Is SETX p.Lys796fs (c.2387_2390del) pathogenic?

SETX p.Lys796fs (c.23872390del) is classified Pathogenic in SETX (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-01). Ultra-rare (popmax 0.0164%, mid); Associated with amyotrophic lateral sclerosis type 4.

What condition is associated with SETX p.Lys796fs (c.2387_2390del)?

SETX p.Lys796fs (c.2387_2390del) is associated with amyotrophic lateral sclerosis type 4, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (ClinVar).

How common is SETX p.Lys796fs (c.2387_2390del) in the general population?

SETX p.Lys796fs (c.2387_2390del) is ultra-rare (popmax 0.0164%, mid) (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.Lys796fs

c.2387_2390del · rs745775419 · VCV959106

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

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	predicted	premature termination codon in exon 10 of 26
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.51	GERP -0.36, phastCons 0.029
Overall
CADD	33.0	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 0.0164% Middle Eastern · 1/6,080 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00149% 24/1,613,634 alleles · ultra-rare exomes 18/1,461,498 · genomes 6/152,136 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,080
South Asian	0.00329%	30,355
African / African-American	0.00267%	37,443
European (non-Finnish)	0.00153%	65,553

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.Lys796fs
Coding: c.2387_2390del
MANE Select: NM_015046
dbSNP: rs745775419
Type: Deletion
Location: chr9:132329208 (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

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 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.Thr1755fs Pathogenic ★★ same condition
SETX p.Arg2529fs Uncertain significance ★★ same condition
SETX p.His476_Leu477del Uncertain significance ★★ same condition
SETX p.Ile664_Glu665del Uncertain significance ★★ same condition
SETX p.Lys870del 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-lys796fs (accessed [today's date]).

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