Is DARS2 p.Phe484Leu (c.1452C>G) pathogenic?

DARS2 p.Phe484Leu (c.1452C>G) is classified Conflicting classifications of pathogenicity in DARS2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-08-17). AlphaMissense: likely pathogenic (0.9919); Very rare (popmax 0.00667%, amr); Associated with leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome.

How common is DARS2 p.Phe484Leu (c.1452C>G) in the general population?

DARS2 p.Phe484Leu (c.1452C>G) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about DARS2 p.Phe484Leu (c.1452C>G)?

AlphaMissense predicts likely pathogenic (score 0.9919) — an in-silico prediction, not a clinical call.

DARS2 p.Phe484Leu

Q: What condition is associated with DARS2 p.Phe484Leu (c.1452C>G)?

DARS2 p.Phe484Leu (c.1452C>G) 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.1452C>G · rs181672516 · VCV1678848

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9919 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.9919	likely pathogenic · top 1% in DARS2
REVEL	0.828	moderately pathogenic-leaning
SaProt	LLR -12.16	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.37	GERP 0.46, phastCons 0.99
Regional constraint	o/e 0.87	unconstrained · MANE · 32 kb · p 0.00036 · regional, not allelic
Overall
CADD	24.5	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 0.00667% Admixed American · 4/60,008 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00062% 10/1,614,114 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	15,002
European (non-Finnish)	0.000508%	196,672

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.Phe484Leu
Coding: c.1452C>G
MANE Select: NM_018122
dbSNP: rs181672516
Type: single nucleotide variant
Location: chr1:173853456 (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 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
DARS2 p.Arg188Ter 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-phe484leu (accessed [today's date]).

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