Is DARS1 p.Phe215Ser (c.644T>C) pathogenic?

DARS1 p.Phe215Ser (c.644T>C) is classified Uncertain significance in DARS1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-05-10). AlphaMissense: likely pathogenic (0.9612); Very rare (popmax 0.00175%, amr); Associated with Inborn genetic diseases.

What condition is associated with DARS1 p.Phe215Ser (c.644T>C)?

DARS1 p.Phe215Ser (c.644T>C) is associated with Inborn genetic diseases, hypomyelination with brain stem and spinal cord involvement and leg spasticity (ClinVar).

How common is DARS1 p.Phe215Ser (c.644T>C) in the general population?

DARS1 p.Phe215Ser (c.644T>C) is very rare (popmax 0.00175%, amr) (gnomAD).

What do computational predictors say about DARS1 p.Phe215Ser (c.644T>C)?

AlphaMissense predicts likely pathogenic (score 0.9612) — an in-silico prediction, not a clinical call.

DARS1 p.Phe215Ser

c.644T>C · rs751774677 · VCV1030430

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9612 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00175%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9612	likely pathogenic
REVEL	0.946	strongly pathogenic-leaning
SaProt	LLR -13.38	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 11	GERP 1.7, 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

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 0.00175% Admixed American · 1/57,238 alleles

Overall 0.000138% 2/1,452,624 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00175%	57,238
European (non-Finnish)	8.49e-05%	1,177,698

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.Phe215Ser
Coding: c.644T>C
MANE Select: NM_001349
dbSNP: rs751774677
Type: single nucleotide variant
Location: chr2:135924419 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypomyelination with brain stem and spinal cord involvement and leg spasticity

Similar variants

DARS1 p.Arg197Cys Uncertain significance ★★ ⚠ same condition
DARS1 p.Arg498Gln Uncertain significance ★★ ⚠ same condition
DARS1 p.Arg63His Uncertain significance ★★ ⚠ same condition
DARS1 p.Arg81His Uncertain significance ★★ ⚠ same condition
DARS1 p.Asn233Ser Uncertain significance ★★ ⚠ same condition
DARS1 p.Glu357Lys Uncertain significance ★★ ⚠ same condition
DARS1 p.Gly170Arg Uncertain significance ★★ same condition
DARS1 p.Gly359Glu Uncertain significance ★★ 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-phe215ser (accessed [today's date]).

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