Is AARS2 p.Phe528= (c.1584C>T) pathogenic?

AARS2 p.Phe528= (c.1584C>T) is classified Likely benign in AARS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-30). Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

What condition is associated with AARS2 p.Phe528= (c.1584C>T)?

AARS2 p.Phe528= (c.1584C>T) is associated with Inborn genetic diseases (ClinVar).

How common is AARS2 p.Phe528= (c.1584C>T) in the general population?

AARS2 p.Phe528= (c.1584C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

AARS2 p.Phe528=

c.1584C>T · rs781363059 · VCV1639913

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.31 · evaluated, not missing
Constraint at this position
Conservation	phyloP -1.1	GERP -4.5
Overall
CADD	1.188	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,052 alleles

Filtering AF 0.00377% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00345%

Overall 0.0039% 63/1,614,016 alleles · ultra-rare exomes 61/1,461,806 · genomes 2/152,210 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,052
European (non-Finnish)	0.00483%	20,702
Admixed American	0.00333%	30,005
African / African-American	0.00267%	37,463
Remaining individualsnot grpmax-eligible	0.0016%	62,476

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.Phe528=
Coding: c.1584C>T
MANE Select: NM_020745
dbSNP: rs781363059
Type: single nucleotide variant
Location: chr6:44304813 (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-phe528 (accessed [today's date]).

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