Is SETX p.Ile2587Val (c.7759A>G) pathogenic?

SETX p.Ile2587Val (c.7759A>G) is classified Benign/Likely benign in SETX (ClinVar, Multiple submitters, 18 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0682); Common (popmax 75.4%, afr) — too common for a highly-penetrant pathogenic allele; Associated with spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2.

What do computational predictors say about SETX p.Ile2587Val (c.7759A>G)?

AlphaMissense predicts likely benign (score 0.0682) — an in-silico prediction, not a clinical call.

SETX p.Ile2587Val

Q: What condition is associated with SETX p.Ile2587Val (c.7759A>G)?

SETX p.Ile2587Val (c.7759A>G) is associated with spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2, amyotrophic lateral sclerosis type 4 (ClinVar).

Q: How common is SETX p.Ile2587Val (c.7759A>G) in the general population?

SETX p.Ile2587Val (c.7759A>G) is common (popmax 75.4%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is Spinocerebellar ataxia with axonal neuropathy type 2 inherited?

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

c.7759A>G · rs1056899 · VCV95669

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 18 submitters

AlphaMissense

likely benign

0.0682 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 75.4%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

Computational evidence

Protein change
AlphaMissense	0.0682	likely benign
REVEL	0.186	benign-leaning
SaProt	LLR -5.49	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.4	GERP -3.2
Regional constraint	o/e 1.05	unconstrained · MANE · 671 bp · p 0.36 · regional, not allelic
Overall
CADD	0.006	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 75.4% African / African-American · 56,469/74,934 alleles

Filtering AF 74.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 74.6%

Overall 33.4% 539,537/1,613,704 alleles · common exomes 471,972/1,461,690 · genomes 67,565/152,014 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	75.4%	1
East Asian	73.5%	1
Middle Eastern	50.5%	2
South Asian	43.8%	2
Ashkenazi Jewishnot grpmax-eligible	38.6%	3
Remaining individualsnot grpmax-eligible	37.3%	3
Admixed American	33%	3
Finnishnot grpmax-eligible	29.9%	3
European (non-Finnish)	28.2%	4
Amishnot grpmax-eligible	20%	5

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.Ile2587Val
Coding: c.7759A>G
MANE Select: NM_015046
dbSNP: rs1056899
Type: single nucleotide variant
Location: chr9:132264514 (GRCh38)
Gene constraint: LOEUF 0.442 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.93
Residue 2587: a UniProt-annotated variant site (in)

Full SETX gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: amyotrophic lateral sclerosis type 4

For Spinocerebellar ataxia with axonal neuropathy type 2 (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 1 000 000 (France)

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-ile2587val (accessed [today's date]).

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