Is SETX p.Pro1331del (c.3989CTC[1]) pathogenic?

SETX p.Pro1331del (c.3989CTC[1]) is classified Uncertain significance in SETX (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-10). Very rare (popmax 0.000678%, nfe); Associated with amyotrophic lateral sclerosis type 4.

What condition is associated with SETX p.Pro1331del (c.3989CTC[1])?

SETX p.Pro1331del (c.3989CTC[1]) is associated with amyotrophic lateral sclerosis type 4, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (ClinVar).

How common is SETX p.Pro1331del (c.3989CTC[1]) in the general population?

SETX p.Pro1331del (c.3989CTC[1]) is very rare (popmax 0.000678%, nfe) (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.Pro1331del

c.3989CTC[1] · rs774598266 · VCV1896044

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

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 0.83	GERP 0.72, phastCons 0.7

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000678% European (non-Finnish) · 8/1,180,022 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000558% 9/1,614,102 alleles · very rare exomes 9/1,461,772 · genomes 0/152,330 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,500
European (non-Finnish)grpmax	0.000678%	147,503

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro1331del
Coding: c.3989CTC[1]
MANE Select: NM_015046
dbSNP: rs774598266
Type: Microsatellite
Location: chr9:132327604 (GRCh38)
Gene constraint: LOEUF 0.442 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.93
Residue 1331: a UniProt-annotated variant site (in)

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.Pro1331Leu Benign/Likely benign ★★ same residue
SETX p.Pro1331Ser Benign ★ same residue
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

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-pro1331del (accessed [today's date]).

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