# NM_020745.4(AARS2):c.1036C>A (p.Pro346Thr)

https://sugi.bio/variant/aars2-p-pro346thr

## Summary

**AARS2 p.Pro346Thr (c.1036C>A)** is classified **Uncertain significance** in AARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-17). AlphaMissense: likely benign (0.0869); Very rare (popmax 0.00167%, amr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1438347145 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the AARS2 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 | [AARS2](https://sugi.bio/atlas/gene/AARS2/) |
| Protein change (HGVS p.) | p.Pro346Thr |
| Coding change (HGVS c.) | c.1036C>A |
| MANE Select transcript | [NM_020745](https://www.ncbi.nlm.nih.gov/nuccore/NM_020745) |
| dbSNP | [rs1438347145](https://www.ncbi.nlm.nih.gov/snp/rs1438347145/) |
| Variant type | single nucleotide variant |
| Location | chr6:44307253-44307253 (GRCh38) |
| ClinVar | [VCV2969061](https://www.ncbi.nlm.nih.gov/clinvar/variation/2969061/) |

**All HGVS expressions:** `NC_000006.11:g.44274990G>T`, `NC_000006.12:g.44307253G>T`, `NG_028283.4:g.795166G>T`, `NG_031952.1:g.11074C>A`, `NG_031952.2:g.11094C>A`, `NM_020745.4:c.1036C>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** (0.0869)
- REVEL 0.135 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.478 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor gain** (Δ 0.92) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 3.927, GERP -0.33, phastCons 0.999 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 28.3**. 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 0.90** across the covering region of the MANE Select transcript (44,300,550–44,313,323), spanning 12,773 bp. Chi-square p 0.00019. 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 **0.14**, acceptor gain **0.01**, donor gain **0.92**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.01**, donor gain **0.92**.
- Pangolin: Δ**0.73** (gain), gain 0.73 / loss 0.51. 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 **0.00167%** (amr) · 1/59,994 in the highest group · 2/1,461,682 alleles overall — very rare (popmax 0.00167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00167% | 59,994 |
| European (non-Finnish) | 8.47e-05% | 1,179,944 |

*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}

**AARS2** population constraint: LOEUF 0.752, pLI 1.8233e-15, missense-Z 1.8985; 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):

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

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 88.05, 62% of residues very-high.

**3 experimental structure(s)** (PDB): [6NLQ](https://www.rcsb.org/structure/6NLQ), [6NLY](https://www.rcsb.org/structure/6NLY), [6NOW](https://www.rcsb.org/structure/6NOW).

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

*Describes the biological roles of AARS2 (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:** AARS2's established molecular role includes alanine-tRNA ligase activity.


### Pathways affected {#pathways}

AARS2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Mitochondrial tRNA aminoacylation](https://reactome.org/content/detail/R-HSA-379726) | electronic |

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

**Molecular function:** alanine-tRNA ligase activity, peptide lactyltransferase (ATP-dependent) activity.

**Biological process:** mitochondrial alanyl-tRNA aminoacylation, negative regulation of cGAS/STING signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-03-17.

**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 | 2025-03-17 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related AARS2 variant pages (same residue, condition, or type): [AARS2 p.Pro346Leu](/variant/aars2-p-pro346leu), [AARS2 c.2146-2A>G](/variant/aars2-c-2146-minus-2a-g), [AARS2 c.2255+1G>A](/variant/aars2-c-2255-plus-1g-a), [AARS2 c.2598+1G>T](/variant/aars2-c-2598-plus-1g-t), [AARS2 p.Arg199Cys](/variant/aars2-p-arg199cys), [AARS2 p.Arg521Ter](/variant/aars2-p-arg521ter), [AARS2 p.Arg580Trp](/variant/aars2-p-arg580trp), [AARS2 p.Arg592Trp](/variant/aars2-p-arg592trp).

### 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 2969061). 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.*