# NM_004539.4(NARS1):c.1460C>T (p.Ala487Val)

https://sugi.bio/variant/nars1-p-ala487val

## Summary

**NARS1 p.Ala487Val (c.1460C>T)** is classified **Likely pathogenic** in NARS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-23). AlphaMissense: likely benign (0.161); Absent from gnomAD v4.1; Associated with neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the NARS1 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018535/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [NARS1](https://sugi.bio/atlas/gene/NARS1/) |
| Protein change (HGVS p.) | p.Ala487Val |
| Coding change (HGVS c.) | c.1460C>T |
| MANE Select transcript | [NM_004539](https://www.ncbi.nlm.nih.gov/nuccore/NM_004539) |
| Variant type | single nucleotide variant |
| Location | chr18:57602410-57602410 (GRCh38) |
| ClinVar | [VCV4538542](https://www.ncbi.nlm.nih.gov/clinvar/variation/4538542/) |

**All HGVS expressions:** `NC_000018.10:g.57602410G>A`, `NC_000018.9:g.55269642G>A`, `NM_004539.4:c.1460C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — AlphaMissense predicts likely-benign.

- AlphaMissense **likely benign** (0.161) — ⚠ discordant with the pathogenic call
- REVEL 0.371 (indeterminate)
- SaProt LLR -10.795 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate
- SpliceAI predicts **donor gain** (Δ 0.93) — consistent with the pathogenic call
- Conservation: phyloP 5.18, GERP 1.89, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.1**. 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 0.96** across the covering region of the MANE Select transcript (57,601,655–57,621,717), spanning 20,062 bp. Chi-square p 0.34. 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 **0.01**, acceptor gain **0.00**, donor gain **0.93**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.01**, acceptor gain **0.00**, donor gain **0.93**.
- Pangolin: Δ**0.83** (gain), gain 0.83 / loss 0.00. 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**NARS1** population constraint: LOEUF 0.919, pLI 3.2746e-12, missense-Z 0.77292. *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):

- **neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities** — Moderate (AD)
- **neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities** — Moderate (AR)

## Protein context {#protein}

Residue **487** lies in a UniProt-annotated variant site (in nedmilg); an α-helix.

AlphaFold model confidence (whole protein): pLDDT 93.96, 81% of residues very-high.

**6 experimental structure(s)** (PDB): [4ZYA](https://www.rcsb.org/structure/4ZYA), [5XIX](https://www.rcsb.org/structure/5XIX), [8H53](https://www.rcsb.org/structure/8H53), [8TC7](https://www.rcsb.org/structure/8TC7), [8TC8](https://www.rcsb.org/structure/8TC8), [8TC9](https://www.rcsb.org/structure/8TC9).

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

*Describes the biological roles of NARS1 (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:** NARS1's established molecular role includes asparagine-tRNA ligase activity.


### Pathways affected {#pathways}

NARS1 participates in **1 Reactome pathway** (⚕ = disease pathway):

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

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

**Molecular function:** asparagine-tRNA ligase activity, CCR3 chemokine receptor binding, protein dimerization activity.

**Biological process:** asparaginyl-tRNA aminoacylation, cell migration, cerebral cortex development.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-23.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-12-23 |

## Associated conditions {#conditions}

[neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities](https://sugi.bio/atlas/disease/neurodevelopmental-disorder-with-microcephaly-impaired-language-epilepsy-and-gait-abnormalities/).

**Reported phenotype names (ClinVar):** Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities.

## Similar variants {#similar}

Related NARS1 variant pages (same residue, condition, or type): [NARS1 p.Arg439Ter](/variant/nars1-p-arg439ter), [NARS1 p.Arg534Ter](/variant/nars1-p-arg534ter), [NARS1 p.Cys342Tyr](/variant/nars1-p-cys342tyr), [NARS1 p.Arg322Leu](/variant/nars1-p-arg322leu), [NARS1 p.Gln126Ter](/variant/nars1-p-gln126ter), [NARS1 p.His403Leu](/variant/nars1-p-his403leu), [NARS1 c.493-1G>T](/variant/nars1-c-493-minus-1g-t), [NARS1 p.Ala216Ser](/variant/nars1-p-ala216ser).

### 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 4538542). 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.*