Is AARS2 p.Arg554His (c.1661G>A) pathogenic?

AARS2 p.Arg554His (c.1661G>A) is classified Likely benign in AARS2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-03-05). AlphaMissense: likely benign (0.0693); Rare (popmax 0.604%, sas); Associated with Inborn genetic diseases.

What condition is associated with AARS2 p.Arg554His (c.1661G>A)?

AARS2 p.Arg554His (c.1661G>A) is associated with Inborn genetic diseases, combined oxidative phosphorylation defect type 8 (ClinVar).

How common is AARS2 p.Arg554His (c.1661G>A) in the general population?

AARS2 p.Arg554His (c.1661G>A) is rare (popmax 0.604%, sas) (gnomAD).

What do computational predictors say about AARS2 p.Arg554His (c.1661G>A)?

AlphaMissense predicts likely benign (score 0.0693) — an in-silico prediction, not a clinical call.

AARS2 p.Arg554His

c.1661G>A · rs139280416 · VCV357067

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0693 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.604%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0693	likely benign
REVEL	0.04	moderately benign-leaning
SaProt	LLR -9.41	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 0.41	GERP -1.1, phastCons 0.98
Regional constraint	o/e 0.90	unconstrained · MANE · 13 kb · p 0.00019 · regional, not allelic
Overall
CADD	18.61	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 0.604% South Asian · 550/91,084 alleles

Filtering AF 0.562% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.546%

Overall 0.0517% 835/1,614,222 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.604%	166
Middle Eastern	0.165%	606
Remaining individualsnot grpmax-eligible	0.0288%	3,473
European (non-Finnish)	0.0205%	4,876
East Asian	0.00891%	11,221
Admixed American	0.00833%	12,006
African / African-American	0.00666%	15,012
Finnishnot grpmax-eligible	0.00156%	64,030

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.Arg554His
Coding: c.1661G>A
MANE Select: NM_020745
dbSNP: rs139280416
Type: single nucleotide variant
Location: chr6:44304736 (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

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

Also linked: combined oxidative phosphorylation defect type 8

Similar variants

AARS2 p.Arg554Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
AARS2 p.Arg554= Likely benign ★ same residue
AARS2 c.2146-2A>G Pathogenic/Likely pathogenic ★★ same condition
AARS2 c.2255+1G>A Pathogenic ★★ same condition
AARS2 p.Arg199Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
AARS2 p.Arg521Ter Pathogenic ★★ same condition
AARS2 p.Arg592Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
AARS2 p.Arg958Ter 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/aars2-p-arg554his (accessed [today's date]).

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