2 linked conditions · very rare (popmax 0.00017%, nfe)

## For patients & families {#patients}

This is a change in the OAT gene that is considered likely disease-causing, submitted by 5 submitters, and is linked to OAT-related disorder.

*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 | [OAT](https://sugi.bio/atlas/gene/OAT/) |
| Protein change (HGVS p.) | p.Arg372fs |
| Coding change (HGVS c.) | c.1112dup |
| MANE Select transcript | [NM_000274](https://www.ncbi.nlm.nih.gov/nuccore/NM_000274) |
| dbSNP | [rs750535638](https://www.ncbi.nlm.nih.gov/snp/rs750535638/) |
| Variant type | Duplication |
| Location | chr10:124400886-124400887 (GRCh38) |
| ClinVar | [VCV2430383](https://www.ncbi.nlm.nih.gov/clinvar/variation/2430383/) |

**All HGVS expressions:** `LRG_685:g.23064dup`, `LRG_685t1:c.1112dup`, `NC_000010.10:g.126089456dup`, `NC_000010.11:g.124400887dup`, `NG_008861.1:g.23064dup`, `NM_000274.4:c.1112dup`, `NM_001171814.2:c.698dup`, `NM_001322965.2:c.1112dup`, `NM_001322966.2:c.1112dup`, `NM_001322967.2:c.1112dup`, `NM_001322968.2:c.1112dup`, `NM_001322969.2:c.1112dup`, `NM_001322970.2:c.1112dup`, `NM_001322971.2:c.791dup`, `NM_001322974.2:c.512dup`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP -5.622, GERP -4.03 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.968, pLI 2.2793e-07. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **within the last 50 nt of the penultimate exon (9 of 10, 46 nt from its 3' end)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- CADD: **PHRED 27.6**. 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: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00017%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,174,470 in the highest group · 3/1,605,932 alleles overall — very rare (popmax 0.00017%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.00156% | 64,034 |
| European (non-Finnish) (grpmax) | 0.00017% | 587,234 |

Finnish 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}

**OAT** population constraint: LOEUF 0.968, pLI 2.2793e-07, missense-Z 1.6632. *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):

- **ornithine aminotransferase deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **372** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 94.29, 92% of residues very-high.

**35 experimental structure(s)** (PDB): [10LW](https://www.rcsb.org/structure/10LW), [10LX](https://www.rcsb.org/structure/10LX), [12AL](https://www.rcsb.org/structure/12AL), [12AV](https://www.rcsb.org/structure/12AV), [12AX](https://www.rcsb.org/structure/12AX), [12AY](https://www.rcsb.org/structure/12AY) — incl. mutant structure 2BYJ.

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

*Describes the biological roles of OAT (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:** OAT's established molecular role includes L-ornithine transaminase activity.


### Pathways affected {#pathways}

OAT participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Glutamate and glutamine metabolism](https://reactome.org/content/detail/R-HSA-8964539) | curated |

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

**Molecular function:** L-ornithine transaminase activity, identical protein binding.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-01-18.

**Submitter consensus:** conflicting (4 Likely pathogenic, 1 Pathogenic).

**Submission history:** 5 submissions (2019–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-08-25 |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-09-07 |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-05-30 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-01-18 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2019-02-26 |

## Associated conditions {#conditions}

[OAT-related disorder](https://sugi.bio/atlas/disease/oat-related-disorder/), [ornithine aminotransferase deficiency](https://sugi.bio/atlas/disease/ornithine-aminotransferase-deficiency/).

**Reported phenotype names (ClinVar):** OAT-related disorder, not provided, Ornithine aminotransferase deficiency, none provided, OAT-related condition, OKT DEFICIENCY, Ornithine ketoacid aminotransferase deficiency, Gyrate atrophy, Gyrate atrophy of choroid and retina, Girate atrophy of the retina.

## Similar variants {#similar}

Related OAT variant pages (same residue, condition, or type): [OAT p.Tyr299Ter](/variant/oat-p-tyr299ter), [OAT c.199+11_199+16dup](/variant/oat-c-199-plus-11-199-plus-16dup), [OAT p.Ala335fs](/variant/oat-p-ala335fs), [OAT p.Arg331fs](/variant/oat-p-arg331fs), [OAT p.Asn117fs](/variant/oat-p-asn117fs), [OAT p.Lys421delinsTrpTer](/variant/oat-p-lys421delinstrpter), [OAT p.Thr128fs](/variant/oat-p-thr128fs), [OAT p.Trp391fs](/variant/oat-p-trp391fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 2430383). 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.*