Is AARS2 p.Thr910fs (c.2728_2755del) pathogenic?

AARS2 p.Thr910fs (c.27282755del) is classified Conflicting classifications of pathogenicity in AARS2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-12). Ultra-rare (popmax 0.0483%, amr).

How common is AARS2 p.Thr910fs (c.2728_2755del) in the general population?

AARS2 p.Thr910fs (c.2728_2755del) is ultra-rare (popmax 0.0483%, amr) (gnomAD).

AARS2 p.Thr910fs

c.2728_2755del · rs780343109 · VCV497299

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0483%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (21 of 22, 38 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 8.3	GERP 0.004, phastCons 1
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0483% Admixed American · 29/60,008 alleles

Filtering AF 0.0345% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0299%

Overall 0.00248% 40/1,613,716 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0483%	2,069
Remaining individualsnot grpmax-eligible	0.0096%	10,416
European (non-Finnish)	0.000424%	235,996

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.Thr910fs
Coding: c.2728_2755del
MANE Select: NM_020745
dbSNP: rs780343109
Type: Deletion
Location: chr6:44301194 (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.Thr910= Likely benign ★★ same residue
AARS2 p.Thr910Arg Uncertain significance ★ ⚠ same residue
AARS2 p.Thr910Met Uncertain significance ★ ⚠ same residue
AARS2 p.Gln261fs Pathogenic/Likely pathogenic ★★ same type
AARS2 p.Gly647fs Pathogenic/Likely pathogenic ★★ same type
AARS2 p.Glu314del Uncertain significance ★★ same type
AARS2 c.(759+1_760-1 Likely pathogenic ★ same type
AARS2 p.Gln568fs 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-thr910fs (accessed [today's date]).

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