Is SETX p.His2457= (c.7371T>C) pathogenic?

SETX p.His2457= (c.7371T>C) is classified Benign/Likely benign in SETX (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-12-15). Low-frequency (popmax 1.34%, afr); Associated with Inborn genetic diseases.

How common is SETX p.His2457= (c.7371T>C) in the general population?

SETX p.His2457= (c.7371T>C) is low-frequency (popmax 1.34%, afr) (gnomAD).

SETX p.His2457=

Q: What condition is associated with SETX p.His2457= (c.7371T>C)?

SETX p.His2457= (c.7371T>C) is associated with Inborn genetic diseases, amyotrophic lateral sclerosis type 4, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (ClinVar).

c.7371T>C · rs113071480 · VCV365344

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.34%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8	GERP -3.3
Overall
CADD	0.044	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.34% African / African-American · 1,003/75,026 alleles

Filtering AF 1.27% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.24%

Overall 0.0682% 1,101/1,614,092 alleles · low-frequency exomes 546/1,461,850 · genomes 555/152,242 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.34%	75
Admixed American	0.0683%	1,464
Remaining individualsnot grpmax-eligible	0.064%	1,563
Middle Eastern	0.033%	3,031
European (non-Finnish)	0.00127%	78,666

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.His2457=
Coding: c.7371T>C
MANE Select: NM_015046
dbSNP: rs113071480
Type: single nucleotide variant
Location: chr9:132264902 (GRCh38)
Gene constraint: LOEUF 0.442 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.93
Residue 2457: the upf1-type sf1b helicase c-terminal 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 hereditary spastic paraplegia

Similar variants

SETX p.His2457Arg 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
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-his2457 (accessed [today's date]).

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