Is GARS1 p.Arg596Ter (c.1786C>T) pathogenic?

GARS1 p.Arg596Ter (c.1786C>T) is classified Uncertain significance in GARS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-04). Very rare (popmax 0.00017%, nfe); Associated with Charcot-Marie-Tooth disease type 2.

What condition is associated with GARS1 p.Arg596Ter (c.1786C>T)?

GARS1 p.Arg596Ter (c.1786C>T) is associated with Charcot-Marie-Tooth disease type 2 (ClinVar).

How common is GARS1 p.Arg596Ter (c.1786C>T) in the general population?

GARS1 p.Arg596Ter (c.1786C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

GARS1 p.Arg596Ter

c.1786C>T · rs2534331976 · VCV2961222

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

Charcot-Marie-Tooth disease type 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 14 of 17
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP -0.13, phastCons 1
Overall
CADD	47.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,177,018 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,610,534 alleles · very rare exomes 2/1,458,328 · genomes 0/152,206 · joint denominator

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: GARS1
Protein: p.Arg596Ter
Coding: c.1786C>T
MANE Select: NM_002047
dbSNP: rs2534331976
Type: single nucleotide variant
Location: chr7:30628646 (GRCh38)
Gene constraint: LOEUF 0.648 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.61 · 14 PDB

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

Disease context

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

Similar variants

GARS1 p.Arg596Gln Uncertain significance ⚠ same residue
GARS1 p.Asp200Asn Pathogenic/Likely pathogenic ★★ same condition
GARS1 p.Gly294Arg Pathogenic/Likely pathogenic ★★ same condition
GARS1 p.Gly339Arg 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.Ile334Thr Pathogenic/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/gars1-p-arg596ter (accessed [today's date]).

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