Is AARS2 p.Cys750Arg (c.2248T>C) pathogenic?

AARS2 p.Cys750Arg (c.2248T>C) is classified Uncertain significance in AARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-08). AlphaMissense: likely pathogenic (0.5988); Very rare (popmax 0.00934%, afr); Associated with Inborn genetic diseases.

What condition is associated with AARS2 p.Cys750Arg (c.2248T>C)?

AARS2 p.Cys750Arg (c.2248T>C) is associated with Inborn genetic diseases (ClinVar).

How common is AARS2 p.Cys750Arg (c.2248T>C) in the general population?

AARS2 p.Cys750Arg (c.2248T>C) is very rare (popmax 0.00934%, afr) (gnomAD).

What do computational predictors say about AARS2 p.Cys750Arg (c.2248T>C)?

AlphaMissense predicts likely pathogenic (score 0.5988) — an in-silico prediction, not a clinical call.

AARS2 p.Cys750Arg

c.2248T>C · VCV4562578

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5988 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00934%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5988	likely pathogenic
REVEL	0.728	pathogenic-leaning
SaProt	LLR -8.20	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 13 kb · p 0.00019 · regional, not allelic
Overall
CADD	27.5	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 0.00934% African / African-American · 7/74,934 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.000434% 7/1,613,946 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.Cys750Arg
Coding: c.2248T>C
MANE Select: NM_020745
Type: single nucleotide variant
Location: chr6:44303073 (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.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
AARS2 p.Ala9Ser 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-cys750arg (accessed [today's date]).

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