Is AARS1 p.Ala676= (c.2028G>A) pathogenic?

AARS1 p.Ala676= (c.2028G>A) is classified Likely benign in AARS1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-03). Very rare (popmax 0.00527%, nfe); Associated with Inborn genetic diseases.

What condition is associated with AARS1 p.Ala676= (c.2028G>A)?

AARS1 p.Ala676= (c.2028G>A) is associated with Inborn genetic diseases, Charcot-Marie-Tooth disease type 2 (ClinVar).

How common is AARS1 p.Ala676= (c.2028G>A) in the general population?

AARS1 p.Ala676= (c.2028G>A) is very rare (popmax 0.00527%, nfe) (gnomAD).

AARS1 p.Ala676=

c.2028G>A · rs376280288 · VCV476737

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00527%, nfe)

Conditions

Inborn genetic diseases

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 -2.8	GERP -3.4
Overall
CADD	0.547	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00527% European (non-Finnish) · 62/1,175,382 alleles

Filtering AF 0.0042% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.00405% 65/1,604,836 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00527%	18,958
Remaining individualsnot grpmax-eligible	0.00161%	62,086
Finnishnot grpmax-eligible	0.00158%	63,422
South Asian	0.00111%	89,812

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.Ala676=
Coding: c.2028G>A
MANE Select: NM_001605
dbSNP: rs376280288
Type: single nucleotide variant
Location: chr16:70258182 (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 type 2

Similar variants

AARS1 p.Ala676Val 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-ala676 (accessed [today's date]).

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