Is AARS1 p.Asn340Ser (c.1019A>G) pathogenic?

AARS1 p.Asn340Ser (c.1019A>G) is classified Conflicting classifications of pathogenicity in AARS1 (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-01-19). AlphaMissense: likely benign (0.0711); Ultra-rare (popmax 0.0288%, nfe); Associated with Inborn genetic diseases.

What condition is associated with AARS1 p.Asn340Ser (c.1019A>G)?

AARS1 p.Asn340Ser (c.1019A>G) is associated with Inborn genetic diseases, Charcot-Marie-Tooth disease axonal type 2N, Charcot-Marie-Tooth disease (ClinVar).

How common is AARS1 p.Asn340Ser (c.1019A>G) in the general population?

AARS1 p.Asn340Ser (c.1019A>G) is ultra-rare (popmax 0.0288%, nfe) (gnomAD).

What do computational predictors say about AARS1 p.Asn340Ser (c.1019A>G)?

AlphaMissense predicts likely benign (score 0.0711) — an in-silico prediction, not a clinical call.

AARS1 p.Asn340Ser

c.1019A>G · rs140135726 · VCV412288

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.0711 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0288%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0711	likely benign
REVEL	0.159	moderately benign-leaning
SaProt	LLR -8.24	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.95	GERP -0.58, phastCons 0.79
Regional constraint	o/e 0.97	unconstrained · MANE · 30 kb · p 0.25 · regional, not allelic
Overall
CADD	19.21	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 0.0288% European (non-Finnish) · 340/1,180,040 alleles

Filtering AF 0.0263% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0253%

Overall 0.0222% 359/1,614,076 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0288%	3,471
Remaining individualsnot grpmax-eligible	0.0192%	5,207
Admixed American	0.00667%	15,002
East Asian	0.00223%	44,886
African / African-American	0.00133%	74,940
South Asian	0.0011%	91,084

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.Asn340Ser
Coding: c.1019A>G
MANE Select: NM_001605
dbSNP: rs140135726
Type: single nucleotide variant
Location: chr16:70268323 (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

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

Also linked: Charcot-Marie-Tooth disease axonal type 2N 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-asn340ser (accessed [today's date]).

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