Is GARS1 p.Ala70Pro (c.208G>C) pathogenic?

GARS1 p.Ala70Pro (c.208G>C) is classified Uncertain significance in GARS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-24). AlphaMissense: likely pathogenic (0.961); Very rare (popmax 0.00137%, afr); Associated with Charcot-Marie-Tooth disease type 2.

What condition is associated with GARS1 p.Ala70Pro (c.208G>C)?

GARS1 p.Ala70Pro (c.208G>C) is associated with Charcot-Marie-Tooth disease type 2 (ClinVar).

How common is GARS1 p.Ala70Pro (c.208G>C) in the general population?

GARS1 p.Ala70Pro (c.208G>C) is very rare (popmax 0.00137%, afr) (gnomAD).

What do computational predictors say about GARS1 p.Ala70Pro (c.208G>C)?

AlphaMissense predicts likely pathogenic (score 0.961) — an in-silico prediction, not a clinical call.

GARS1 p.Ala70Pro

c.208G>C · rs1008199275 · VCV1680884

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.961 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00137%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 2

Computational evidence

Protein change
AlphaMissense	0.961	likely pathogenic
REVEL	0.29	benign-leaning
SaProt	LLR -13.17	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 1.2, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 5,108 bp · p 0.097 · regional, not allelic
Overall
CADD	32.0	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 0.00137% African / African-American · 1/73,168 alleles

Overall 6.5e-05% 1/1,538,376 alleles · very rare exomes 0/1,386,140 · genomes 1/152,236 · 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.Ala70Pro
Coding: c.208G>C
MANE Select: NM_002047
dbSNP: rs1008199275
Type: single nucleotide variant
Location: chr7:30595129 (GRCh38)
Gene constraint: LOEUF 0.648 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.61 · 14 PDB
Residue 70: the whep-trs domain; an α-helix

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.Ala70= Likely benign ★ same residue
GARS1 p.Ala70Val 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

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-ala70pro (accessed [today's date]).

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