Is RIOX2 p.Pro358Arg (c.1073C>G) pathogenic?

RIOX2 p.Pro358Arg (c.1073C>G) is classified Uncertain significance in RIOX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-18). AlphaMissense: likely pathogenic (0.8203); Very rare (popmax 0.00924%, nfe).

How common is RIOX2 p.Pro358Arg (c.1073C>G) in the general population?

RIOX2 p.Pro358Arg (c.1073C>G) is very rare (popmax 0.00924%, nfe) (gnomAD).

What do computational predictors say about RIOX2 p.Pro358Arg (c.1073C>G)?

AlphaMissense predicts likely pathogenic (score 0.8203) — an in-silico prediction, not a clinical call.

RIOX2 p.Pro358Arg

c.1073C>G · rs117990049 · VCV2548478

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8203 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00924%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8203	likely pathogenic
REVEL	0.561	indeterminate
SaProt	LLR -15.73	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 22 kb · p 0.86 · regional, not allelic
Overall
CADD	27.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00924% European (non-Finnish) · 109/1,179,266 alleles

Filtering AF 0.00783% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00728%

Overall 0.00707% 114/1,612,746 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00924%	10,819
Remaining individualsnot grpmax-eligible	0.00641%	15,604
African / African-American	0.00134%	74,760

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: RIOX2
Protein: p.Pro358Arg
Coding: c.1073C>G
MANE Select: NM_153182
dbSNP: rs117990049
Type: single nucleotide variant
Location: chr3:97947437 (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-pro358arg (accessed [today's date]).

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