Is DARS2 p.Arg179His (c.536G>A) pathogenic?

DARS2 p.Arg179His (c.536G>A) is classified Pathogenic/Likely pathogenic in DARS2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-06-10). AlphaMissense: likely pathogenic (0.7826); Very rare (popmax 0.00483%, nfe); Associated with DARS2-related disorder.

What condition is associated with DARS2 p.Arg179His (c.536G>A)?

DARS2 p.Arg179His (c.536G>A) is associated with DARS2-related disorder, leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome (ClinVar).

How common is DARS2 p.Arg179His (c.536G>A) in the general population?

DARS2 p.Arg179His (c.536G>A) is very rare (popmax 0.00483%, nfe) (gnomAD).

What do computational predictors say about DARS2 p.Arg179His (c.536G>A)?

AlphaMissense predicts likely pathogenic (score 0.7826) — an in-silico prediction, not a clinical call.

DARS2 p.Arg179His

c.536G>A · rs121918210 · VCV1064

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.7826 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00483%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

DARS2-related disorder

Computational evidence

Protein change
AlphaMissense	0.7826	likely pathogenic ✓ concordant with ClinVar
REVEL	0.898	moderately pathogenic-leaning
SaProt	LLR -11.13	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
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 0.00483% European (non-Finnish) · 57/1,179,760 alleles

Filtering AF 0.00378% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00345%

Overall 0.00366% 59/1,613,588 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00483%	20,698
East Asian	0.00223%	44,860
Admixed American	0.00167%	60,004

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.Arg179His
Coding: c.536G>A
MANE Select: NM_018122
dbSNP: rs121918210
Type: single nucleotide variant
Location: chr1:173833419 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.91 · 1 PDB
Residue 179: a UniProt-annotated variant site (in lbsl)

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

Disease context

DARS2-related disorder

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

Similar variants

DARS2 p.Arg179Cys Conflicting classifications of pathogenicity ★ ⚠ 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.Arg188Ter 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-arg179his (accessed [today's date]).

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