Is AARS2 p.Ile766Ser (c.2297T>G) pathogenic?

AARS2 p.Ile766Ser (c.2297T>G) is classified Uncertain significance in AARS2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-04-09). AlphaMissense: likely benign (0.2277); Very rare (popmax 0.00864%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with AARS2 p.Ile766Ser (c.2297T>G)?

AARS2 p.Ile766Ser (c.2297T>G) is associated with Cardiovascular phenotype, combined oxidative phosphorylation defect type 8 (ClinVar).

How common is AARS2 p.Ile766Ser (c.2297T>G) in the general population?

AARS2 p.Ile766Ser (c.2297T>G) is very rare (popmax 0.00864%, nfe) (gnomAD).

What do computational predictors say about AARS2 p.Ile766Ser (c.2297T>G)?

AlphaMissense predicts likely benign (score 0.2277) — an in-silico prediction, not a clinical call.

AARS2 p.Ile766Ser

c.2297T>G · rs200410313 · VCV910126

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2277 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00864%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.2277	likely benign
REVEL	0.292	indeterminate
SaProt	LLR -6.22	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -0.17
Regional constraint	o/e 0.90	unconstrained · MANE · 13 kb · p 0.00019 · regional, not allelic
Overall
CADD	18.12	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00864% European (non-Finnish) · 102/1,180,028 alleles

Filtering AF 0.00724% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00676%

Overall 0.00682% 110/1,614,000 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00864%	11,569
Remaining individualsnot grpmax-eligible	0.008%	12,497
Finnishnot grpmax-eligible	0.00313%	31,993
African / African-American	0.00133%	74,924

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.Ile766Ser
Coding: c.2297T>G
MANE Select: NM_020745
dbSNP: rs200410313
Type: single nucleotide variant
Location: chr6:44302869 (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

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: combined oxidative phosphorylation defect type 8

Similar variants

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
AARS2 p.Thr782Ile Likely pathogenic ★★ same condition
AARS2 c.*718C>A Uncertain significance ★★ 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-ile766ser (accessed [today's date]).

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