Is GARS1 p.Phe549Ser (c.1646T>C) pathogenic?

GARS1 p.Phe549Ser (c.1646T>C) is classified Uncertain significance in GARS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-11). AlphaMissense: likely pathogenic (0.7932); Very rare (popmax 8.51e-05%, nfe); Associated with Charcot-Marie-Tooth disease type 2.

What condition is associated with GARS1 p.Phe549Ser (c.1646T>C)?

GARS1 p.Phe549Ser (c.1646T>C) is associated with Charcot-Marie-Tooth disease type 2 (ClinVar).

How common is GARS1 p.Phe549Ser (c.1646T>C) in the general population?

GARS1 p.Phe549Ser (c.1646T>C) is very rare (popmax 8.51e-05%, nfe) (gnomAD).

What do computational predictors say about GARS1 p.Phe549Ser (c.1646T>C)?

AlphaMissense predicts likely pathogenic (score 0.7932) — an in-silico prediction, not a clinical call.

GARS1 p.Phe549Ser

c.1646T>C · rs2534327563 · VCV3020312

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7932 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.51e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 2

Computational evidence

Protein change
AlphaMissense	0.7932	likely pathogenic
REVEL	0.844	moderately pathogenic-leaning
SaProt	LLR -15.30	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 34 kb · p 2.2e-07 · regional, not allelic
Overall
CADD	28.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.51e-05% European (non-Finnish) · 1/1,175,138 alleles

Overall 6.22e-05% 1/1,608,636 alleles · very rare exomes 1/1,456,306 · genomes 0/152,330 · 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.Phe549Ser
Coding: c.1646T>C
MANE Select: NM_002047
dbSNP: rs2534327563
Type: single nucleotide variant
Location: chr7:30626266 (GRCh38)
Gene constraint: LOEUF 0.648 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.61 · 14 PDB
Residue 549: a β-strand

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-phe549ser (accessed [today's date]).

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