Is APTX p.Pro206Leu (c.617C>T) pathogenic?

APTX p.Pro206Leu (c.617C>T) is classified Pathogenic in APTX (ClinVar, Single submitter, 2 submitters; last evaluated 2024-02-13). Ultra-rare (popmax 0.0164%, mid); Associated with APTX-related disorder.

What condition is associated with APTX p.Pro206Leu (c.617C>T)?

APTX p.Pro206Leu (c.617C>T) is associated with APTX-related disorder, ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia (ClinVar).

How common is APTX p.Pro206Leu (c.617C>T) in the general population?

APTX p.Pro206Leu (c.617C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

APTX p.Pro206Leu

c.617C>T · rs121908131 · VCV4426

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

APTX-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.894	moderately pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 16 kb · p 0.77 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000991% 16/1,614,054 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
East Asian	0.00668%	14,967
South Asian	0.0011%	91,088
European (non-Finnish)	0.000932%	107,276

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.Pro206Leu
Coding: c.617C>T
MANE Select: NM_001195248
dbSNP: rs121908131
Type: single nucleotide variant
Location: chr9:32984784 (GRCh38)
Gene constraint: LOEUF 0.973 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.52 · 11 PDB
Residue 206: 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

Similar variants

APTX p.Pro206= Likely benign ★ 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.Trp279Ter Pathogenic ★★ same condition
APTX p.Arg247Gln 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-pro206leu (accessed [today's date]).

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