Is GARS1 p.Val396= (c.1188T>C) pathogenic?

GARS1 p.Val396= (c.1188T>C) is classified Conflicting classifications of pathogenicity in GARS1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-06-10). Ultra-rare (popmax 0.0121%, sas); Associated with neuronopathy, distal hereditary motor, type 5A.

What condition is associated with GARS1 p.Val396= (c.1188T>C)?

GARS1 p.Val396= (c.1188T>C) is associated with neuronopathy, distal hereditary motor, type 5A, Charcot-Marie-Tooth disease type 2D, distal hereditary motor neuropathy (ClinVar).

How common is GARS1 p.Val396= (c.1188T>C) in the general population?

GARS1 p.Val396= (c.1188T>C) is ultra-rare (popmax 0.0121%, sas) (gnomAD).

How is Distal hereditary motor neuropathy type 5 inherited?

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

GARS1 p.Val396=

c.1188T>C · rs779184435 · VCV911861

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, sas)

Conditions

neuronopathy, distal hereditary motor, type 5A

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 -2.1	GERP -3.6
Overall
CADD	2.814	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0121% South Asian · 11/91,082 alleles

Filtering AF 0.00676% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00522%

Overall 0.000681% 11/1,614,214 alleles · ultra-rare exomes 11/1,461,882 · genomes 0/152,332 · 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.Val396=
Coding: c.1188T>C
MANE Select: NM_002047
dbSNP: rs779184435
Type: single nucleotide variant
Location: chr7:30616052 (GRCh38)
Gene constraint: LOEUF 0.648 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.61 · 14 PDB
Residue 396: an α-helix

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

Disease context

neuronopathy, distal hereditary motor, type 5A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Charcot-Marie-Tooth disease type 2D distal hereditary motor neuropathy Charcot-Marie-Tooth disease type 2

For Distal hereditary motor neuropathy type 5 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

GARS1 p.Val396Ile 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-val396 (accessed [today's date]).

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