Is AARS2 p.Ala152Asp (c.455C>A) pathogenic?

AARS2 p.Ala152Asp (c.455C>A) is classified Uncertain significance in AARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-21). AlphaMissense: likely pathogenic (0.9533); Very rare (popmax 0.0011%, sas); Associated with AARS2-related disorder.

What condition is associated with AARS2 p.Ala152Asp (c.455C>A)?

AARS2 p.Ala152Asp (c.455C>A) is associated with AARS2-related disorder (ClinVar).

How common is AARS2 p.Ala152Asp (c.455C>A) in the general population?

AARS2 p.Ala152Asp (c.455C>A) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about AARS2 p.Ala152Asp (c.455C>A)?

AlphaMissense predicts likely pathogenic (score 0.9533) — an in-silico prediction, not a clinical call.

AARS2 p.Ala152Asp

c.455C>A · rs2153357333 · VCV2634748

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9533 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

AARS2-related disorder

Computational evidence

Protein change
AlphaMissense	0.9533	likely pathogenic · top 1% in AARS2
REVEL	0.947	strongly pathogenic-leaning
SaProt	LLR -14.44	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 13 kb · p 0.00019 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0011% South Asian · 1/91,066 alleles

Overall 6.84e-05% 1/1,461,266 alleles · very rare

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.Ala152Asp
Coding: c.455C>A
MANE Select: NM_020745
dbSNP: rs2153357333
Type: single nucleotide variant
Location: chr6:44311516 (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

AARS2-related disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AARS2 p.Ala152Gly Uncertain significance ★ ⚠ same residue
AARS2 c.2598+1G>T Pathogenic/Likely pathogenic ★★ same condition
AARS2 p.Arg199Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
AARS2 p.Arg592Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
AARS2 p.Gln798Ter Likely pathogenic ★★ same condition
AARS2 p.Met1Thr Likely pathogenic ★★ same condition
AARS2 p.Ala275Val Uncertain significance ★★ ⚠ same condition
AARS2 c.2007+8C>T Benign/Likely benign ★★ 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-ala152asp (accessed [today's date]).

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