Is SETX p.Arg502Trp (c.1504C>T) pathogenic?

SETX p.Arg502Trp (c.1504C>T) is classified Conflicting classifications of pathogenicity in SETX (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2025-12-03). AlphaMissense: likely benign (0.1956); Rare (popmax 0.323%, sas); Associated with spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2.

What condition is associated with SETX p.Arg502Trp (c.1504C>T)?

SETX p.Arg502Trp (c.1504C>T) is associated with spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2, amyotrophic lateral sclerosis type 4, Charcot-Marie-Tooth disease (ClinVar).

How common is SETX p.Arg502Trp (c.1504C>T) in the general population?

SETX p.Arg502Trp (c.1504C>T) is rare (popmax 0.323%, sas) (gnomAD).

What do computational predictors say about SETX p.Arg502Trp (c.1504C>T)?

AlphaMissense predicts likely benign (score 0.1956) — an in-silico prediction, not a clinical call.

SETX p.Arg502Trp

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.1504C>T · rs534723946 · VCV155742

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.1956 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.323%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

Computational evidence

Protein change
AlphaMissense	0.1956	likely benign
REVEL	0.796	moderately pathogenic-leaning
SaProt	LLR -7.97	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 522 bp · p 0.2 · regional, not allelic
Overall
CADD	27.5	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 0.323% South Asian · 294/91,086 alleles

Filtering AF 0.292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.281%

Overall 0.0258% 416/1,614,192 alleles · rare exomes 372/1,461,848 · genomes 44/152,344 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.323%	310
Remaining individualsnot grpmax-eligible	0.032%	3,125
East Asian	0.0223%	4,489
African / African-American	0.0107%	9,382
Admixed American	0.00999%	10,005
European (non-Finnish)	0.00661%	15,128

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.Arg502Trp
Coding: c.1504C>T
MANE Select: NM_015046
dbSNP: rs534723946
Type: single nucleotide variant
Location: chr9:132330094 (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 Charcot-Marie-Tooth disease

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.Arg502Gln Conflicting classifications of pathogenicity ★ ⚠ 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-arg502trp (accessed [today's date]).

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