Is AARS1 p.Val703= (c.2109G>C) pathogenic?

AARS1 p.Val703= (c.2109G>C) is classified Conflicting classifications of pathogenicity in AARS1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-01-15). Ultra-rare (popmax 0.0156%, eas); Associated with Charcot-Marie-Tooth disease axonal type 2N.

What condition is associated with AARS1 p.Val703= (c.2109G>C)?

AARS1 p.Val703= (c.2109G>C) is associated with Charcot-Marie-Tooth disease axonal type 2N, Charcot-Marie-Tooth disease type 2 (ClinVar).

How common is AARS1 p.Val703= (c.2109G>C) in the general population?

AARS1 p.Val703= (c.2109G>C) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

AARS1 p.Val703=

Q: How is Autosomal dominant Charcot-Marie-Tooth disease type 2N inherited?

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

c.2109G>C · rs777499923 · VCV320334

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Conditions

Charcot-Marie-Tooth disease axonal type 2N

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 0.81	GERP 0.71, phastCons 1
Overall
CADD	2.938	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0156% East Asian · 7/44,898 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00514%

Overall 0.000991% 16/1,613,998 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,414
Remaining individualsnot grpmax-eligible	0.0144%	6,943

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: AARS1
Protein: p.Val703=
Coding: c.2109G>C
MANE Select: NM_001605
dbSNP: rs777499923
Type: single nucleotide variant
Location: chr16:70258101 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 90.66 · 10 PDB

Full AARS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Charcot-Marie-Tooth disease axonal type 2N — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Charcot-Marie-Tooth disease type 2

For Autosomal dominant Charcot-Marie-Tooth disease type 2N (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

AARS1 p.Val703Glu Uncertain significance ★ ⚠ same residue
AARS1 c.2177+1G>A Pathogenic/Likely pathogenic ★★ same condition
AARS1 p.Arg13Ter Pathogenic ★★ same condition
AARS1 p.Arg246Ter Pathogenic/Likely pathogenic ★★ same condition
AARS1 p.Arg329Cys Likely pathogenic ★★ same condition
AARS1 p.Arg329His Pathogenic/Likely pathogenic ★★ same condition
AARS1 p.Arg330Ter Pathogenic/Likely pathogenic ★★ same condition
AARS1 p.Arg333Ter 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/aars1-p-val703 (accessed [today's date]).

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