# NM_020745.4(AARS2):c.1584C>T (p.Phe528=)

https://sugi.bio/variant/aars2-p-phe528

## Summary

**AARS2 p.Phe528= (c.1584C>T)** is classified **Likely benign** in AARS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-30). Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs781363059 · 2 submitters · 1 linked condition · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the AARS2 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to Inborn genetic diseases.

*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.Phe528= |
| Coding change (HGVS c.) | c.1584C>T |
| MANE Select transcript | [NM_020745](https://www.ncbi.nlm.nih.gov/nuccore/NM_020745) |
| dbSNP | [rs781363059](https://www.ncbi.nlm.nih.gov/snp/rs781363059/) |
| Variant type | single nucleotide variant |
| Location | chr6:44304813-44304813 (GRCh38) |
| ClinVar | [VCV1639913](https://www.ncbi.nlm.nih.gov/clinvar/variation/1639913/) |

**All HGVS expressions:** `NC_000006.11:g.44272550G>A`, `NC_000006.12:g.44304813G>A`, `NG_028283.4:g.792726G>A`, `NG_031952.2:g.13534C>T`, `NM_020745.2:c.1584C>T`, `NM_020745.4:c.1584C>T`

## 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 -1.079, GERP -4.45 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 1.188**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.31 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 **0.0165%** (mid) · FAF95 0.00377% · FAF99 0.00345% · 1/6,052 in the highest group · 63/1,614,016 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,052 |
| European (non-Finnish) | 0.00483% | 20,702 |
| Admixed American | 0.00333% | 30,005 |
| African / African-American | 0.00267% | 37,463 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,476 |

*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 gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *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}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-07-30.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2025-01-22 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-07-30 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

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

## Similar variants {#similar}

Related AARS2 variant pages (same residue, condition, or type): [AARS2 p.Arg958Ter](/variant/aars2-p-arg958ter), [AARS2 p.Met1Thr](/variant/aars2-p-met1thr), [AARS2 p.Ala275Val](/variant/aars2-p-ala275val), [AARS2 p.Ala37Thr](/variant/aars2-p-ala37thr), [AARS2 p.Ala566Thr](/variant/aars2-p-ala566thr), [AARS2 p.Ala737Gly](/variant/aars2-p-ala737gly), [AARS2 p.Ala741Thr](/variant/aars2-p-ala741thr), [AARS2 p.Ala9Ser](/variant/aars2-p-ala9ser).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 1639913). 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.*