Is RIOX2 p.Leu397Val (c.1189T>G) pathogenic?

RIOX2 p.Leu397Val (c.1189T>G) is classified Uncertain significance in RIOX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-26). AlphaMissense: likely benign (0.1341); Absent from gnomAD v4.1.

How common is RIOX2 p.Leu397Val (c.1189T>G) in the general population?

RIOX2 p.Leu397Val (c.1189T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RIOX2 p.Leu397Val (c.1189T>G)?

AlphaMissense predicts likely benign (score 0.1341) — an in-silico prediction, not a clinical call.

RIOX2 p.Leu397Val

c.1189T>G · VCV4578259

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1341 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1341	likely benign
REVEL	0.259	benign-leaning
SaProt	LLR -8.78	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 4.8	GERP -0.61, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 22 kb · p 0.86 · regional, not allelic
Overall
CADD	21.4	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: RIOX2
Protein: p.Leu397Val
Coding: c.1189T>G
MANE Select: NM_153182
Type: single nucleotide variant
Location: chr3:97945848 (GRCh38)
Gene constraint: LOEUF 0.978 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.76 · 3 PDB

Full RIOX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RIOX2 p.Ala133Thr Uncertain significance ★ ⚠ same type
RIOX2 p.Ala171Thr Uncertain significance ★ ⚠ same type
RIOX2 p.Ala246Val Uncertain significance ★ ⚠ same type
RIOX2 p.Ala249Val Uncertain significance ★ ⚠ same type
RIOX2 p.Ala304Asp Uncertain significance ★ ⚠ same type
RIOX2 p.Ala304Ser Uncertain significance ★ ⚠ same type
RIOX2 p.Arg104Gln Uncertain significance ★ ⚠ same type
RIOX2 p.Arg104Trp Uncertain significance ★ ⚠ 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/riox2-p-leu397val (accessed [today's date]).

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