Is AARS2 p.Pro163Ser (c.487C>T) pathogenic?

AARS2 p.Pro163Ser (c.487C>T) is classified Uncertain significance in AARS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-28). AlphaMissense: likely benign (0.1146); Ultra-rare (popmax 0.0822%, mid); Associated with mitochondrial disease.

What condition is associated with AARS2 p.Pro163Ser (c.487C>T)?

AARS2 p.Pro163Ser (c.487C>T) is associated with mitochondrial disease (ClinVar).

How common is AARS2 p.Pro163Ser (c.487C>T) in the general population?

AARS2 p.Pro163Ser (c.487C>T) is ultra-rare (popmax 0.0822%, mid) (gnomAD).

What do computational predictors say about AARS2 p.Pro163Ser (c.487C>T)?

AlphaMissense predicts likely benign (score 0.1146) — an in-silico prediction, not a clinical call.

AARS2 p.Pro163Ser

c.487C>T · rs368559173 · VCV3138695

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1146 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0822%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

mitochondrial disease

Computational evidence

Protein change
AlphaMissense	0.1146	likely benign
REVEL	0.423	indeterminate
SaProt	LLR -10.06	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 13 kb · p 0.00019 · regional, not allelic
Overall
CADD	26.1	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 0.0822% Middle Eastern · 5/6,084 alleles

Filtering AF 0.0323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.021%

Overall 0.000434% 7/1,613,940 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0822%	1,217
European (non-Finnish)	0.000169%	590,019

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.Pro163Ser
Coding: c.487C>T
MANE Select: NM_020745
dbSNP: rs368559173
Type: single nucleotide variant
Location: chr6:44311484 (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

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

Similar variants

AARS2 p.Arg592Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
AARS2 p.Ala802Val Uncertain significance ★★ ⚠ same condition
AARS2 p.Arg28Gly Uncertain significance ★★ ⚠ same condition
AARS2 p.Arg316His Uncertain significance ★★ ⚠ same condition
AARS2 p.Arg777Cys Uncertain significance ★★ ⚠ same condition
AARS2 p.Gly415Asp Uncertain significance ★★ ⚠ same condition
AARS2 p.Thr938Pro Uncertain significance ★★ ⚠ same condition
AARS2 p.Arg841Gln Conflicting classifications of pathogenicity ★ ⚠ 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-pro163ser (accessed [today's date]).

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