Is AARS2 p.Met850Val (c.2548A>G) pathogenic?

AARS2 p.Met850Val (c.2548A>G) is classified Benign in AARS2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-25). AlphaMissense: likely benign (0.0731); Common (popmax 5.91%, afr) — too common for a highly-penetrant pathogenic allele; Associated with combined oxidative phosphorylation defect type 8.

What condition is associated with AARS2 p.Met850Val (c.2548A>G)?

AARS2 p.Met850Val (c.2548A>G) is associated with combined oxidative phosphorylation defect type 8, AARS2-related disorder (ClinVar).

What do computational predictors say about AARS2 p.Met850Val (c.2548A>G)?

AlphaMissense predicts likely benign (score 0.0731) — an in-silico prediction, not a clinical call.

AARS2 p.Met850Val

Q: How common is AARS2 p.Met850Val (c.2548A>G) in the general population?

AARS2 p.Met850Val (c.2548A>G) is common (popmax 5.91%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.2548A>G · rs35783144 · VCV136218

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0731 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 5.91%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

combined oxidative phosphorylation defect type 8

Computational evidence

Protein change
AlphaMissense	0.0731	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -4.38	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 -1.1	GERP -4.2
Regional constraint	o/e 0.90	unconstrained · MANE · 13 kb · p 0.00019 · regional, not allelic
Overall
CADD	1.394	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 5.91% African / African-American · 4,435/75,050 alleles

Filtering AF 5.76% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.7%

Overall 0.302% 4,881/1,613,934 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.91%	17
Remaining individualsnot grpmax-eligible	0.338%	296
Admixed American	0.292%	343
Middle Eastern	0.099%	1,010
South Asian	0.0121%	8,280
European (non-Finnish)	0.00364%	27,442

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.Met850Val
Coding: c.2548A>G
MANE Select: NM_020745
dbSNP: rs35783144
Type: single nucleotide variant
Location: chr6:44302110 (GRCh38)
Gene constraint: LOEUF 0.752 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.05 · 3 PDB
Residue 850: a UniProt-annotated variant site (in); an α-helix

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

Also linked: AARS2-related disorder

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 c.2598+1G>T Pathogenic/Likely 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.Gln798Ter 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-met850val (accessed [today's date]).

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