Is SETX p.Ile2145= (c.6435C>T) pathogenic?

SETX p.Ile2145= (c.6435C>T) is classified Conflicting classifications of pathogenicity in SETX (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-12-08). Ultra-rare (popmax 0.0157%, nfe); Associated with hereditary spastic paraplegia.

What condition is associated with SETX p.Ile2145= (c.6435C>T)?

SETX p.Ile2145= (c.6435C>T) is associated with hereditary spastic paraplegia, amyotrophic lateral sclerosis type 4, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (ClinVar).

How common is SETX p.Ile2145= (c.6435C>T) in the general population?

SETX p.Ile2145= (c.6435C>T) is ultra-rare (popmax 0.0157%, nfe) (gnomAD).

SETX p.Ile2145=

c.6435C>T · rs374110190 · VCV913536

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0157%, nfe)

Conditions

hereditary spastic paraplegia

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 0.42	GERP -2.6, phastCons 0.013
Overall
CADD	6.568	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0157% European (non-Finnish) · 185/1,180,044 alleles

Filtering AF 0.0138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0131%

Overall 0.0121% 195/1,614,074 alleles · ultra-rare exomes 189/1,461,886 · genomes 6/152,188 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0157%	6,379
Admixed American	0.00667%	15,000
Remaining individualsnot grpmax-eligible	0.0064%	15,622
African / African-American	0.00267%	37,465

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.Ile2145=
Coding: c.6435C>T
MANE Select: NM_015046
dbSNP: rs374110190
Type: single nucleotide variant
Location: chr9:132283375 (GRCh38)
Gene constraint: LOEUF 0.442 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.93
Residue 2145: the upf1-type sf1b helicase atp-binding domain

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

Disease context

hereditary spastic paraplegia — 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.Ile2145Ser 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-ile2145 (accessed [today's date]).

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