Is DARS2 p.Arg263Ter (c.787C>T) pathogenic?

DARS2 p.Arg263Ter (c.787C>T) is classified Pathogenic in DARS2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-01-21). Very rare (popmax 0.00144%, nfe); Associated with leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome.

How common is DARS2 p.Arg263Ter (c.787C>T) in the general population?

DARS2 p.Arg263Ter (c.787C>T) is very rare (popmax 0.00144%, nfe) (gnomAD).

DARS2 p.Arg263Ter

Q: What condition is associated with DARS2 p.Arg263Ter (c.787C>T)?

DARS2 p.Arg263Ter (c.787C>T) is associated with leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome (ClinVar).

Q: How is Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.787C>T · rs121918206 · VCV1059

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00144%, nfe)

Conditions

leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 17
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP 1.7, phastCons 1
Overall
CADD	38.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00144% European (non-Finnish) · 17/1,179,296 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000718%

Overall 0.00123% 18/1,461,054 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,478
European (non-Finnish)grpmax	0.00144%	69,370

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: DARS2
Protein: p.Arg263Ter
Coding: c.787C>T
MANE Select: NM_018122
dbSNP: rs121918206
Type: single nucleotide variant
Location: chr1:173838206 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.91 · 1 PDB
Residue 263: a UniProt-annotated variant site (in lbsl; no effect on its mitochondrial localization)

Full DARS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal

Similar variants

DARS2 p.Arg263Gln Pathogenic/Likely pathogenic ★★ ⚠ same residue
DARS2 c.228-15C>A Pathogenic/Likely pathogenic ★★ same condition
DARS2 c.228-16C>A Pathogenic/Likely pathogenic ★★ same condition
DARS2 c.397-2A>G Pathogenic/Likely pathogenic ★★ same condition
DARS2 c.492+2T>C Pathogenic ★★ same condition
DARS2 c.493-1G>C Likely pathogenic ★★ same condition
DARS2 p.Ala262Val Likely pathogenic ★★ same condition
DARS2 p.Arg179His Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/dars2-p-arg263ter (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown