Is DARS1 p.Ser277Phe (c.830C>T) pathogenic?

DARS1 p.Ser277Phe (c.830C>T) is classified Uncertain significance in DARS1 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely pathogenic (0.9961); Very rare (popmax 8.48e-05%, nfe); Associated with hypomyelination with brain stem and spinal cord involvement and leg spasticity.

What condition is associated with DARS1 p.Ser277Phe (c.830C>T)?

DARS1 p.Ser277Phe (c.830C>T) is associated with hypomyelination with brain stem and spinal cord involvement and leg spasticity (ClinVar).

How common is DARS1 p.Ser277Phe (c.830C>T) in the general population?

DARS1 p.Ser277Phe (c.830C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about DARS1 p.Ser277Phe (c.830C>T)?

AlphaMissense predicts likely pathogenic (score 0.9961) — an in-silico prediction, not a clinical call.

DARS1 p.Ser277Phe

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.830C>T · VCV4856992

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9961 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypomyelination with brain stem and spinal cord involvement and leg spasticity

Computational evidence

Protein change
AlphaMissense	0.9961	likely pathogenic · top 5% in DARS1
REVEL	0.922	moderately pathogenic-leaning
SaProt	LLR -13.91	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 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

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 8.48e-05% European (non-Finnish) · 1/1,179,026 alleles

Overall 6.86e-05% 1/1,458,400 alleles · very rare

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.Ser277Phe
Coding: c.830C>T
MANE Select: NM_001349
Type: single nucleotide variant
Location: chr2:135920582 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.69 · 3 PDB

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.Ser277Cys Uncertain significance ★ ⚠ 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
DARS1 p.Arg494His 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-ser277phe (accessed [today's date]).

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