Is DARS2 p.Arg188Gln (c.563G>A) pathogenic?

DARS2 p.Arg188Gln (c.563G>A) is classified Conflicting classifications of pathogenicity in DARS2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-03-18). AlphaMissense: likely benign (0.1729); Very rare (popmax 0.00223%, eas); Associated with leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome.

How common is DARS2 p.Arg188Gln (c.563G>A) in the general population?

DARS2 p.Arg188Gln (c.563G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about DARS2 p.Arg188Gln (c.563G>A)?

AlphaMissense predicts likely benign (score 0.1729) — an in-silico prediction, not a clinical call.

DARS2 p.Arg188Gln

Q: What condition is associated with DARS2 p.Arg188Gln (c.563G>A)?

DARS2 p.Arg188Gln (c.563G>A) 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.563G>A · rs182811621 · VCV694538

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1729 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.1729	likely benign
REVEL	0.704	pathogenic-leaning
SaProt	LLR -10.42	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 32 kb · p 0.00036 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,866 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000372% 6/1,614,078 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,252
East Asiangrpmax	0.00223%	44,866
African / African-American	0.00133%	75,050
European (non-Finnish)	0.000169%	589,981

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.Arg188Gln
Coding: c.563G>A
MANE Select: NM_018122
dbSNP: rs182811621
Type: single nucleotide variant
Location: chr1:173833446 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.91 · 1 PDB

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.Arg188Ter 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-arg188gln (accessed [today's date]).

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