Is DARS2 p.Arg274fs (c.822_825del) pathogenic?

DARS2 p.Arg274fs (c.822825del) is classified Likely pathogenic in DARS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-21). Very rare (popmax 0.000933%, nfe); Associated with DARS2-related disorder.

What condition is associated with DARS2 p.Arg274fs (c.822_825del)?

DARS2 p.Arg274fs (c.822_825del) is associated with DARS2-related disorder, leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome (ClinVar).

How common is DARS2 p.Arg274fs (c.822_825del) in the general population?

DARS2 p.Arg274fs (c.822_825del) is very rare (popmax 0.000933%, nfe) (gnomAD).

DARS2 p.Arg274fs

c.822_825del · VCV3776820

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000933%, nfe)

Conditions

DARS2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 17
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000933% European (non-Finnish) · 11/1,179,584 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000821% 12/1,461,328 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)grpmax	0.000933%	107,235

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.Arg274fs
Coding: c.822_825del
MANE Select: NM_018122
Type: Microsatellite
Location: chr1:173838234 (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

DARS2-related disorder

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

Similar variants

DARS2 c.127+94ATT[10] Benign ★★ same condition
DARS2 p.His502_Pro503insHis Likely pathogenic ★ same condition
DARS2 p.Ile41fs Pathogenic ★ same condition
DARS2 p.Arg274= 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.228-21_228-20delinsC Pathogenic ★★ same condition
DARS2 c.397-2A>G 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-arg274fs (accessed [today's date]).

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