Is SETX p.Arg1364del (c.4090_4092del) pathogenic?

SETX p.Arg1364del (c.40904092del) is classified Uncertain significance in SETX (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-27). Ultra-rare (popmax 0.0154%, sas); Associated with amyotrophic lateral sclerosis type 4.

What condition is associated with SETX p.Arg1364del (c.4090_4092del)?

SETX p.Arg1364del (c.4090_4092del) is associated with amyotrophic lateral sclerosis type 4, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (ClinVar).

How common is SETX p.Arg1364del (c.4090_4092del) in the general population?

SETX p.Arg1364del (c.4090_4092del) is ultra-rare (popmax 0.0154%, sas) (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.Arg1364del

c.4090_4092del · rs1300386374 · VCV2929805

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0154%, sas)

Conditions

amyotrophic lateral sclerosis type 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.18	GERP -3.6

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0154% South Asian · 14/91,082 alleles

Filtering AF 0.00919% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00735%

Overall 0.000929% 15/1,614,086 alleles · ultra-rare exomes 15/1,461,760 · genomes 0/152,326 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0154%	6,506
Admixed American	0.00167%	60,020

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.Arg1364del
Coding: c.4090_4092del
MANE Select: NM_015046
dbSNP: rs1300386374
Type: Deletion
Location: chr9:132327506 (GRCh38)
Gene constraint: LOEUF 0.442 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.93
Residue 1364: 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.Arg1364Gly Benign/Likely benign ★★ 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.Arg2529fs Uncertain significance ★★ same condition
SETX p.His476_Leu477del 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-arg1364del (accessed [today's date]).

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