Is AARS2 p.Asn76Ser (c.227A>G) pathogenic?

AARS2 p.Asn76Ser (c.227A>G) is classified Uncertain significance in AARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-22). AlphaMissense: likely benign (0.1641); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with AARS2 p.Asn76Ser (c.227A>G)?

AARS2 p.Asn76Ser (c.227A>G) is associated with Inborn genetic diseases (ClinVar).

How common is AARS2 p.Asn76Ser (c.227A>G) in the general population?

AARS2 p.Asn76Ser (c.227A>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about AARS2 p.Asn76Ser (c.227A>G)?

AlphaMissense predicts likely benign (score 0.1641) — an in-silico prediction, not a clinical call.

AARS2 p.Asn76Ser

c.227A>G · rs1294144659 · VCV2597488

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1641 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1641	likely benign
REVEL	0.762	pathogenic-leaning
SaProt	LLR -9.85	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.1, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 13 kb · p 0.00019 · regional, not allelic
Overall
CADD	26.3	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 0.00133% African / African-American · 1/74,952 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,613,454 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,952
European (non-Finnish)	0.000339%	294,990

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.Asn76Ser
Coding: c.227A>G
MANE Select: NM_020745
dbSNP: rs1294144659
Type: single nucleotide variant
Location: chr6:44313097 (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-asn76ser (accessed [today's date]).

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