Is SETX p.Arg168Gln (c.503G>A) pathogenic?

SETX p.Arg168Gln (c.503G>A) is classified Conflicting classifications of pathogenicity in SETX (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-03). AlphaMissense: ambiguous (0.5638); Ultra-rare (popmax 0.0496%, mid); Associated with spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2.

How common is SETX p.Arg168Gln (c.503G>A) in the general population?

SETX p.Arg168Gln (c.503G>A) is ultra-rare (popmax 0.0496%, mid) (gnomAD).

What do computational predictors say about SETX p.Arg168Gln (c.503G>A)?

AlphaMissense predicts ambiguous (score 0.5638) — an in-silico prediction, not a clinical call.

SETX p.Arg168Gln

Q: What condition is associated with SETX p.Arg168Gln (c.503G>A)?

SETX p.Arg168Gln (c.503G>A) 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.503G>A · rs772017103 · VCV1421207

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5638 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0496%, mid)

Conditions

spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

Computational evidence

Protein change
AlphaMissense	0.5638	ambiguous
REVEL	0.555	indeterminate
SaProt	LLR -8.15	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 12 kb · p 0.91 · regional, not allelic
Overall
CADD	28.7	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 0.0496% Middle Eastern · 3/6,050 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.00261% 42/1,608,992 alleles · ultra-rare exomes 37/1,456,788 · genomes 5/152,204 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0496%	2,017
Admixed American	0.02%	5,000
Remaining individualsnot grpmax-eligible	0.00321%	31,153
African / African-American	0.00267%	37,447
East Asian	0.00223%	44,854
South Asian	0.0022%	45,476
European (non-Finnish)	0.0017%	58,773

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.Arg168Gln
Coding: c.503G>A
MANE Select: NM_015046
dbSNP: rs772017103
Type: single nucleotide variant
Location: chr9:132336511 (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

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.Arg168Trp Likely benign ★ 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-arg168gln (accessed [today's date]).

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