Is SETX p.Ile2326Val (c.6976A>G) pathogenic?

SETX p.Ile2326Val (c.6976A>G) is classified Uncertain significance in SETX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2020-05-05). AlphaMissense: likely benign (0.1771); Absent from gnomAD v4.1.

How common is SETX p.Ile2326Val (c.6976A>G) in the general population?

SETX p.Ile2326Val (c.6976A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SETX p.Ile2326Val (c.6976A>G)?

AlphaMissense predicts likely benign (score 0.1771) — an in-silico prediction, not a clinical call.

SETX p.Ile2326Val

c.6976A>G · rs751216566 · VCV805432

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1771 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1771	likely benign
REVEL	0.248	benign-leaning
SaProt	LLR -8.18	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 -0.26	GERP -3.6, phastCons 0.23
Regional constraint	o/e 0.70	unconstrained · MANE · 32 kb · p 3e-13 · regional, not allelic
Overall
CADD	13.69	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

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.Ile2326Val
Coding: c.6976A>G
MANE Select: NM_015046
dbSNP: rs751216566
Type: single nucleotide variant
Location: chr9:132275380 (GRCh38)
Gene constraint: LOEUF 0.442 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.93
Residue 2326: the upf1-type sf1b helicase c-terminal domain

Full SETX gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SETX p.Arg111Ter Pathogenic ★★ same type
SETX p.Arg1363Ter Pathogenic ★★ same type
SETX p.Arg1606Ter Pathogenic ★★ same type
SETX p.Arg1778Ter Pathogenic/Likely pathogenic ★★ same type
SETX p.Arg2098Ter Pathogenic ★★ same type
SETX p.Arg332Trp Pathogenic/Likely pathogenic ★★ same type
SETX p.Arg778Ter Pathogenic/Likely pathogenic ★★ same type
SETX p.Gln1695Ter Pathogenic/Likely pathogenic ★★ same type

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-ile2326val (accessed [today's date]).

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