Is SETX p.Leu389Phe (c.1167A>C) pathogenic?

SETX p.Leu389Phe (c.1167A>C) is classified Likely pathogenic in SETX (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-04). AlphaMissense: likely pathogenic (0.6023); Absent from gnomAD v4.1; Associated with amyotrophic lateral sclerosis type 4.

What condition is associated with SETX p.Leu389Phe (c.1167A>C)?

SETX p.Leu389Phe (c.1167A>C) is associated with amyotrophic lateral sclerosis type 4 (ClinVar).

How common is SETX p.Leu389Phe (c.1167A>C) in the general population?

SETX p.Leu389Phe (c.1167A>C) is absent from gnomAD v4.1 (gnomAD).

How is Amyotrophic lateral sclerosis type 4 inherited?

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

What do computational predictors say about SETX p.Leu389Phe (c.1167A>C)?

AlphaMissense predicts likely pathogenic (score 0.6023) — an in-silico prediction, not a clinical call.

SETX p.Leu389Phe

c.1167A>C · rs2131463306 · VCV1685438

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6023 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

amyotrophic lateral sclerosis type 4

Computational evidence

Protein change
AlphaMissense	0.6023	likely pathogenic ✓ concordant with ClinVar
REVEL	0.477	indeterminate
SaProt	LLR -7.22	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.51	GERP -3, phastCons 0.99
Regional constraint	o/e 0.46	unconstrained · MANE · 754 bp · p 6.5e-07 · regional, not allelic
Overall
CADD	20.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SETX
Protein: p.Leu389Phe
Coding: c.1167A>C
MANE Select: NM_015046
dbSNP: rs2131463306
Type: single nucleotide variant
Location: chr9:132330431 (GRCh38)
Gene constraint: LOEUF 0.442 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.93
Residue 389: a UniProt-annotated variant site (in als4; does not affect the interaction with exosc9 and ube2i; does not decrease sumoylation and ubiquitination; does not inhibit homodimerization; unlike the wild-type protein the mutant induces interaction with slirp-ot1)

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

For Amyotrophic lateral sclerosis type 4 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Childhood

Similar variants

SETX p.Leu389Ser Pathogenic ★★ ⚠ same residue
SETX p.Leu389del Likely pathogenic ★ same residue
SETX p.Arg111Ter Pathogenic ★★ same condition
SETX p.Arg1363Ter Pathogenic ★★ same condition
SETX p.Arg1606Ter Pathogenic ★★ same condition
SETX p.Arg2098Ter Pathogenic ★★ same condition
SETX p.Gln1695Ter Pathogenic/Likely pathogenic ★★ same condition
SETX p.Gln1774Ter Pathogenic/Likely pathogenic ★★ 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-leu389phe (accessed [today's date]).

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