Is APTX p.Trp279Ter (c.837G>A) pathogenic?

APTX p.Trp279Ter (c.837G>A) is classified Pathogenic in APTX (ClinVar, Multiple submitters, 24 submitters; last evaluated 2026-03-29). Ultra-rare (popmax 0.0461%, nfe); Associated with APTX-related disorder.

What condition is associated with APTX p.Trp279Ter (c.837G>A)?

APTX p.Trp279Ter (c.837G>A) is associated with APTX-related disorder, ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia, hereditary ataxia (ClinVar).

How common is APTX p.Trp279Ter (c.837G>A) in the general population?

APTX p.Trp279Ter (c.837G>A) is ultra-rare (popmax 0.0461%, nfe) (gnomAD).

APTX p.Trp279Ter

c.837G>A · rs104894103 · VCV4431

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 24 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0461%, nfe)

Conditions

APTX-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (7 of 8, 37 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.29 · evaluated, not missing
Pangolin	Δ0.34	loss · gain 0.00 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 7.5	GERP 1.7, phastCons 1
Overall
CADD	42.0	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 0.0461% European (non-Finnish) · 542/1,175,986 alleles

Filtering AF 0.0429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0416%

Overall 0.0369% 594/1,608,946 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0461%	2,170
Remaining individualsnot grpmax-eligible	0.0385%	2,597
Admixed American	0.0367%	2,726
African / African-American	0.00802%	12,465

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.Trp279Ter
Coding: c.837G>A
MANE Select: NM_001195248
dbSNP: rs104894103
Type: single nucleotide variant
Location: chr9:32974495 (GRCh38)
Gene constraint: LOEUF 0.973 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.52 · 11 PDB
Residue 279: the hit domain; a β-strand

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

Disease context

APTX-related disorder

Also linked: ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia hereditary ataxia

Similar variants

APTX p.Trp279Arg Pathogenic/Likely pathogenic ★★ 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.Arg247Ter Pathogenic/Likely pathogenic ★★ same condition
APTX p.Gln130Ter Pathogenic/Likely 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-trp279ter (accessed [today's date]).

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