Is DARS2 p.Arg58His (c.173G>A) pathogenic?

DARS2 p.Arg58His (c.173G>A) is classified Conflicting classifications of pathogenicity in DARS2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-01-15). AlphaMissense: likely benign (0.1124); Very rare (popmax 0.00314%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DARS2 p.Arg58His (c.173G>A)?

DARS2 p.Arg58His (c.173G>A) is associated with Inborn genetic diseases, leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome (ClinVar).

How common is DARS2 p.Arg58His (c.173G>A) in the general population?

DARS2 p.Arg58His (c.173G>A) is very rare (popmax 0.00314%, nfe) (gnomAD).

What do computational predictors say about DARS2 p.Arg58His (c.173G>A)?

AlphaMissense predicts likely benign (score 0.1124) — an in-silico prediction, not a clinical call.

DARS2 p.Arg58His

c.173G>A · rs773592266 · VCV2179363

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1124 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00314%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1124	likely benign
REVEL	0.416	indeterminate
SaProt	LLR -11.54	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 32 kb · p 0.00036 · regional, not allelic
Overall
CADD	32.0	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 0.00314% European (non-Finnish) · 37/1,179,558 alleles

Filtering AF 0.00231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00202%

Overall 0.00261% 42/1,610,998 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00314%	31,880
South Asian	0.0022%	45,508
Admixed American	0.00168%	59,646
Remaining individualsnot grpmax-eligible	0.0016%	62,438
Finnishnot grpmax-eligible	0.00159%	63,084

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.Arg58His
Coding: c.173G>A
MANE Select: NM_018122
dbSNP: rs773592266
Type: single nucleotide variant
Location: chr1:173826732 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

DARS2 p.Arg58Gly Pathogenic/Likely pathogenic ★★ ⚠ same residue
DARS2 p.Arg58= Likely benign ★ 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

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-arg58his (accessed [today's date]).

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