Is SETX p.His58Arg (c.173A>G) pathogenic?

SETX p.His58Arg (c.173A>G) is classified Uncertain significance in SETX (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-12). AlphaMissense: ambiguous (0.4941); Absent from gnomAD v4.1; Associated with amyotrophic lateral sclerosis type 4.

What condition is associated with SETX p.His58Arg (c.173A>G)?

SETX p.His58Arg (c.173A>G) is associated with amyotrophic lateral sclerosis type 4, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (ClinVar).

How common is SETX p.His58Arg (c.173A>G) in the general population?

SETX p.His58Arg (c.173A>G) is absent from gnomAD v4.1 (gnomAD).

How is Amyotrophic lateral sclerosis type 4 inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about SETX p.His58Arg (c.173A>G)?

AlphaMissense predicts ambiguous (score 0.4941) — an in-silico prediction, not a clinical call.

SETX p.His58Arg

c.173A>G · rs2539258376 · VCV2931721

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4941 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

amyotrophic lateral sclerosis type 4

Computational evidence

Protein change
AlphaMissense	0.4941	ambiguous
REVEL	0.526	indeterminate
SaProt	LLR -3.77	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 3,163 bp · p 0.74 · regional, not allelic
Overall
CADD	25.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SETX
Protein: p.His58Arg
Coding: c.173A>G
MANE Select: NM_015046
dbSNP: rs2539258376
Type: single nucleotide variant
Location: chr9:132349256 (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

amyotrophic lateral sclerosis type 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

For Amyotrophic lateral sclerosis type 4 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Childhood

Similar variants

SETX p.His58Tyr Conflicting classifications of pathogenicity ★ same residue
SETX p.His58= 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

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-his58arg (accessed [today's date]).

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