Is AARS2 p.Ala320Val (c.959C>T) pathogenic?

AARS2 p.Ala320Val (c.959C>T) is classified Conflicting classifications of pathogenicity in AARS2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-06-12). AlphaMissense: likely pathogenic (0.6335); Very rare (popmax 0.0022%, sas).

How common is AARS2 p.Ala320Val (c.959C>T) in the general population?

AARS2 p.Ala320Val (c.959C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about AARS2 p.Ala320Val (c.959C>T)?

AlphaMissense predicts likely pathogenic (score 0.6335) — an in-silico prediction, not a clinical call.

AARS2 p.Ala320Val

c.959C>T · rs201471937 · VCV932473

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6335 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6335	likely pathogenic
REVEL	0.627	indeterminate
SaProt	LLR -15.68	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
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	31.0	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 0.0022% South Asian · 2/90,858 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000205% 3/1,460,964 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,429
European (non-Finnish)	8.48e-05%	1,179,668

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.Ala320Val
Coding: c.959C>T
MANE Select: NM_020745
dbSNP: rs201471937
Type: single nucleotide variant
Location: chr6:44307330 (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

Similar variants

AARS2 p.Ala320= Likely benign ★ same residue
AARS2 c.2146-2A>G Pathogenic/Likely pathogenic ★★ same type
AARS2 c.2255+1G>A Pathogenic ★★ same type
AARS2 c.2598+1G>T Pathogenic/Likely pathogenic ★★ same type
AARS2 p.Arg199Cys Pathogenic/Likely pathogenic ★★ ⚠ same type
AARS2 p.Arg521Ter Pathogenic ★★ same type
AARS2 p.Arg580Trp Likely pathogenic ★★ ⚠ same type
AARS2 p.Arg592Trp Pathogenic/Likely pathogenic ★★ ⚠ same type

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-ala320val (accessed [today's date]).

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