Is AARS1 p.Val503= (c.1509G>A) pathogenic?

AARS1 p.Val503= (c.1509G>A) is classified Conflicting classifications of pathogenicity in AARS1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-11-25). Ultra-rare (popmax 0.0959%, eas); Associated with Charcot-Marie-Tooth disease type 2.

What condition is associated with AARS1 p.Val503= (c.1509G>A)?

AARS1 p.Val503= (c.1509G>A) is associated with Charcot-Marie-Tooth disease type 2, Charcot-Marie-Tooth disease axonal type 2N (ClinVar).

How common is AARS1 p.Val503= (c.1509G>A) in the general population?

AARS1 p.Val503= (c.1509G>A) is ultra-rare (popmax 0.0959%, eas) (gnomAD).

AARS1 p.Val503=

c.1509G>A · rs138406510 · VCV543286

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0959%, eas)

Conditions

Charcot-Marie-Tooth disease type 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.21	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 0.57	GERP -0.3, phastCons 1
Overall
CADD	8.71	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0959% East Asian · 43/44,848 alleles

Filtering AF 0.0731% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0651%

Overall 0.0122% 197/1,613,188 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.25%	400
East Asiangrpmax	0.0959%	1,043
Remaining individualsnot grpmax-eligible	0.0272%	3,675
South Asian	0.0253%	3,960
European (non-Finnish)	0.00339%	29,481

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val503=
Coding: c.1509G>A
MANE Select: NM_001605
dbSNP: rs138406510
Type: single nucleotide variant
Location: chr16:70262508 (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 type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Charcot-Marie-Tooth disease axonal type 2N

Similar variants

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
AARS1 p.Arg598Ter 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-val503 (accessed [today's date]).

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