# NM_002080.4(GOT2):c.247G>T (p.Ala83Ser)

https://sugi.bio/variant/got2-p-ala83ser

## Summary

**GOT2 p.Ala83Ser (c.247G>T)** is classified **Uncertain significance** in GOT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-25). AlphaMissense: likely benign (0.3095); Ultra-rare (popmax 0.0167%, amr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs139272931 · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0167%, amr)

## For patients & families {#patients}

This is a change in the GOT2 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 | [GOT2](https://sugi.bio/atlas/gene/GOT2/) |
| Protein change (HGVS p.) | p.Ala83Ser |
| Coding change (HGVS c.) | c.247G>T |
| MANE Select transcript | [NM_002080](https://www.ncbi.nlm.nih.gov/nuccore/NM_002080) |
| dbSNP | [rs139272931](https://www.ncbi.nlm.nih.gov/snp/rs139272931/) |
| Variant type | single nucleotide variant |
| Location | chr16:58722278-58722278 (GRCh38) |
| ClinVar | [VCV1933187](https://www.ncbi.nlm.nih.gov/clinvar/variation/1933187/) |

**All HGVS expressions:** `NC_000016.10:g.58722278C>A`, `NC_000016.9:g.58756182C>A`, `NM_001286220.2:c.246+1468G>T`, `NM_002080.4:c.247G>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.3095)
- REVEL 0.823 (moderately pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -12.306 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** REVEL and SaProt call this damaging; AlphaMissense does not
- Conservation: phyloP 7.546, GERP 1.68, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 34.0**. 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 0.77** across the covering region of the MANE Select transcript (58,708,174–58,734,228), spanning 26,054 bp. Chi-square p 4.2e-08. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.22 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0167%** (amr) · FAF95 0.009% · FAF99 0.00681% · 10/60,002 in the highest group · 14/1,613,184 alleles overall — ultra-rare (popmax 0.0167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0167% | 6,000 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,470 |
| European (non-Finnish) | 0.000254% | 393,120 |

*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}

**GOT2** population constraint: LOEUF 0.591, pLI 0.49396, missense-Z 1.7443. *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):

- **mitochondrial disease** — Moderate (AR)

## Protein context {#protein}

Residue **83** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 94.77, 92% of residues very-high.

**3 experimental structure(s)** (PDB): [5AX8](https://www.rcsb.org/structure/5AX8), [8SKR](https://www.rcsb.org/structure/8SKR), [9YB6](https://www.rcsb.org/structure/9YB6).

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

*Describes the biological roles of GOT2 (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:** GOT2's established molecular role includes RNA binding.


### Pathways affected {#pathways}

GOT2 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Aspartate and asparagine metabolism](https://reactome.org/content/detail/R-HSA-8963693) | curated |
| [Glutamate and glutamine metabolism](https://reactome.org/content/detail/R-HSA-8964539) | curated |
| [Glyoxylate metabolism and glycine degradation](https://reactome.org/content/detail/R-HSA-389661) | curated |
| [Malate-aspartate shuttle](https://reactome.org/content/detail/R-HSA-9856872) | curated |
| [Degradation of cysteine and homocysteine](https://reactome.org/content/detail/R-HSA-1614558) | electronic |

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

**Molecular function:** RNA binding, L-aspartate:2-oxoglutarate transaminase activity.

**Biological process:** L-aspartate catabolic process, fatty acid transport, malate-aspartate shuttle, response to ethanol.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-05-25.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-05-25 |

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

## Similar variants {#similar}

Related GOT2 variant pages (same residue, condition, or type): [GOT2 p.Arg262Gly](/variant/got2-p-arg262gly), [GOT2 p.Gly366Val](/variant/got2-p-gly366val), [GOT2 p.Ala89Ser](/variant/got2-p-ala89ser), [GOT2 p.Arg325Gln](/variant/got2-p-arg325gln), [GOT2 p.Asp190Val](/variant/got2-p-asp190val), [GOT2 p.Asp197Asn](/variant/got2-p-asp197asn), [GOT2 p.Gln357Glu](/variant/got2-p-gln357glu), [GOT2 p.Gln372Arg](/variant/got2-p-gln372arg).

### 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 1933187). 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.*