# NM_018122.5(DARS2):c.788G>A (p.Arg263Gln)

https://sugi.bio/variant/dars2-p-arg263gln

## Summary

**DARS2 p.Arg263Gln (c.788G>A)** is classified **Pathogenic/Likely pathogenic** in DARS2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-01-21). AlphaMissense: likely benign (0.3354); Ultra-rare (popmax 0.0329%, mid); Associated with DARS2-related disorder.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs121918207 · 7 submitters · 2 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.0329%, mid)

## For patients & families {#patients}

This is a change in the DARS2 gene that is considered likely disease-causing, submitted by 7 submitters, and is linked to DARS2-related disorder.

*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 | [DARS2](https://sugi.bio/atlas/gene/DARS2/) |
| Protein change (HGVS p.) | p.Arg263Gln |
| Coding change (HGVS c.) | c.788G>A |
| MANE Select transcript | [NM_018122](https://www.ncbi.nlm.nih.gov/nuccore/NM_018122) |
| dbSNP | [rs121918207](https://www.ncbi.nlm.nih.gov/snp/rs121918207/) |
| Variant type | single nucleotide variant |
| Location | chr1:173838207-173838207 (GRCh38) |
| ClinVar | [VCV1060](https://www.ncbi.nlm.nih.gov/clinvar/variation/1060/) |

**All HGVS expressions:** `LRG_1270:g.18549G>A`, `LRG_1270t1:c.788G>A`, `NC_000001.10:g.173807345G>A`, `NC_000001.11:g.173838207G>A`, `NG_016138.1:g.18549G>A`, `NM_001365212.1:c.788G>A`, `NM_001365213.2:c.788G>A`, `NM_018122.5:c.788G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.3354) — ⚠ discordant with the pathogenic call
- REVEL 0.911 (moderately pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -13.69 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** REVEL and SaProt call this damaging; AlphaMissense does not
- Conservation: phyloP 11.862, GERP 2.52, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 34.0**. 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 **0.0329%** (mid) · FAF95 0.0058% · FAF99 0.00241% · 2/6,082 in the highest group · 36/1,613,262 alleles overall — ultra-rare (popmax 0.0329%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0329% | 3,041 |
| South Asian | 0.00659% | 15,179 |
| African / African-American | 0.00534% | 18,722 |
| Admixed American | 0.00333% | 29,996 |
| European (non-Finnish) | 0.00187% | 53,609 |

*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}

Residue **263** lies in a UniProt-annotated variant site (in lbsl; no effect on its mitochondrial localization).

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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-01-21.

**Submitter consensus:** conflicting (3 Pathogenic, 2 Likely pathogenic, 1 Likely Pathogenic, 1 not provided).

**Submission history:** 7 submissions (2007–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Pathogenic | criteria provided, single submitter | clinical testing | 2016-02-17 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-11-06 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2007-04-01 |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-04-18 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-03-18 |
| Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Likely Pathogenic | criteria provided, single submitter | curation | 2025-01-21 |
| GenomeConnect, ClinGen | not provided | no classification provided | phenotyping only |  |

## Associated conditions {#conditions}

[DARS2-related disorder](https://sugi.bio/atlas/disease/dars2-related-disorder/), [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):** DARS2-related disorder, Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome, not provided, DARS2-related condition, none provided, MITOCHONDRIAL ASPARTYL-tRNA SYNTHETASE DEFICIENCY, LEUKOENCEPHALOPATHY WITH BRAINSTEM AND SPINAL CORD INVOLVEMENT AND LACTATE ELEVATION, MILD, Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation.

## Same-residue context {#hotspot}

Residue **263** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [DARS2 p.Arg263Ter](/variant/dars2-p-arg263ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related DARS2 variant pages (same residue, condition, or type): [DARS2 p.Arg263Ter](/variant/dars2-p-arg263ter), [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).

### 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 1060). 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.*