Is SETX p.Val356Ile (c.1066G>A) pathogenic?

SETX p.Val356Ile (c.1066G>A) is classified Conflicting classifications of pathogenicity in SETX (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-14). AlphaMissense: likely benign (0.1775); Ultra-rare (popmax 0.0533%, afr); Associated with amyotrophic lateral sclerosis type 4.

What condition is associated with SETX p.Val356Ile (c.1066G>A)?

SETX p.Val356Ile (c.1066G>A) is associated with amyotrophic lateral sclerosis type 4, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (ClinVar).

How common is SETX p.Val356Ile (c.1066G>A) in the general population?

SETX p.Val356Ile (c.1066G>A) is ultra-rare (popmax 0.0533%, 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.Val356Ile (c.1066G>A)?

AlphaMissense predicts likely benign (score 0.1775) — an in-silico prediction, not a clinical call.

SETX p.Val356Ile

c.1066G>A · rs143270460 · VCV845589

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1775 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0533%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

amyotrophic lateral sclerosis type 4

Computational evidence

Protein change
AlphaMissense	0.1775	likely benign
REVEL	0.187	benign-leaning
SaProt	LLR -6.38	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.46	unconstrained · MANE · 754 bp · p 6.5e-07 · regional, not allelic
Overall
CADD	26.0	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 0.0533% African / African-American · 40/75,026 alleles

Filtering AF 0.0402% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0356%

Overall 0.0044% 71/1,613,030 alleles · ultra-rare exomes 43/1,460,758 · genomes 28/152,272 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0533%	1,876
Middle Eastern	0.0331%	3,025
Admixed American	0.025%	4,000
Remaining individualsnot grpmax-eligible	0.016%	6,248
South Asian	0.0011%	91,068
European (non-Finnish)	0.000254%	393,017

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.Val356Ile
Coding: c.1066G>A
MANE Select: NM_015046
dbSNP: rs143270460
Type: single nucleotide variant
Location: chr9:132331084 (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.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
SETX p.Arg778Ter Pathogenic/Likely pathogenic ★★ same condition
SETX p.Gln1695Ter 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-val356ile (accessed [today's date]).

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