Is SETX p.Asp2496Glu (c.7488C>G) pathogenic?

SETX p.Asp2496Glu (c.7488C>G) is classified Conflicting classifications of pathogenicity in SETX (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-06-01). AlphaMissense: likely benign (0.1513); Very rare (popmax 0.00186%, nfe); Associated with spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2.

How common is SETX p.Asp2496Glu (c.7488C>G) in the general population?

SETX p.Asp2496Glu (c.7488C>G) is very rare (popmax 0.00186%, nfe) (gnomAD).

What do computational predictors say about SETX p.Asp2496Glu (c.7488C>G)?

AlphaMissense predicts likely benign (score 0.1513) — an in-silico prediction, not a clinical call.

SETX p.Asp2496Glu

Q: What condition is associated with SETX p.Asp2496Glu (c.7488C>G)?

SETX p.Asp2496Glu (c.7488C>G) is associated with spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2, amyotrophic lateral sclerosis type 4 (ClinVar).

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.7488C>G · rs1240185024 · VCV1759125

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1513 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00186%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

Computational evidence

Protein change
AlphaMissense	0.1513	likely benign
REVEL	0.219	benign-leaning
SaProt	LLR -6.04	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 1.9	GERP -2.8, phastCons 0.98
Regional constraint	o/e 1.05	unconstrained · MANE · 671 bp · p 0.36 · regional, not allelic
Overall
CADD	13.96	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 0.00186% European (non-Finnish) · 22/1,180,046 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00136% 22/1,614,098 alleles · very rare exomes 19/1,461,890 · genomes 3/152,208 · joint denominator

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.Asp2496Glu
Coding: c.7488C>G
MANE Select: NM_015046
dbSNP: rs1240185024
Type: single nucleotide variant
Location: chr9:132264785 (GRCh38)
Gene constraint: LOEUF 0.442 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.93
Residue 2496: the 'disordered' region

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.Asp2496Gly 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
SETX p.Arg778Ter 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-asp2496glu (accessed [today's date]).

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