Is SETX p.Cys451Ser (c.1352G>C) pathogenic?

SETX p.Cys451Ser (c.1352G>C) is classified Uncertain significance in SETX (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-14). AlphaMissense: ambiguous (0.5058); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with SETX p.Cys451Ser (c.1352G>C)?

SETX p.Cys451Ser (c.1352G>C) is associated with Inborn genetic diseases (ClinVar).

How common is SETX p.Cys451Ser (c.1352G>C) in the general population?

SETX p.Cys451Ser (c.1352G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SETX p.Cys451Ser (c.1352G>C)?

AlphaMissense predicts ambiguous (score 0.5058) — an in-silico prediction, not a clinical call.

SETX p.Cys451Ser

c.1352G>C · rs1847137835 · VCV2236915

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5058 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5058	ambiguous
REVEL	0.809	moderately pathogenic-leaning
SaProt	LLR -3.39	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 522 bp · p 0.2 · regional, not allelic
Overall
CADD	25.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SETX
Protein: p.Cys451Ser
Coding: c.1352G>C
MANE Select: NM_015046
dbSNP: rs1847137835
Type: single nucleotide variant
Location: chr9:132330246 (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

Similar variants

SETX p.Arg1363Ter Pathogenic ★★ same condition
SETX p.Ala1945Val Uncertain significance ★★ ⚠ same condition
SETX p.Ala2596Pro Uncertain significance ★★ ⚠ same condition
SETX p.Ala488Thr Uncertain significance ★★ ⚠ same condition
SETX p.Arg1214Ser Uncertain significance ★★ ⚠ same condition
SETX p.Arg1302Leu Uncertain significance ★★ same condition
SETX p.Arg1846His Uncertain significance ★★ ⚠ same condition
SETX p.Arg1846Leu Uncertain significance ★★ ⚠ 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-cys451ser (accessed [today's date]).

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