Is SETX p.Ala1112= (c.3336T>C) pathogenic?

SETX p.Ala1112= (c.3336T>C) is classified Benign/Likely benign in SETX (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-02-16). Rare (popmax 0.102%, nfe); Associated with spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2.

What condition is associated with SETX p.Ala1112= (c.3336T>C)?

SETX p.Ala1112= (c.3336T>C) is associated with spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2, amyotrophic lateral sclerosis type 4, hereditary spastic paraplegia (ClinVar).

How common is SETX p.Ala1112= (c.3336T>C) in the general population?

SETX p.Ala1112= (c.3336T>C) is rare (popmax 0.102%, nfe) (gnomAD).

SETX p.Ala1112=

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.3336T>C · rs150687078 · VCV448322

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

gnomAD v4.1

Rare

rare (popmax 0.102%, nfe)

Conditions

spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.87	GERP -2.1, phastCons 0.002
Overall
CADD	2.191	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.102% European (non-Finnish) · 1,206/1,180,012 alleles

Filtering AF 0.0974% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0955%

Overall 0.0784% 1,265/1,613,956 alleles · rare exomes 1,190/1,461,752 · genomes 75/152,204 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.102%	978
Remaining individualsnot grpmax-eligible	0.0752%	1,329
African / African-American	0.0147%	6,811
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,600

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.Ala1112=
Coding: c.3336T>C
MANE Select: NM_015046
dbSNP: rs150687078
Type: single nucleotide variant
Location: chr9:132328262 (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

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 hereditary spastic paraplegia

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-ala1112 (accessed [today's date]).

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