Is DARS1 p.Arg460His (c.1379G>A) pathogenic?

DARS1 p.Arg460His (c.1379G>A) is classified Likely pathogenic in DARS1 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-09-26). AlphaMissense: likely benign (0.168); Very rare (popmax 0.0078%, sas); Associated with hypomyelination with brain stem and spinal cord involvement and leg spasticity.

What condition is associated with DARS1 p.Arg460His (c.1379G>A)?

DARS1 p.Arg460His (c.1379G>A) is associated with hypomyelination with brain stem and spinal cord involvement and leg spasticity (ClinVar).

How common is DARS1 p.Arg460His (c.1379G>A) in the general population?

DARS1 p.Arg460His (c.1379G>A) is very rare (popmax 0.0078%, sas) (gnomAD).

What do computational predictors say about DARS1 p.Arg460His (c.1379G>A)?

AlphaMissense predicts likely benign (score 0.168) — an in-silico prediction, not a clinical call.

DARS1 p.Arg460His

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.1379G>A · rs587776985 · VCV50990

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.168 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0078%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hypomyelination with brain stem and spinal cord involvement and leg spasticity

Computational evidence

Protein change
AlphaMissense	0.168	likely benign ⚠ discordant with ClinVar
REVEL	0.593	indeterminate
SaProt	LLR -11.36	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.9, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 78 kb · p 0.69 · regional, not allelic
Overall
CADD	32.0	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 0.0078% South Asian · 7/89,688 alleles

Filtering AF 0.00364% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00258%

Overall 0.00168% 26/1,550,894 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0103%	9,727
South Asiangrpmax	0.0078%	12,813
Remaining individualsnot grpmax-eligible	0.00332%	30,154
Admixed American	0.00167%	59,806
European (non-Finnish)	0.00116%	86,389

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg460His
Coding: c.1379G>A
MANE Select: NM_001349
dbSNP: rs587776985
Type: single nucleotide variant
Location: chr2:135911174 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.69 · 3 PDB
Residue 460: a UniProt-annotated variant site (in hbsl); a turn

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.Arg460= Likely benign ★ 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.Arg494Gly Likely pathogenic ★ same condition
DARS1 p.Arg494His Likely pathogenic ★ same condition
DARS1 p.Tyr245Ter 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-arg460his (accessed [today's date]).

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