Is APTX p.Glu125Asp (c.375A>T) pathogenic?

APTX p.Glu125Asp (c.375A>T) is classified Uncertain significance in APTX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-09-12). Ultra-rare (popmax 0.015%, amr); Associated with ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia.

What condition is associated with APTX p.Glu125Asp (c.375A>T)?

APTX p.Glu125Asp (c.375A>T) is associated with ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia (ClinVar).

How common is APTX p.Glu125Asp (c.375A>T) in the general population?

APTX p.Glu125Asp (c.375A>T) is ultra-rare (popmax 0.015%, amr) (gnomAD).

How is Ataxia-oculomotor apraxia type 1 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

APTX p.Glu125Asp

c.375A>T · rs886063858 · VCV366594

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Conditions

ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.185	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.85	GERP 1.6, phastCons 0.5
Regional constraint	o/e 1.01	unconstrained · MANE · 16 kb · p 0.77 · regional, not allelic
Overall
CADD	10.12	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.015% Admixed American · 9/60,004 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00578%

Overall 0.000558% 9/1,614,086 alleles · ultra-rare

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: APTX
Protein: p.Glu125Asp
Coding: c.375A>T
MANE Select: NM_001195248
dbSNP: rs886063858
Type: single nucleotide variant
Location: chr9:32987652 (GRCh38)
Gene constraint: LOEUF 0.973 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.52 · 11 PDB
Residue 125: the 'disordered' region

Full APTX gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Ataxia-oculomotor apraxia type 1 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

APTX c.875-2A>G Pathogenic/Likely pathogenic ★★ same condition
APTX p.Ala198Val Likely pathogenic ★★ same condition
APTX p.Arg16Ter Pathogenic/Likely pathogenic ★★ same condition
APTX p.Gln130Ter Pathogenic/Likely pathogenic ★★ same condition
APTX p.Trp279Ter Pathogenic ★★ same condition
APTX p.Arg247Gln Uncertain significance ★★ same condition
APTX p.His166Tyr Uncertain significance ★★ same condition
APTX p.His258Arg 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/aptx-p-glu125asp (accessed [today's date]).

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