Is DARS2 p.Asp461Tyr (c.1381G>T) pathogenic?

DARS2 p.Asp461Tyr (c.1381G>T) is classified Uncertain significance in DARS2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-17). AlphaMissense: likely benign (0.1838); Absent from gnomAD v4.1; Associated with leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome.

How common is DARS2 p.Asp461Tyr (c.1381G>T) in the general population?

DARS2 p.Asp461Tyr (c.1381G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DARS2 p.Asp461Tyr (c.1381G>T)?

AlphaMissense predicts likely benign (score 0.1838) — an in-silico prediction, not a clinical call.

DARS2 p.Asp461Tyr

Q: What condition is associated with DARS2 p.Asp461Tyr (c.1381G>T)?

DARS2 p.Asp461Tyr (c.1381G>T) 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.1381G>T · rs2525926644 · VCV2037410

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1838 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.1838	likely benign
REVEL	0.435	indeterminate
SaProt	LLR -9.41	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.23	acceptor loss, 36 bp away · masked 0 · deltas
Pangolin	Δ0.31	loss · gain 0.11 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 6.7	GERP 1.4, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 32 kb · p 0.00036 · regional, not allelic
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DARS2
Protein: p.Asp461Tyr
Coding: c.1381G>T
MANE Select: NM_018122
dbSNP: rs2525926644
Type: single nucleotide variant
Location: chr1:173853385 (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.Asp461Glu Uncertain significance ★ ⚠ 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.Arg179His 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-asp461tyr (accessed [today's date]).

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