Is DARS1 p.Ala274Val (c.821C>T) pathogenic?

DARS1 p.Ala274Val (c.821C>T) is classified Pathogenic in DARS1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2013-05-02). AlphaMissense: likely pathogenic (0.9949); Very rare (popmax 0.00179%, amr); Associated with hypomyelination with brain stem and spinal cord involvement and leg spasticity.

What condition is associated with DARS1 p.Ala274Val (c.821C>T)?

DARS1 p.Ala274Val (c.821C>T) is associated with hypomyelination with brain stem and spinal cord involvement and leg spasticity (ClinVar).

How common is DARS1 p.Ala274Val (c.821C>T) in the general population?

DARS1 p.Ala274Val (c.821C>T) is very rare (popmax 0.00179%, amr) (gnomAD).

What do computational predictors say about DARS1 p.Ala274Val (c.821C>T)?

AlphaMissense predicts likely pathogenic (score 0.9949) — an in-silico prediction, not a clinical call.

DARS1 p.Ala274Val

Q: How is Hypomyelination with brain stem and spinal cord involvement and leg spasticity inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.821C>T · rs369152939 · VCV50987

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9949 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00179%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hypomyelination with brain stem and spinal cord involvement and leg spasticity

Computational evidence

Protein change
AlphaMissense	0.9949	likely pathogenic ✓ concordant with ClinVar · top 8% in DARS1
REVEL	0.622	indeterminate
SaProt	LLR -14.03	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 78 kb · p 0.69 · regional, not allelic
Overall
CADD	33.0	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 0.00179% Admixed American · 1/56,004 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000313% 5/1,598,230 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00179%	56,004
European (non-Finnish)	0.00034%	293,759

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: DARS1
Protein: p.Ala274Val
Coding: c.821C>T
MANE Select: NM_001349
dbSNP: rs369152939
Type: single nucleotide variant
Location: chr2:135920591 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.69 · 3 PDB
Residue 274: a UniProt-annotated variant site (in hbsl); a binding site

Full DARS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypomyelination with brain stem and spinal cord involvement and leg spasticity — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hypomyelination with brain stem and spinal cord involvement and leg spasticity (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Infancy, Neonatal

Similar variants

DARS1 p.Ala274= Benign/Likely benign ★★ same residue
DARS1 p.Ala274Gly Pathogenic ★ same residue
DARS1 p.Arg498Gln Uncertain significance ★★ ⚠ same condition
DARS1 p.Arg81His Uncertain significance ★★ ⚠ same condition
DARS1 p.Phe215Ser Uncertain significance ★★ ⚠ same condition
DARS1 c.505-13T>C Benign ★★ same condition
DARS1 p.Arg460His Likely pathogenic ★ ⚠ same condition
DARS1 p.Arg494Gly 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/dars1-p-ala274val (accessed [today's date]).

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