Is DARS2 p.Phe478Ser (c.1433T>C) pathogenic?

DARS2 p.Phe478Ser (c.1433T>C) is classified Uncertain significance in DARS2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-21). AlphaMissense: likely pathogenic (0.8685); Very rare (popmax 0.00695%, nfe); Associated with leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome.

How common is DARS2 p.Phe478Ser (c.1433T>C) in the general population?

DARS2 p.Phe478Ser (c.1433T>C) is very rare (popmax 0.00695%, nfe) (gnomAD).

What do computational predictors say about DARS2 p.Phe478Ser (c.1433T>C)?

AlphaMissense predicts likely pathogenic (score 0.8685) — an in-silico prediction, not a clinical call.

DARS2 p.Phe478Ser

Q: What condition is associated with DARS2 p.Phe478Ser (c.1433T>C)?

DARS2 p.Phe478Ser (c.1433T>C) 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.1433T>C · rs774738795 · VCV2202882

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8685 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00695%, nfe)

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	0.8685	likely pathogenic
REVEL	0.904	moderately pathogenic-leaning
SaProt	LLR -12.64	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.43 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 32 kb · p 0.00036 · regional, not allelic
Overall
CADD	29.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Grpmax group 0.00695% European (non-Finnish) · 82/1,180,034 alleles

Filtering AF 0.00571% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00525%

Overall 0.00508% 82/1,613,992 alleles · very rare exomes 80/1,461,892 · genomes 2/152,100 · joint denominator

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.Phe478Ser
Coding: c.1433T>C
MANE Select: NM_018122
dbSNP: rs774738795
Type: single nucleotide variant
Location: chr1:173853437 (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-phe478ser (accessed [today's date]).

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