Is AARS2 p.Tyr226= (c.678C>T) pathogenic?

AARS2 p.Tyr226= (c.678C>T) is classified Benign/Likely benign in AARS2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-07-24). Rare (popmax 0.277%, sas); Associated with AARS2-related disorder.

What condition is associated with AARS2 p.Tyr226= (c.678C>T)?

AARS2 p.Tyr226= (c.678C>T) is associated with AARS2-related disorder (ClinVar).

How common is AARS2 p.Tyr226= (c.678C>T) in the general population?

AARS2 p.Tyr226= (c.678C>T) is rare (popmax 0.277%, sas) (gnomAD).

AARS2 p.Tyr226=

c.678C>T · rs78135749 · VCV136223

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.277%, sas)

Conditions

AARS2-related disorder

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 0.88	GERP -0.016, phastCons 0.97
Overall
CADD	7.322	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.277% South Asian · 252/91,086 alleles

Filtering AF 0.249% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.238%

Overall 0.0266% 429/1,614,076 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.277%	361
African / African-American	0.0586%	1,706
Middle Eastern	0.0495%	2,021
Remaining individualsnot grpmax-eligible	0.0368%	2,718
East Asian	0.0178%	5,609
European (non-Finnish)	0.00805%	12,421
Ashkenazi Jewishnot grpmax-eligible	0.00675%	14,804
Admixed American	0.00333%	30,014

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: AARS2
Protein: p.Tyr226=
Coding: c.678C>T
MANE Select: NM_020745
dbSNP: rs78135749
Type: single nucleotide variant
Location: chr6:44311065 (GRCh38)
Gene constraint: LOEUF 0.752 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.05 · 3 PDB

Full AARS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

AARS2-related disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AARS2 c.2598+1G>T Pathogenic/Likely pathogenic ★★ same condition
AARS2 p.Arg199Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
AARS2 p.Arg592Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
AARS2 p.Gln798Ter Likely pathogenic ★★ same condition
AARS2 p.Met1Thr Likely pathogenic ★★ same condition
AARS2 p.Ala275Val Uncertain significance ★★ ⚠ same condition
AARS2 c.2007+8C>T Benign/Likely benign ★★ same condition
AARS2 p.Arg877Trp Benign/Likely benign ★★ ⚠ 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/aars2-p-tyr226 (accessed [today's date]).

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