Is SETX p.Pro1266Ser (c.3796C>T) pathogenic?

SETX p.Pro1266Ser (c.3796C>T) is classified Uncertain significance in SETX (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-13). AlphaMissense: ambiguous (0.5207); Very rare (popmax 0.00771%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SETX p.Pro1266Ser (c.3796C>T)?

SETX p.Pro1266Ser (c.3796C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SETX p.Pro1266Ser (c.3796C>T) in the general population?

SETX p.Pro1266Ser (c.3796C>T) is very rare (popmax 0.00771%, nfe) (gnomAD).

What do computational predictors say about SETX p.Pro1266Ser (c.3796C>T)?

AlphaMissense predicts ambiguous (score 0.5207) — an in-silico prediction, not a clinical call.

SETX p.Pro1266Ser

c.3796C>T · rs751603620 · VCV1734985

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5207 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00771%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5207	ambiguous
REVEL	0.619	indeterminate
SaProt	LLR -5.95	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 3,399 bp · p 2.4e-06 · regional, not allelic
Overall
CADD	26.4	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 0.00771% European (non-Finnish) · 91/1,180,034 alleles

Filtering AF 0.00639% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00592%

Overall 0.00576% 93/1,614,048 alleles · very rare exomes 92/1,461,880 · genomes 1/152,168 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00771%	12,967
Remaining individualsnot grpmax-eligible	0.0032%	31,245

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.Pro1266Ser
Coding: c.3796C>T
MANE Select: NM_015046
dbSNP: rs751603620
Type: single nucleotide variant
Location: chr9:132327802 (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-pro1266ser (accessed [today's date]).

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