Is AARS2 p.Arg711Cys (c.2131C>T) pathogenic?

AARS2 p.Arg711Cys (c.2131C>T) is classified Uncertain significance in AARS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-19). AlphaMissense: likely benign (0.1118); Ultra-rare (popmax 0.0414%, afr); Associated with Inborn genetic diseases.

What condition is associated with AARS2 p.Arg711Cys (c.2131C>T)?

AARS2 p.Arg711Cys (c.2131C>T) is associated with Inborn genetic diseases (ClinVar).

How common is AARS2 p.Arg711Cys (c.2131C>T) in the general population?

AARS2 p.Arg711Cys (c.2131C>T) is ultra-rare (popmax 0.0414%, afr) (gnomAD).

What do computational predictors say about AARS2 p.Arg711Cys (c.2131C>T)?

AlphaMissense predicts likely benign (score 0.1118) — an in-silico prediction, not a clinical call.

AARS2 p.Arg711Cys

c.2131C>T · rs758466937 · VCV1421263

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1118 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0414%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1118	likely benign
REVEL	0.595	indeterminate
SaProt	LLR -10.88	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 8.6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 13 kb · p 0.00019 · regional, not allelic
Overall
CADD	28.7	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 0.0414% African / African-American · 31/74,938 alleles

Filtering AF 0.0299% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.026%

Overall 0.00421% 68/1,613,994 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0414%	2,417
South Asian	0.00878%	11,386
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
East Asian	0.00223%	44,894
European (non-Finnish)	0.00212%	47,202
Admixed American	0.00167%	60,006
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Arg711Cys
Coding: c.2131C>T
MANE Select: NM_020745
dbSNP: rs758466937
Type: single nucleotide variant
Location: chr6:44303300 (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.Arg711His Uncertain significance ★★ ⚠ same residue
AARS2 p.Arg711= Likely benign ★ 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

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-arg711cys (accessed [today's date]).

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