Is AARS2 p.Pro20= (c.60C>T) pathogenic?

AARS2 p.Pro20= (c.60C>T) is classified Conflicting classifications of pathogenicity in AARS2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-28). Ultra-rare (popmax 0.043%, amr); Associated with combined oxidative phosphorylation defect type 8.

What condition is associated with AARS2 p.Pro20= (c.60C>T)?

AARS2 p.Pro20= (c.60C>T) is associated with combined oxidative phosphorylation defect type 8 (ClinVar).

How common is AARS2 p.Pro20= (c.60C>T) in the general population?

AARS2 p.Pro20= (c.60C>T) is ultra-rare (popmax 0.043%, amr) (gnomAD).

AARS2 p.Pro20=

Q: How is Combined oxidative phosphorylation defect type 8 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.60C>T · rs781361302 · VCV909156

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.043%, amr)

Conditions

combined oxidative phosphorylation defect type 8

Computational evidence

Protein change
Missense predictors do not apply to this variant type.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Overall
CADD	5.706	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.043% Admixed American · 25/58,202 alleles

Filtering AF 0.0298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0255%

Overall 0.00326% 52/1,597,176 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.043%	2,328
Remaining individualsnot grpmax-eligible	0.00485%	20,627
European (non-Finnish)	0.00187%	53,434
African / African-American	0.00134%	74,758
South Asian	0.00111%	89,696

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.Pro20=
Coding: c.60C>T
MANE Select: NM_020745
dbSNP: rs781361302
Type: single nucleotide variant
Location: chr6:44313264 (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

combined oxidative phosphorylation defect type 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Combined oxidative phosphorylation defect type 8 (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

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-pro20 (accessed [today's date]).

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