Is SETX p.Thr3= (c.9A>G) pathogenic?

SETX p.Thr3= (c.9A>G) is classified Conflicting classifications of pathogenicity in SETX (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-05-08). Ultra-rare (popmax 0.0668%, eas); Associated with Inborn genetic diseases.

How common is SETX p.Thr3= (c.9A>G) in the general population?

SETX p.Thr3= (c.9A>G) is ultra-rare (popmax 0.0668%, eas) (gnomAD).

SETX p.Thr3=

Q: What condition is associated with SETX p.Thr3= (c.9A>G)?

SETX p.Thr3= (c.9A>G) is associated with Inborn genetic diseases, amyotrophic lateral sclerosis type 4, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (ClinVar).

c.9A>G · rs139681694 · VCV365381

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0668%, eas)

Conditions

Inborn genetic diseases

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 -6.7	GERP -3.2
Overall
CADD	2.565	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0668% East Asian · 30/44,900 alleles

Filtering AF 0.0481% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0417%

Overall 0.00589% 95/1,614,024 alleles · ultra-rare exomes 88/1,461,876 · genomes 7/152,148 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0668%	1,497
Middle Eastern	0.0164%	6,084
European (non-Finnish)	0.00508%	19,667
South Asian	0.0022%	45,542
Admixed American	0.00167%	59,982
African / African-American	0.00133%	74,910

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.Thr3=
Coding: c.9A>G
MANE Select: NM_015046
dbSNP: rs139681694
Type: single nucleotide variant
Location: chr9:132349420 (GRCh38)
Gene constraint: LOEUF 0.442 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.93
Residue 3: a UniProt-annotated variant site (in als4; heterozygous; does not affect the interaction with exosc9 and ube2i; does not decrease sumoylation)

Full SETX gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: amyotrophic lateral sclerosis type 4 spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

Similar variants

SETX p.Thr3Ile Likely pathogenic ★★ 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-thr3 (accessed [today's date]).

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