Is GARS1 p.Val233= (c.699C>T) pathogenic?

GARS1 p.Val233= (c.699C>T) is classified Benign/Likely benign in GARS1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-11). Rare (popmax 0.195%, afr); Associated with distal hereditary motor neuropathy.

What condition is associated with GARS1 p.Val233= (c.699C>T)?

GARS1 p.Val233= (c.699C>T) 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.Val233= (c.699C>T) in the general population?

GARS1 p.Val233= (c.699C>T) is rare (popmax 0.195%, afr) (gnomAD).

GARS1 p.Val233=

c.699C>T · rs187937286 · VCV360004

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

rare (popmax 0.195%, 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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.4	GERP -0.52, phastCons 0.001
Overall
CADD	9.193	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.195% African / African-American · 146/75,014 alleles

Filtering AF 0.169% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.159%

Overall 0.0123% 199/1,613,772 alleles · rare exomes 108/1,461,574 · genomes 91/152,198 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.195%	514
Admixed American	0.0566%	1,766
Middle Eastern	0.0333%	3,006
Remaining individualsnot grpmax-eligible	0.016%	6,250
South Asian	0.0011%	91,060
European (non-Finnish)	0.000509%	196,648

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.Val233=
Coding: c.699C>T
MANE Select: NM_002047
dbSNP: rs187937286
Type: single nucleotide variant
Location: chr7:30603536 (GRCh38)
Gene constraint: LOEUF 0.648 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.61 · 14 PDB
Residue 233: 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.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
GARS1 p.Ser265Phe 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-val233 (accessed [today's date]).

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