Is AARS1 p.Phe515= (c.1545C>T) pathogenic?

AARS1 p.Phe515= (c.1545C>T) is classified Likely benign in AARS1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-30). Very rare (popmax 0.00446%, eas); Associated with Charcot-Marie-Tooth disease type 2.

What condition is associated with AARS1 p.Phe515= (c.1545C>T)?

AARS1 p.Phe515= (c.1545C>T) is associated with Charcot-Marie-Tooth disease type 2 (ClinVar).

How common is AARS1 p.Phe515= (c.1545C>T) in the general population?

AARS1 p.Phe515= (c.1545C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

AARS1 p.Phe515=

c.1545C>T · rs200578293 · VCV2893122

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

Charcot-Marie-Tooth disease type 2

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 -3.1	GERP -3.7
Overall
CADD	3.613	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,886 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000743% 12/1,614,016 alleles · very rare exomes 10/1,461,870 · genomes 2/152,146 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,443
Finnishnot grpmax-eligible	0.00312%	32,014
African / African-American	0.00133%	74,920
European (non-Finnish)	0.000593%	168,577

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.Phe515=
Coding: c.1545C>T
MANE Select: NM_001605
dbSNP: rs200578293
Type: single nucleotide variant
Location: chr16:70262472 (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

Similar variants

AARS1 p.Phe515Leu 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-phe515 (accessed [today's date]).

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