Is SETX p.Phe2499fs (c.7493dup) pathogenic?

SETX p.Phe2499fs (c.7493dup) is classified Likely pathogenic in SETX (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-15). Associated with SETX-related disorder.

What condition is associated with SETX p.Phe2499fs (c.7493dup)?

SETX p.Phe2499fs (c.7493dup) is associated with SETX-related disorder (ClinVar).

SETX p.Phe2499fs

c.7493dup · VCV4905069

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

SETX-related disorder

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 -6.2	GERP -3.2

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: SETX
Protein: p.Phe2499fs
Coding: c.7493dup
MANE Select: NM_015046
Type: Duplication
Location: chr9:132264779 (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

SETX-related disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SETX p.Thr2523fs Likely pathogenic ★ same condition
SETX p.Asn1768fs Likely pathogenic same condition
SETX c.5547_5548+2del Pathogenic/Likely pathogenic ★★ same condition
SETX p.Leu1976Arg Pathogenic ★★ same condition
SETX p.Leu389Ser Pathogenic ★★ ⚠ same condition
SETX p.Leu1070Val Uncertain significance ★★ ⚠ same condition
SETX p.Leu223His Uncertain significance ★★ ⚠ same condition
SETX p.Lys713Asn 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-phe2499fs (accessed [today's date]).

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