Is GARS1 p.Pro298Leu (c.893C>T) pathogenic?

GARS1 p.Pro298Leu (c.893C>T) is classified Conflicting classifications of pathogenicity in GARS1 (ClinVar, No assertion criteria, 3 submitters; last evaluated 2016-01-06). AlphaMissense: likely pathogenic (0.998); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease type 2D.

What condition is associated with GARS1 p.Pro298Leu (c.893C>T)?

GARS1 p.Pro298Leu (c.893C>T) is associated with Charcot-Marie-Tooth disease type 2D (ClinVar).

How common is GARS1 p.Pro298Leu (c.893C>T) in the general population?

GARS1 p.Pro298Leu (c.893C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GARS1 p.Pro298Leu (c.893C>T)?

AlphaMissense predicts likely pathogenic (score 0.998) — an in-silico prediction, not a clinical call.

GARS1 p.Pro298Leu

Q: How is Autosomal dominant Charcot-Marie-Tooth disease type 2D inherited?

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

c.893C>T · rs137852648 · VCV9209

Conflicting classifications of pathogenicity No assertion criteria

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.998 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 2D

Computational evidence

Protein change
AlphaMissense	0.998	likely pathogenic · top 8% in GARS1
REVEL	0.853	moderately pathogenic-leaning
SaProt	LLR -14.17	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 7.7	GERP 0.97, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 34 kb · p 2.2e-07 · 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GARS1
Protein: p.Pro298Leu
Coding: c.893C>T
MANE Select: NM_002047
dbSNP: rs137852648
Type: single nucleotide variant
Location: chr7:30612107 (GRCh38)
Gene constraint: LOEUF 0.648 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.61 · 14 PDB
Residue 298: a UniProt-annotated variant site (in cmt2d; shows a large reduction in aminoacylation activity; demonstrates a change in subcellular location pattern; does not associate with granules); a β-strand

Full GARS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Charcot-Marie-Tooth disease type 2D — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant Charcot-Marie-Tooth disease type 2D (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult

Similar variants

GARS1 p.Pro298Arg Likely pathogenic ★ same residue
GARS1 p.Gly294Arg Pathogenic/Likely pathogenic ★★ same condition
GARS1 p.His472Arg Pathogenic ★★ same condition
GARS1 p.Ile334Asn Pathogenic/Likely pathogenic ★★ same condition
GARS1 p.Ile334Phe Pathogenic ★★ same condition
GARS1 p.Ala12Thr Uncertain significance ★★ ⚠ same condition
GARS1 p.Ala38Thr Uncertain significance ★★ ⚠ same condition
GARS1 p.Gly407Ser 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/gars1-p-pro298leu (accessed [today's date]).

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