Is AARS1 p.Arg599Ser (c.1797A>T) pathogenic?

AARS1 p.Arg599Ser (c.1797A>T) is classified Uncertain significance in AARS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-17). AlphaMissense: likely pathogenic (0.7038); Very rare (popmax 0.00133%, afr); Associated with Charcot-Marie-Tooth disease type 2.

What condition is associated with AARS1 p.Arg599Ser (c.1797A>T)?

AARS1 p.Arg599Ser (c.1797A>T) is associated with Charcot-Marie-Tooth disease type 2 (ClinVar).

How common is AARS1 p.Arg599Ser (c.1797A>T) in the general population?

AARS1 p.Arg599Ser (c.1797A>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about AARS1 p.Arg599Ser (c.1797A>T)?

AlphaMissense predicts likely pathogenic (score 0.7038) — an in-silico prediction, not a clinical call.

AARS1 p.Arg599Ser

c.1797A>T · rs753398944 · VCV577053

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7038 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 2

Computational evidence

Protein change
AlphaMissense	0.7038	likely pathogenic
REVEL	0.276	benign-leaning
SaProt	LLR -7.25	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP 0.45, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 30 kb · p 0.25 · regional, not allelic
Overall
CADD	18.06	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 0.00133% African / African-American · 1/75,040 alleles

Overall 0.000124% 2/1,614,034 alleles · very rare exomes 2/1,461,786 · genomes 0/152,248 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,040
European (non-Finnish)	8.47e-05%	1,180,013

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.Arg599Ser
Coding: c.1797A>T
MANE Select: NM_001605
dbSNP: rs753398944
Type: single nucleotide variant
Location: chr16:70259175 (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.Arg599= Likely benign ★ 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-arg599ser (accessed [today's date]).

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