Is GARS1 p.Phe604Val (c.1810T>G) pathogenic?

GARS1 p.Phe604Val (c.1810T>G) is classified Uncertain significance in GARS1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-19). AlphaMissense: ambiguous (0.4658); Ultra-rare (popmax 0.0164%, mid); Associated with Charcot-Marie-Tooth disease type 2.

What condition is associated with GARS1 p.Phe604Val (c.1810T>G)?

GARS1 p.Phe604Val (c.1810T>G) is associated with Charcot-Marie-Tooth disease type 2 (ClinVar).

How common is GARS1 p.Phe604Val (c.1810T>G) in the general population?

GARS1 p.Phe604Val (c.1810T>G) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about GARS1 p.Phe604Val (c.1810T>G)?

AlphaMissense predicts ambiguous (score 0.4658) — an in-silico prediction, not a clinical call.

GARS1 p.Phe604Val

c.1810T>G · VCV3665851

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4658 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Charcot-Marie-Tooth disease type 2

Computational evidence

Protein change
AlphaMissense	0.4658	ambiguous
REVEL	0.239	benign-leaning
SaProt	LLR -6.97	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	Δ0.20	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 7.9	GERP 2, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 34 kb · p 2.2e-07 · regional, not allelic
Overall
CADD	24.5	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 0.0164% Middle Eastern · 1/6,080 alleles

Filtering AF 0.00178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000892%

Overall 0.00031% 5/1,611,530 alleles · ultra-rare exomes 4/1,459,294 · genomes 1/152,236 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,080
East Asian	0.00669%	14,944
South Asian	0.0011%	91,042

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.Phe604Val
Coding: c.1810T>G
MANE Select: NM_002047
Type: single nucleotide variant
Location: chr7:30631448 (GRCh38)
Gene constraint: LOEUF 0.648 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.61 · 14 PDB
Residue 604: 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.Phe604Leu 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-phe604val (accessed [today's date]).

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