Is SETX p.Arg2529fs (c.7585del) pathogenic?

SETX p.Arg2529fs (c.7585del) is classified Uncertain significance in SETX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-14). Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

How common is SETX p.Arg2529fs (c.7585del) in the general population?

SETX p.Arg2529fs (c.7585del) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

SETX p.Arg2529fs

Q: What condition is associated with SETX p.Arg2529fs (c.7585del)?

SETX p.Arg2529fs (c.7585del) is associated with Inborn genetic diseases, amyotrophic lateral sclerosis type 4, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (ClinVar).

c.7585del · rs1457817950 · VCV1759630

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	escapes	premature termination codon in the last exon (26 of 26) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.6	GERP 1.5, phastCons 0.016
Overall
CADD	27.5	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 8.47e-05% European (non-Finnish) · 1/1,180,044 alleles

Overall 6.2e-05% 1/1,614,062 alleles · very rare exomes 0/1,461,890 · genomes 1/152,172 · joint denominator

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: SETX
Protein: p.Arg2529fs
Coding: c.7585del
MANE Select: NM_015046
dbSNP: rs1457817950
Type: Deletion
Location: chr9:132264688 (GRCh38)
Gene constraint: LOEUF 0.442 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.93

Full SETX 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

Also linked: amyotrophic lateral sclerosis type 4 spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

Similar variants

SETX p.Arg2529Gly Uncertain significance ★ ⚠ same residue
SETX c.6843-3_6843-1del Likely pathogenic ★★ same condition
SETX p.Asp2332fs Pathogenic/Likely pathogenic ★★ same condition
SETX p.Gln1864fs Pathogenic/Likely pathogenic ★★ same condition
SETX p.Lys796fs Pathogenic ★★ same condition
SETX p.Thr1755fs Pathogenic ★★ same condition
SETX p.His476_Leu477del Uncertain significance ★★ same condition
SETX p.Ile664_Glu665del 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/setx-p-arg2529fs (accessed [today's date]).

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