Is APTX p.Pro254= (c.762G>A) pathogenic?

APTX p.Pro254= (c.762G>A) is classified Benign/Likely benign in APTX (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-12-24). Rare (popmax 0.653%, sas); Associated with ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia.

What condition is associated with APTX p.Pro254= (c.762G>A)?

APTX p.Pro254= (c.762G>A) is associated with ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia (ClinVar).

How common is APTX p.Pro254= (c.762G>A) in the general population?

APTX p.Pro254= (c.762G>A) is rare (popmax 0.653%, sas) (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.Pro254=

c.762G>A · rs571475924 · VCV281340

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

rare (popmax 0.653%, sas)

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.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.2	GERP -3.4, phastCons 0.043
Overall
CADD	9.89	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.653% South Asian · 595/91,078 alleles

Filtering AF 0.61% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.593%

Overall 0.0486% 784/1,614,184 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.653%	153
Middle Eastern	0.363%	276
Remaining individualsnot grpmax-eligible	0.0816%	1,226
Admixed American	0.02%	5,002
Finnishnot grpmax-eligible	0.00937%	10,672
European (non-Finnish)	0.00805%	12,421
African / African-American	0.004%	25,020

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.Pro254=
Coding: c.762G>A
MANE Select: NM_001195248
dbSNP: rs571475924
Type: single nucleotide variant
Location: chr9:32984639 (GRCh38)
Gene constraint: LOEUF 0.973 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.52 · 11 PDB
Residue 254: the hit domain; an α-helix

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 p.Pro254Leu Uncertain significance ★ same residue
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.Glu125Asp 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-pro254 (accessed [today's date]).

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