Is AARS1 p.Arg751Gly (c.2251A>G) pathogenic?

AARS1 p.Arg751Gly (c.2251A>G) is classified Conflicting classifications of pathogenicity in AARS1 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2025-12-07). AlphaMissense: likely pathogenic (0.9949); Ultra-rare (popmax 0.0178%, nfe); Associated with Inborn genetic diseases.

What condition is associated with AARS1 p.Arg751Gly (c.2251A>G)?

AARS1 p.Arg751Gly (c.2251A>G) is associated with Inborn genetic diseases, Charcot-Marie-Tooth disease axonal type 2N, developmental and epileptic encephalopathy, 29 (ClinVar).

How common is AARS1 p.Arg751Gly (c.2251A>G) in the general population?

AARS1 p.Arg751Gly (c.2251A>G) is ultra-rare (popmax 0.0178%, nfe) (gnomAD).

What do computational predictors say about AARS1 p.Arg751Gly (c.2251A>G)?

AlphaMissense predicts likely pathogenic (score 0.9949) — an in-silico prediction, not a clinical call.

AARS1 p.Arg751Gly

c.2251A>G · rs143370729 · VCV190103

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely pathogenic

0.9949 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9949	likely pathogenic · top 7% in AARS1
REVEL	0.965	strongly pathogenic-leaning
SaProt	LLR -14.48	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 0.53, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 30 kb · p 0.25 · regional, not allelic
Overall
CADD	32.0	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 0.0178% European (non-Finnish) · 210/1,180,020 alleles

Filtering AF 0.0158% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0151%

Overall 0.0135% 218/1,614,142 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0178%	5,619
Remaining individualsnot grpmax-eligible	0.008%	12,502
African / African-American	0.004%	25,010

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.Arg751Gly
Coding: c.2251A>G
MANE Select: NM_001605
dbSNP: rs143370729
Type: single nucleotide variant
Location: chr16:70255763 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 90.66 · 10 PDB
Residue 751: a UniProt-annotated variant site (in dee29; results in 10-fold reduction in aminoacylation efficiency)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Charcot-Marie-Tooth disease axonal type 2N developmental and epileptic encephalopathy, 29 Charcot-Marie-Tooth disease Charcot-Marie-Tooth disease type 2

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-arg751gly (accessed [today's date]).

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