Is SETX p.Leu389Ser (c.1166T>C) pathogenic?

SETX p.Leu389Ser (c.1166T>C) is classified Pathogenic in SETX (ClinVar, Multiple submitters, 8 submitters; last evaluated 2024-08-12). AlphaMissense: likely pathogenic (0.8993); Absent from gnomAD v4.1; Associated with SETX-related disorder.

What condition is associated with SETX p.Leu389Ser (c.1166T>C)?

SETX p.Leu389Ser (c.1166T>C) is associated with SETX-related disorder, amyotrophic lateral sclerosis type 4, distal hereditary motor neuropathy (ClinVar).

How common is SETX p.Leu389Ser (c.1166T>C) in the general population?

SETX p.Leu389Ser (c.1166T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SETX p.Leu389Ser (c.1166T>C)?

AlphaMissense predicts likely pathogenic (score 0.8993) — an in-silico prediction, not a clinical call.

SETX p.Leu389Ser

c.1166T>C · rs29001584 · VCV2289

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.8993 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

SETX-related disorder

Computational evidence

Protein change
AlphaMissense	0.8993	likely pathogenic ✓ concordant with ClinVar · top 10% in SETX
REVEL	0.729	pathogenic-leaning
SaProt	LLR -6.43	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.46	unconstrained · MANE · 754 bp · p 6.5e-07 · regional, not allelic
Overall
CADD	25.7	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.Leu389Ser
Coding: c.1166T>C
MANE Select: NM_015046
dbSNP: rs29001584
Type: single nucleotide variant
Location: chr9:132330432 (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

Also linked: amyotrophic lateral sclerosis type 4 distal hereditary motor neuropathy spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

Similar variants

SETX p.Leu389Phe Likely 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.Arg1778Ter Pathogenic/Likely pathogenic ★★ same condition
SETX p.Arg2098Ter Pathogenic ★★ same condition
SETX p.Arg332Trp 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-leu389ser (accessed [today's date]).

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