# NM_018122.5(DARS2):c.1825C>T (p.Arg609Trp)

https://sugi.bio/variant/dars2-p-arg609trp

## Summary

**DARS2 p.Arg609Trp (c.1825C>T)** is classified **Uncertain significance** in DARS2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-01-22). AlphaMissense: likely benign (0.1803); Very rare (popmax 0.00549%, sas); Associated with leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs200670286 · 6 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00549%, sas)

## For patients & families {#patients}

This is a change in the DARS2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 6 submitters, and is linked to leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal |
| Clinical trials | 5 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | DARS2 is a diagnostic-grade gene on 22 Genomics England panels |

**Commonly reported features of Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormality of the dorsal column of the spinal cord — Very frequent (99-80%)
- Babinski sign — Frequent (79-30%)
- Dysarthria — Frequent (79-30%)
- Gait disturbance — Frequent (79-30%)
- Abnormal cerebellum morphology — Frequent (79-30%)
- Tremor — Frequent (79-30%)
- Progressive cerebellar ataxia — Frequent (79-30%)
- Abnormality of speech or vocalization — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012652/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DARS2](https://sugi.bio/atlas/gene/DARS2/) |
| Protein change (HGVS p.) | p.Arg609Trp |
| Coding change (HGVS c.) | c.1825C>T |
| MANE Select transcript | [NM_018122](https://www.ncbi.nlm.nih.gov/nuccore/NM_018122) |
| dbSNP | [rs200670286](https://www.ncbi.nlm.nih.gov/snp/rs200670286/) |
| Variant type | single nucleotide variant |
| Location | chr1:173857592-173857592 (GRCh38) |
| ClinVar | [VCV30863](https://www.ncbi.nlm.nih.gov/clinvar/variation/30863/) |

**All HGVS expressions:** `LRG_1270:g.37934C>T`, `LRG_1270t1:c.1825C>T`, `NC_000001.10:g.173826730C>T`, `NC_000001.11:g.173857592C>T`, `NG_016138.1:g.37934C>T`, `NM_001365212.1:c.1672C>T`, `NM_018122.5:c.1825C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1803)
- REVEL 0.77 (pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -7.479 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** REVEL calls this damaging; AlphaMissense and SaProt do not
- Conservation: phyloP 6.11, GERP 1.9, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 32.0**. 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 0.87** across the covering region of the MANE Select transcript (173,825,230–173,857,702), spanning 32,472 bp. Chi-square p 0.00036. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00549%** (sas) · FAF95 0.0021% · FAF99 0.00136% · 5/91,092 in the highest group · 34/1,614,002 alleles overall — very rare (popmax 0.00549%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00549% | 18,218 |
| East Asian | 0.00445% | 22,450 |
| European (non-Finnish) | 0.0022% | 45,385 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,482 |

*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}

**DARS2** population constraint: LOEUF 0.923, pLI 8.0697e-13, missense-Z 1.4245. *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 88.91, 77% of residues very-high.

**1 experimental structure(s)** (PDB): [4AH6](https://www.rcsb.org/structure/4AH6).

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

*Describes the biological roles of DARS2 (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:** DARS2's established molecular role includes aspartate-tRNA ligase activity.


### Pathways affected {#pathways}

DARS2 participates in **1 Reactome pathway** (⚕ = disease pathway):

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

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

**Molecular function:** aspartate-tRNA ligase activity, protein homodimerization activity, aspartate-tRNA(Asn) ligase activity.

**Biological process:** tRNA aminoacylation, mitochondrial asparaginyl-tRNA aminoacylation.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-01-22.

**Submitter consensus:** conflicting (4 Uncertain significance, 1 Pathogenic, 1 Uncertain Significance).

**Submission history:** 6 submissions (2011–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2011-10-01 |
| Dubai Health Genomic Medicine Center, Dubai Health | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-08-04 |
| Genome-Nilou Lab | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-04-11 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-09-23 |
| Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Uncertain Significance | criteria provided, single submitter | curation | 2025-01-22 |
| CeGaT Center for Human Genetics Tuebingen | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-02-01 |

## Associated conditions {#conditions}

[leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome](https://sugi.bio/atlas/disease/leukoencephalopathy-with-brain-stem-and-spinal-cord-involvement-high-lactate-syndrome/).

**Reported phenotype names (ClinVar):** Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome, not provided, none provided, LEUKOENCEPHALOPATHY WITH BRAINSTEM AND SPINAL CORD INVOLVEMENT AND LACTATE ELEVATION, MILD, Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation, MITOCHONDRIAL ASPARTYL-tRNA SYNTHETASE DEFICIENCY.

## Similar variants {#similar}

Related DARS2 variant pages (same residue, condition, or type): [DARS2 c.228-15C>A](/variant/dars2-c-228-minus-15c-a), [DARS2 c.228-16C>A](/variant/dars2-c-228-minus-16c-a), [DARS2 c.397-2A>G](/variant/dars2-c-397-minus-2a-g), [DARS2 c.492+2T>C](/variant/dars2-c-492-plus-2t-c), [DARS2 c.493-1G>C](/variant/dars2-c-493-minus-1g-c), [DARS2 p.Ala262Val](/variant/dars2-p-ala262val), [DARS2 p.Arg179His](/variant/dars2-p-arg179his), [DARS2 p.Arg188Ter](/variant/dars2-p-arg188ter).

### 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 30863). 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.*