Is SETX p.Tyr359= (c.1077T>C) pathogenic?

SETX p.Tyr359= (c.1077T>C) is classified Benign in SETX (ClinVar, Multiple submitters, 18 submitters; last evaluated 2026-02-04). Common (popmax 85%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with amyotrophic lateral sclerosis type 4.

What condition is associated with SETX p.Tyr359= (c.1077T>C)?

SETX p.Tyr359= (c.1077T>C) is associated with amyotrophic lateral sclerosis type 4, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (ClinVar).

How is Amyotrophic lateral sclerosis type 4 inherited?

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

SETX p.Tyr359=

Q: How common is SETX p.Tyr359= (c.1077T>C) in the general population?

SETX p.Tyr359= (c.1077T>C) is common (popmax 85%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1077T>C · rs9411449 · VCV95658

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 18 submitters

gnomAD v4.1

Common

common (popmax 85%, nfe) — too common for a highly-penetrant pathogenic allele

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 · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.84	GERP -3.8
Overall
CADD	4.436	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 85% European (non-Finnish) · 1,001,095/1,178,024 alleles

Filtering AF 84.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 84.8%

Overall 80.4% 1,295,997/1,611,662 alleles · common exomes 1,181,901/1,459,576 · genomes 114,096/152,086 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	86.1%	1
European (non-Finnish)grpmax	85%	1
Finnishnot grpmax-eligible	83.1%	1
Admixed American	80.7%	1
Remaining individualsnot grpmax-eligible	77.2%	1
Ashkenazi Jewishnot grpmax-eligible	74.5%	1
Middle Eastern	67.4%	1
South Asian	63.7%	2
African / African-American	61.3%	2
East Asian	31.9%	3

Amish 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.Tyr359=
Coding: c.1077T>C
MANE Select: NM_015046
dbSNP: rs9411449
Type: single nucleotide variant
Location: chr9:132331073 (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.Tyr359His Likely benign ★ same residue
SETX p.Tyr359Cys Uncertain significance ★ ⚠ 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-tyr359 (accessed [today's date]).

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