Is AARS2 p.Asp512His (c.1534G>C) pathogenic?

AARS2 p.Asp512His (c.1534G>C) is classified Conflicting classifications of pathogenicity in AARS2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-06-01). AlphaMissense: likely pathogenic (0.6866); Ultra-rare (popmax 0.0293%, nfe); Associated with combined oxidative phosphorylation defect type 8.

What condition is associated with AARS2 p.Asp512His (c.1534G>C)?

AARS2 p.Asp512His (c.1534G>C) is associated with combined oxidative phosphorylation defect type 8 (ClinVar).

How common is AARS2 p.Asp512His (c.1534G>C) in the general population?

AARS2 p.Asp512His (c.1534G>C) is ultra-rare (popmax 0.0293%, nfe) (gnomAD).

What do computational predictors say about AARS2 p.Asp512His (c.1534G>C)?

AlphaMissense predicts likely pathogenic (score 0.6866) — an in-silico prediction, not a clinical call.

AARS2 p.Asp512His

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.1534G>C · rs146512155 · VCV357070

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.6866 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0293%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

combined oxidative phosphorylation defect type 8

Computational evidence

Protein change
AlphaMissense	0.6866	likely pathogenic
REVEL	0.448	indeterminate
SaProt	LLR -10.44	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 0.74, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 13 kb · p 0.00019 · regional, not allelic
Overall
CADD	25.2	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 0.0293% European (non-Finnish) · 346/1,180,042 alleles

Filtering AF 0.0267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0257%

Overall 0.0249% 402/1,613,950 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0516%	1,937
European (non-Finnish)grpmax	0.0293%	3,411
Ashkenazi Jewishnot grpmax-eligible	0.027%	3,701
Remaining individualsnot grpmax-eligible	0.0208%	4,807
African / African-American	0.00267%	37,463

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asp512His
Coding: c.1534G>C
MANE Select: NM_020745
dbSNP: rs146512155
Type: single nucleotide variant
Location: chr6:44305099 (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-asp512his (accessed [today's date]).

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