Is AARS2 p.Ala295Ser (c.883G>T) pathogenic?

AARS2 p.Ala295Ser (c.883G>T) is classified Uncertain significance in AARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-18). AlphaMissense: likely benign (0.1164); Ultra-rare (popmax 0.0139%, amr); Associated with Inborn genetic diseases.

What condition is associated with AARS2 p.Ala295Ser (c.883G>T)?

AARS2 p.Ala295Ser (c.883G>T) is associated with Inborn genetic diseases (ClinVar).

How common is AARS2 p.Ala295Ser (c.883G>T) in the general population?

AARS2 p.Ala295Ser (c.883G>T) is ultra-rare (popmax 0.0139%, amr) (gnomAD).

What do computational predictors say about AARS2 p.Ala295Ser (c.883G>T)?

AlphaMissense predicts likely benign (score 0.1164) — an in-silico prediction, not a clinical call.

AARS2 p.Ala295Ser

c.883G>T · VCV3825367

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1164 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0139%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1164	likely benign
REVEL	0.29	benign-leaning
SaProt	LLR -9.15	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 5.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 13 kb · p 0.00019 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0139% Admixed American · 8/57,614 alleles

Filtering AF 0.00685% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.005%

Overall 0.00075% 12/1,600,890 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0139%	7,202
Remaining individualsnot grpmax-eligible	0.00161%	62,042
African / African-American	0.00134%	74,842
European (non-Finnish)	0.00017%	586,734

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.Ala295Ser
Coding: c.883G>T
MANE Select: NM_020745
Type: single nucleotide variant
Location: chr6:44310310 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AARS2 p.Ala295Thr Uncertain significance ★ ⚠ same residue
AARS2 p.Arg958Ter Pathogenic/Likely pathogenic ★★ same condition
AARS2 p.Met1Thr Likely pathogenic ★★ same condition
AARS2 p.Ala275Val Uncertain significance ★★ ⚠ same condition
AARS2 p.Ala37Thr Uncertain significance ★★ ⚠ same condition
AARS2 p.Ala566Thr Uncertain significance ★★ ⚠ same condition
AARS2 p.Ala737Gly Uncertain significance ★★ ⚠ same condition
AARS2 p.Ala741Thr 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-ala295ser (accessed [today's date]).

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