Is SETX p.Phe458Leu (c.1374T>G) pathogenic?

SETX p.Phe458Leu (c.1374T>G) is classified Conflicting classifications of pathogenicity in SETX (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-21). AlphaMissense: likely pathogenic (0.9375); Very rare (popmax 0.00553%, nfe); Associated with Inborn genetic diseases.

How common is SETX p.Phe458Leu (c.1374T>G) in the general population?

SETX p.Phe458Leu (c.1374T>G) is very rare (popmax 0.00553%, nfe) (gnomAD).

What do computational predictors say about SETX p.Phe458Leu (c.1374T>G)?

AlphaMissense predicts likely pathogenic (score 0.9375) — an in-silico prediction, not a clinical call.

SETX p.Phe458Leu

Q: What condition is associated with SETX p.Phe458Leu (c.1374T>G)?

SETX p.Phe458Leu (c.1374T>G) is associated with Inborn genetic diseases, amyotrophic lateral sclerosis type 4, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (ClinVar).

c.1374T>G · rs201441886 · VCV579304

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9375 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00553%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9375	likely pathogenic · top 8% in SETX
REVEL	0.57	indeterminate
SaProt	LLR -5.55	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.67	GERP -3.3, phastCons 0.95
Regional constraint	o/e 0.91	unconstrained · MANE · 522 bp · p 0.2 · regional, not allelic
Overall
CADD	20.1	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 0.00553% European (non-Finnish) · 64/1,158,354 alleles

Filtering AF 0.00443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00403%

Overall 0.00446% 70/1,569,642 alleles · very rare exomes 58/1,417,390 · genomes 12/152,252 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00553%	18,099
Remaining individualsnot grpmax-eligible	0.00497%	20,137
Finnishnot grpmax-eligible	0.00481%	20,773

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.Phe458Leu
Coding: c.1374T>G
MANE Select: NM_015046
dbSNP: rs201441886
Type: single nucleotide variant
Location: chr9:132330224 (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

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.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
SETX p.Gln1695Ter 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-phe458leu (accessed [today's date]).

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