Is SETX p.Arg2674fs (c.8022_8025del) pathogenic?

SETX p.Arg2674fs (c.80228025del) is classified Uncertain significance in SETX (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-30). No gnomAD frequency available for this variant; Associated with amyotrophic lateral sclerosis type 4.

What condition is associated with SETX p.Arg2674fs (c.8022_8025del)?

SETX p.Arg2674fs (c.8022_8025del) is associated with amyotrophic lateral sclerosis type 4, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (ClinVar).

How common is SETX p.Arg2674fs (c.8022_8025del) in the general population?

SETX p.Arg2674fs (c.8022_8025del) is no gnomAD frequency available for this variant (gnomAD).

How is Amyotrophic lateral sclerosis type 4 inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

SETX p.Arg2674fs

c.8022_8025del · rs2538817760 · VCV2066901

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

amyotrophic lateral sclerosis type 4

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 0.48	GERP -3.6, phastCons 0.006

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: SETX
Protein: p.Arg2674fs
Coding: c.8022_8025del
MANE Select: NM_015046
dbSNP: rs2538817760
Type: Microsatellite
Location: chr9:132264248 (GRCh38)
Gene constraint: LOEUF 0.442 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.93
Residue 2674: the 'necessary for nuclear localization' region; the 'disordered' region

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

Disease context

amyotrophic lateral sclerosis type 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

For Amyotrophic lateral sclerosis type 4 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Childhood

Similar variants

SETX p.Glu1770fs Pathogenic/Likely pathogenic ★★ same condition
SETX p.His2243fs Pathogenic/Likely pathogenic ★★ same condition
SETX p.Val2374fs Pathogenic/Likely pathogenic ★★ same condition
SETX p.Ile1016del Uncertain significance ★★ same condition
SETX p.Ile741del Uncertain significance ★★ same condition
SETX p.Lys909del Uncertain significance ★★ same condition
SETX p.Pro1587del Uncertain significance ★★ same condition
SETX p.Pro2571del 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-arg2674fs (accessed [today's date]).

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