Is SETX p.Ala1945Val (c.5834C>T) pathogenic?

SETX p.Ala1945Val (c.5834C>T) is classified Uncertain significance in SETX (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-02-08). AlphaMissense: likely pathogenic (0.7395); Very rare (popmax 0.00667%, amr); Associated with Inborn genetic diseases.

How common is SETX p.Ala1945Val (c.5834C>T) in the general population?

SETX p.Ala1945Val (c.5834C>T) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about SETX p.Ala1945Val (c.5834C>T)?

AlphaMissense predicts likely pathogenic (score 0.7395) — an in-silico prediction, not a clinical call.

SETX p.Ala1945Val

Q: What condition is associated with SETX p.Ala1945Val (c.5834C>T)?

SETX p.Ala1945Val (c.5834C>T) is associated with Inborn genetic diseases, amyotrophic lateral sclerosis type 4, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (ClinVar).

c.5834C>T · rs1009296937 · VCV1304702

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7395 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7395	likely pathogenic
REVEL	0.604	indeterminate
SaProt	LLR -8.38	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 29 kb · p 0.045 · regional, not allelic
Overall
CADD	28.3	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 0.00667% Admixed American · 4/59,990 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000558% 9/1,613,702 alleles · very rare exomes 7/1,461,574 · genomes 2/152,128 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,997
Remaining individualsnot grpmax-eligible	0.0016%	62,476
African / African-American	0.00134%	74,890
European (non-Finnish)	0.000254%	393,278

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.Ala1945Val
Coding: c.5834C>T
MANE Select: NM_015046
dbSNP: rs1009296937
Type: single nucleotide variant
Location: chr9:132297002 (GRCh38)
Gene constraint: LOEUF 0.442 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.93
Residue 1945: the upf1-type sf1b helicase atp-binding domain

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.Ala1945= Likely benign ★ same residue
SETX p.Ala1945Pro Uncertain significance ★ ⚠ 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

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-ala1945val (accessed [today's date]).

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