Is SETX p.Pro864Leu (c.2591C>T) pathogenic?

SETX p.Pro864Leu (c.2591C>T) is classified Conflicting classifications of pathogenicity in SETX (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-08-26). AlphaMissense: likely benign (0.0644); Ultra-rare (popmax 0.012%, afr); Associated with amyotrophic lateral sclerosis type 4.

What condition is associated with SETX p.Pro864Leu (c.2591C>T)?

SETX p.Pro864Leu (c.2591C>T) is associated with amyotrophic lateral sclerosis type 4, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (ClinVar).

How common is SETX p.Pro864Leu (c.2591C>T) in the general population?

SETX p.Pro864Leu (c.2591C>T) is ultra-rare (popmax 0.012%, afr) (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.Pro864Leu (c.2591C>T)?

AlphaMissense predicts likely benign (score 0.0644) — an in-silico prediction, not a clinical call.

SETX p.Pro864Leu

c.2591C>T · rs139427451 · VCV1934669

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0644 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

amyotrophic lateral sclerosis type 4

Computational evidence

Protein change
AlphaMissense	0.0644	likely benign
REVEL	0.203	benign-leaning
SaProt	LLR -5.36	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP -3.3, phastCons 0.003
Regional constraint	o/e 1.13	unconstrained · MANE · 3,399 bp · p 2.4e-06 · regional, not allelic
Overall
CADD	1.913	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 0.012% African / African-American · 9/74,780 alleles

Filtering AF 0.00624% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.00212% 34/1,606,308 alleles · ultra-rare exomes 28/1,454,242 · genomes 6/152,066 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,309
European (non-Finnish)	0.00195%	51,178
Admixed American	0.00169%	59,212
South Asian	0.00111%	90,350

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.Pro864Leu
Coding: c.2591C>T
MANE Select: NM_015046
dbSNP: rs139427451
Type: single nucleotide variant
Location: chr9:132329007 (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

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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-pro864leu (accessed [today's date]).

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