Is GARS1 p.Val91Ile (c.271G>A) pathogenic?

GARS1 p.Val91Ile (c.271G>A) is classified Conflicting classifications of pathogenicity in GARS1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-11-15). AlphaMissense: likely benign (0.0699); Very rare (popmax 0.00169%, nfe); Associated with Charcot-Marie-Tooth disease type 2.

What condition is associated with GARS1 p.Val91Ile (c.271G>A)?

GARS1 p.Val91Ile (c.271G>A) is associated with Charcot-Marie-Tooth disease type 2 (ClinVar).

How common is GARS1 p.Val91Ile (c.271G>A) in the general population?

GARS1 p.Val91Ile (c.271G>A) is very rare (popmax 0.00169%, nfe) (gnomAD).

What do computational predictors say about GARS1 p.Val91Ile (c.271G>A)?

AlphaMissense predicts likely benign (score 0.0699) — an in-silico prediction, not a clinical call.

GARS1 p.Val91Ile

c.271G>A · rs374616031 · VCV515220

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0699 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00169%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 2

Computational evidence

Protein change
AlphaMissense	0.0699	likely benign
REVEL	0.018	moderately benign-leaning
SaProt	LLR -4.90	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.5	GERP -0.49, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 5,108 bp · p 0.097 · regional, not allelic
Overall
CADD	15.78	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

Grpmax group 0.00169% European (non-Finnish) · 20/1,180,030 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00124% 20/1,614,060 alleles · very rare exomes 17/1,461,872 · genomes 3/152,188 · 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.Val91Ile
Coding: c.271G>A
MANE Select: NM_002047
dbSNP: rs374616031
Type: single nucleotide variant
Location: chr7:30598844 (GRCh38)
Gene constraint: LOEUF 0.648 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.61 · 14 PDB
Residue 91: the whep-trs domain

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.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-val91ile (accessed [today's date]).

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