Is SETX p.Ala289Val (c.866C>T) pathogenic?

SETX p.Ala289Val (c.866C>T) is classified Conflicting classifications of pathogenicity in SETX (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-08-18). AlphaMissense: likely pathogenic (0.5793); Very rare (popmax 0.00802%, afr); Associated with amyotrophic lateral sclerosis type 4.

What condition is associated with SETX p.Ala289Val (c.866C>T)?

SETX p.Ala289Val (c.866C>T) is associated with amyotrophic lateral sclerosis type 4, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (ClinVar).

How common is SETX p.Ala289Val (c.866C>T) in the general population?

SETX p.Ala289Val (c.866C>T) is very rare (popmax 0.00802%, afr) (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.Ala289Val (c.866C>T)?

AlphaMissense predicts likely pathogenic (score 0.5793) — an in-silico prediction, not a clinical call.

SETX p.Ala289Val

c.866C>T · rs1237541645 · VCV952015

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.5793 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00802%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

amyotrophic lateral sclerosis type 4

Computational evidence

Protein change
AlphaMissense	0.5793	likely pathogenic
REVEL	0.264	benign-leaning
SaProt	LLR -10.59	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 12 kb · p 0.91 · regional, not allelic
Overall
CADD	28.2	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

Grpmax group 0.00802% African / African-American · 6/74,842 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.000682% 11/1,613,770 alleles · very rare exomes 10/1,461,766 · genomes 1/152,004 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00802%	12,474
East Asian	0.00223%	44,880
European (non-Finnish)	0.000339%	294,991

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.Ala289Val
Coding: c.866C>T
MANE Select: NM_015046
dbSNP: rs1237541645
Type: single nucleotide variant
Location: chr9:132331421 (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 p.Ala289Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
SETX p.Ala289= Likely benign ★ 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-ala289val (accessed [today's date]).

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