Is DARS2 p.Arg58Gly (c.172C>G) pathogenic?

DARS2 p.Arg58Gly (c.172C>G) is classified Pathogenic/Likely pathogenic in DARS2 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-01-15). AlphaMissense: likely benign (0.1728); Very rare (popmax 0.00772%, nfe); Associated with Inborn genetic diseases.

How common is DARS2 p.Arg58Gly (c.172C>G) in the general population?

DARS2 p.Arg58Gly (c.172C>G) is very rare (popmax 0.00772%, nfe) (gnomAD).

What do computational predictors say about DARS2 p.Arg58Gly (c.172C>G)?

AlphaMissense predicts likely benign (score 0.1728) — an in-silico prediction, not a clinical call.

DARS2 p.Arg58Gly

Q: What condition is associated with DARS2 p.Arg58Gly (c.172C>G)?

DARS2 p.Arg58Gly (c.172C>G) is associated with Inborn genetic diseases, leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome, mitochondrial disease (ClinVar).

c.172C>G · rs375700548 · VCV1188834

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.1728 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00772%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1728	likely benign ⚠ discordant with ClinVar
REVEL	0.461	indeterminate
SaProt	LLR -11.78	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 2.2	GERP 0.93, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 32 kb · p 0.00036 · regional, not allelic
Overall
CADD	22.5	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 0.00772% European (non-Finnish) · 91/1,179,334 alleles

Filtering AF 0.0064% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00592%

Overall 0.0059% 95/1,609,978 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00772%	12,960
Remaining individualsnot grpmax-eligible	0.00481%	20,797
African / African-American	0.00136%	73,384

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.Arg58Gly
Coding: c.172C>G
MANE Select: NM_018122
dbSNP: rs375700548
Type: single nucleotide variant
Location: chr1:173826731 (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 mitochondrial disease

Similar variants

DARS2 p.Arg58His Conflicting classifications of pathogenicity ★ ⚠ 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-arg58gly (accessed [today's date]).

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