Is SETX p.Gln1864Pro (c.5591A>C) pathogenic?

SETX p.Gln1864Pro (c.5591A>C) is classified Conflicting classifications of pathogenicity in SETX (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-05-19). AlphaMissense: likely benign (0.1796); Ultra-rare (popmax 0.0109%, nfe); Associated with amyotrophic lateral sclerosis type 4.

What condition is associated with SETX p.Gln1864Pro (c.5591A>C)?

SETX p.Gln1864Pro (c.5591A>C) is associated with amyotrophic lateral sclerosis type 4, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (ClinVar).

How common is SETX p.Gln1864Pro (c.5591A>C) in the general population?

SETX p.Gln1864Pro (c.5591A>C) is ultra-rare (popmax 0.0109%, nfe) (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.Gln1864Pro (c.5591A>C)?

AlphaMissense predicts likely benign (score 0.1796) — an in-silico prediction, not a clinical call.

SETX p.Gln1864Pro

c.5591A>C · rs375747001 · VCV586551

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1796 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0109%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

amyotrophic lateral sclerosis type 4

Computational evidence

Protein change
AlphaMissense	0.1796	likely benign
REVEL	0.557	indeterminate
SaProt	LLR -5.19	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.1	GERP 1.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 29 kb · p 0.045 · regional, not allelic
Overall
CADD	23.9	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 0.0109% European (non-Finnish) · 129/1,179,990 alleles

Filtering AF 0.00936% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0088%

Overall 0.00824% 133/1,613,986 alleles · ultra-rare exomes 127/1,461,812 · genomes 6/152,174 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0109%	9,147
Remaining individualsnot grpmax-eligible	0.0064%	15,622

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.Gln1864Pro
Coding: c.5591A>C
MANE Select: NM_015046
dbSNP: rs375747001
Type: single nucleotide variant
Location: chr9:132298270 (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.Gln1864fs Pathogenic/Likely pathogenic ★★ same residue
SETX p.Gln1864Arg Uncertain significance ★ ⚠ same residue
SETX p.Gln1864Glu 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

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-gln1864pro (accessed [today's date]).

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