Is SETX p.Pro1732Ser (c.5194C>T) pathogenic?

SETX p.Pro1732Ser (c.5194C>T) is classified Uncertain significance in SETX (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-04-17). AlphaMissense: likely benign (0.1007); Very rare (popmax 8.48e-05%, nfe); Associated with SETX-related disorder.

What condition is associated with SETX p.Pro1732Ser (c.5194C>T)?

SETX p.Pro1732Ser (c.5194C>T) is associated with SETX-related disorder (ClinVar).

How common is SETX p.Pro1732Ser (c.5194C>T) in the general population?

SETX p.Pro1732Ser (c.5194C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about SETX p.Pro1732Ser (c.5194C>T)?

AlphaMissense predicts likely benign (score 0.1007) — an in-silico prediction, not a clinical call.

SETX p.Pro1732Ser

c.5194C>T · VCV3347937

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1007 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

SETX-related disorder

Computational evidence

Protein change
AlphaMissense	0.1007	likely benign
REVEL	0.117	moderately benign-leaning
SaProt	LLR -8.47	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.1	GERP -2.3, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 29 kb · p 0.045 · regional, not allelic
Overall
CADD	9.433	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,934 alleles

Overall 6.2e-05% 1/1,614,088 alleles · very rare exomes 1/1,461,770 · genomes 0/152,318 · joint denominator

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.Pro1732Ser
Coding: c.5194C>T
MANE Select: NM_015046
Type: single nucleotide variant
Location: chr9:132326404 (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

SETX-related disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SETX p.Pro1732= Likely benign ★ same residue
SETX p.Leu1976Arg Pathogenic ★★ same condition
SETX p.Leu389Ser Pathogenic ★★ ⚠ same condition
SETX p.Leu1070Val Uncertain significance ★★ ⚠ same condition
SETX p.Leu223His Uncertain significance ★★ ⚠ same condition
SETX p.Lys713Asn Uncertain significance ★★ ⚠ same condition
SETX p.Leu2043Ter Likely pathogenic ★ same condition
SETX p.Arg1323Gln Conflicting classifications of pathogenicity ★ ⚠ 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-pro1732ser (accessed [today's date]).

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