Is SETX p.Arg332Trp (c.994C>T) pathogenic?

SETX p.Arg332Trp (c.994C>T) is classified Pathogenic/Likely pathogenic in SETX (ClinVar, Multiple submitters, 6 submitters; last evaluated 2023-02-08). AlphaMissense: ambiguous (0.4921); Very rare (popmax 0.00267%, afr); Associated with spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2.

What condition is associated with SETX p.Arg332Trp (c.994C>T)?

SETX p.Arg332Trp (c.994C>T) is associated with spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (ClinVar).

How common is SETX p.Arg332Trp (c.994C>T) in the general population?

SETX p.Arg332Trp (c.994C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about SETX p.Arg332Trp (c.994C>T)?

AlphaMissense predicts ambiguous (score 0.4921) — an in-silico prediction, not a clinical call.

SETX p.Arg332Trp

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.994C>T · rs29001665 · VCV2288

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.4921 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

Computational evidence

Protein change
AlphaMissense	0.4921	ambiguous
REVEL	0.453	indeterminate
SaProt	LLR -6.79	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.1, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 12 kb · p 0.91 · regional, not allelic
Overall
CADD	25.1	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 0.00267% African / African-American · 2/74,892 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000372% 6/1,613,894 alleles · very rare exomes 4/1,461,762 · genomes 2/152,132 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,446
Admixed American	0.00167%	59,998
European (non-Finnish)	0.000254%	393,328

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.Arg332Trp
Coding: c.994C>T
MANE Select: NM_015046
dbSNP: rs29001665
Type: single nucleotide variant
Location: chr9:132331293 (GRCh38)
Gene constraint: LOEUF 0.442 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.93
Residue 332: a UniProt-annotated variant site (in scan2)

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

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.Arg778Ter Pathogenic/Likely pathogenic ★★ same condition
SETX p.Gln1695Ter Pathogenic/Likely pathogenic ★★ same condition
SETX p.Gln1774Ter Pathogenic/Likely pathogenic ★★ same condition
SETX p.Gln2108Ter 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-arg332trp (accessed [today's date]).

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