# NM_001605.3(AARS1):c.743dup (p.Ser249fs)

https://sugi.bio/variant/aars1-p-ser249fs

## Summary

**AARS1 p.Ser249fs (c.743dup)** is classified **Pathogenic** in AARS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-03). Very rare (popmax 0.00178%, nfe); Associated with Charcot-Marie-Tooth disease type 2.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 0.00178%, nfe)

## For patients & families {#patients}

This is a change in the AARS1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Charcot-Marie-Tooth disease type 2.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012431/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [AARS1](https://sugi.bio/atlas/gene/AARS1/) |
| Protein change (HGVS p.) | p.Ser249fs |
| Coding change (HGVS c.) | c.743dup |
| MANE Select transcript | [NM_001605](https://www.ncbi.nlm.nih.gov/nuccore/NM_001605) |
| Variant type | Duplication |
| Location | chr16:70270268-70270269 (GRCh38) |
| ClinVar | [VCV3605723](https://www.ncbi.nlm.nih.gov/clinvar/variation/3605723/) |

**All HGVS expressions:** `LRG_359:g.24241dup`, `LRG_359t1:c.743dup`, `NC_000016.10:g.70270269dup`, `NC_000016.9:g.70304172dup`, `NG_023191.1:g.24241dup`, `NM_001605.3:c.743dup`

## 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 -0.479, GERP -3.32, phastCons 0.031 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.772, pLI 4.04e-14. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 6 of 21**, so the transcript is predicted to undergo NMD.
- 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 **0.00178%** (nfe) · FAF95 0.00114% · FAF99 0.000971% · 21/1,180,024 in the highest group · 22/1,461,876 alleles overall — very rare (popmax 0.00178%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00178% | 56,192 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,510 |

*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}

**AARS1** population constraint: LOEUF 0.772, pLI 4.04e-14, missense-Z 1.0453; ClinGen dosage — haploinsufficiency 0, triplosensitivity 0 (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):

- **AARS1-related leukoencephalopathy** — Limited (AD)
- **developmental and epileptic encephalopathy, 29** — Definitive (AR)
- **Charcot-Marie-Tooth disease axonal type 2N** — Definitive (AD)

## Protein context {#protein}

Residue **249** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 90.66, 70% of residues very-high.

**10 experimental structure(s)** (PDB): [4XEM](https://www.rcsb.org/structure/4XEM), [4XEO](https://www.rcsb.org/structure/4XEO), [5KNN](https://www.rcsb.org/structure/5KNN), [5T5S](https://www.rcsb.org/structure/5T5S), [5T76](https://www.rcsb.org/structure/5T76), [5V59](https://www.rcsb.org/structure/5V59).

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

*Describes the biological roles of AARS1 (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:** AARS1's established molecular role includes aminoacyl-tRNA deacylase activity.


### Pathways affected {#pathways}

AARS1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cytosolic tRNA aminoacylation](https://reactome.org/content/detail/R-HSA-379716) | other |

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

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

**Biological process:** alanyl-tRNA aminoacylation, positive regulation of hippo signaling, negative regulation of signal transduction by p53 class mediator.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-11-03.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-11-03 |

## Associated conditions {#conditions}

[Charcot-Marie-Tooth disease type 2](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease-type-2/).

**Reported phenotype names (ClinVar):** Charcot-Marie-Tooth disease type 2, Charcot-Marie-Tooth type 2.

## Similar variants {#similar}

Related AARS1 variant pages (same residue, condition, or type): [AARS1 c.2722-28_2740dup](/variant/aars1-c-2722-minus-28-2740dup), [AARS1 p.Gln541fs](/variant/aars1-p-gln541fs), [AARS1 p.Leu877fs](/variant/aars1-p-leu877fs), [AARS1 p.Thr38fs](/variant/aars1-p-thr38fs), [AARS1 p.Tyr497Ter](/variant/aars1-p-tyr497ter), [AARS1 p.Pro693_Val694insAspPro](/variant/aars1-p-pro693-val694insasppro), [AARS1 c.144+12dup](/variant/aars1-c-144-plus-12dup), [AARS1 c.2178-4dup](/variant/aars1-c-2178-minus-4dup).

### 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 3605723). 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.*