Is GARS1 p.Arg474= (c.1420C>A) pathogenic?

GARS1 p.Arg474= (c.1420C>A) is classified Benign/Likely benign in GARS1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-01-26). Rare (popmax 0.656%, afr); Associated with distal hereditary motor neuropathy.

What condition is associated with GARS1 p.Arg474= (c.1420C>A)?

GARS1 p.Arg474= (c.1420C>A) is associated with distal hereditary motor neuropathy, Charcot-Marie-Tooth disease type 2D, neuronopathy, distal hereditary motor, type 5A (ClinVar).

How common is GARS1 p.Arg474= (c.1420C>A) in the general population?

GARS1 p.Arg474= (c.1420C>A) is rare (popmax 0.656%, afr) (gnomAD).

GARS1 p.Arg474=

c.1420C>A · rs113958280 · VCV360013

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

rare (popmax 0.656%, afr)

Conditions

distal hereditary motor neuropathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP -2.8, phastCons 0.3
Overall
CADD	7.753	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.656% African / African-American · 492/75,020 alleles

Filtering AF 0.608% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.589%

Overall 0.0356% 575/1,614,092 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.656%	152
Remaining individualsnot grpmax-eligible	0.0688%	1,454
Admixed American	0.0417%	2,400
East Asian	0.00891%	11,222
South Asian	0.00659%	15,180
European (non-Finnish)	0.000424%	236,002

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.Arg474=
Coding: c.1420C>A
MANE Select: NM_002047
dbSNP: rs113958280
Type: single nucleotide variant
Location: chr7:30621453 (GRCh38)
Gene constraint: LOEUF 0.648 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.61 · 14 PDB
Residue 474: an α-helix

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

Disease context

distal hereditary motor neuropathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Charcot-Marie-Tooth disease type 2D neuronopathy, distal hereditary motor, type 5A Charcot-Marie-Tooth disease Charcot-Marie-Tooth disease type 2

Similar variants

GARS1 p.Arg474Gln Uncertain significance ★ ⚠ same residue
GARS1 p.Arg474Gly Uncertain significance ★ ⚠ same residue
GARS1 p.Arg474Ter 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

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-arg474 (accessed [today's date]).

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