Is DARS2 p.Ile399fs (c.1196del) pathogenic?

DARS2 p.Ile399fs (c.1196del) is classified Pathogenic in DARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-05-28). Absent from gnomAD; Associated with leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome.

How common is DARS2 p.Ile399fs (c.1196del) in the general population?

DARS2 p.Ile399fs (c.1196del) is absent from gnomAD (gnomAD).

DARS2 p.Ile399fs

Q: What condition is associated with DARS2 p.Ile399fs (c.1196del)?

DARS2 p.Ile399fs (c.1196del) 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.1196del · rs1571995707 · VCV801580

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

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

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 13 of 17
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.2	GERP 1.5, phastCons 1

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: DARS2
Protein: p.Ile399fs
Coding: c.1196del
MANE Select: NM_018122
dbSNP: rs1571995707
Type: Deletion
Location: chr1:173850331 (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.Ala392fs Pathogenic/Likely pathogenic ★★ same condition
DARS2 p.Gly365fs Likely pathogenic ★★ same condition
DARS2 p.Gly467fs Pathogenic ★★ same condition
DARS2 p.Leu187fs Pathogenic/Likely pathogenic ★★ same condition
DARS2 p.Lys362fs Pathogenic/Likely pathogenic ★★ same condition
DARS2 p.Pro317fs Pathogenic/Likely pathogenic ★★ same condition
DARS2 c.228-10del Benign ★★ same condition
DARS2 c.664-17_664-14del Likely benign ★★ 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-ile399fs (accessed [today's date]).

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