Is AARS2 p.Ala275Val (c.824C>T) pathogenic?

AARS2 p.Ala275Val (c.824C>T) is classified Uncertain significance in AARS2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-03). AlphaMissense: likely benign (0.2117); Ultra-rare (popmax 0.0617%, amr); Associated with Inborn genetic diseases.

What condition is associated with AARS2 p.Ala275Val (c.824C>T)?

AARS2 p.Ala275Val (c.824C>T) is associated with Inborn genetic diseases, AARS2-related disorder (ClinVar).

How common is AARS2 p.Ala275Val (c.824C>T) in the general population?

AARS2 p.Ala275Val (c.824C>T) is ultra-rare (popmax 0.0617%, amr) (gnomAD).

What do computational predictors say about AARS2 p.Ala275Val (c.824C>T)?

AlphaMissense predicts likely benign (score 0.2117) — an in-silico prediction, not a clinical call.

AARS2 p.Ala275Val

c.824C>T · rs753386864 · VCV1435777

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2117 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0617%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2117	likely benign
REVEL	0.648	pathogenic-leaning
SaProt	LLR -10.11	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 13 kb · p 0.00019 · regional, not allelic
Overall
CADD	25.5	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 0.0617% Admixed American · 37/59,984 alleles

Filtering AF 0.0459% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0405%

Overall 0.00279% 45/1,613,962 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0617%	1,621
Remaining individualsnot grpmax-eligible	0.0064%	15,618
African / African-American	0.004%	24,986
European (non-Finnish)	8.47e-05%	1,179,998

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.Ala275Val
Coding: c.824C>T
MANE Select: NM_020745
dbSNP: rs753386864
Type: single nucleotide variant
Location: chr6:44310369 (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

Also linked: AARS2-related disorder

Similar variants

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.Arg958Ter Pathogenic/Likely pathogenic ★★ same condition
AARS2 p.Gln798Ter Likely pathogenic ★★ same condition
AARS2 p.Met1Thr Likely pathogenic ★★ same condition
AARS2 p.Ala37Thr Uncertain significance ★★ ⚠ same condition
AARS2 p.Ala566Thr 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-ala275val (accessed [today's date]).

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