Is RIOX2 p.Arg92Trp (c.274C>T) pathogenic?

RIOX2 p.Arg92Trp (c.274C>T) is classified Uncertain significance in RIOX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-21). AlphaMissense: likely benign (0.0842); Ultra-rare (popmax 0.0164%, mid).

How common is RIOX2 p.Arg92Trp (c.274C>T) in the general population?

RIOX2 p.Arg92Trp (c.274C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about RIOX2 p.Arg92Trp (c.274C>T)?

AlphaMissense predicts likely benign (score 0.0842) — an in-silico prediction, not a clinical call.

RIOX2 p.Arg92Trp

c.274C>T · VCV3789267

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0842 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0842	likely benign
REVEL	0.091	moderately benign-leaning
SaProt	LLR -9.58	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 3.4	GERP 0.87, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 22 kb · p 0.86 · regional, not allelic
Overall
CADD	20.1	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

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00514% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00375%

Overall 0.00452% 73/1,613,952 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
South Asian	0.00988%	10,120
European (non-Finnish)	0.005%	20,000
Remaining individualsnot grpmax-eligible	0.0032%	31,243
African / African-American	0.00267%	37,440

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.Arg92Trp
Coding: c.274C>T
MANE Select: NM_153182
Type: single nucleotide variant
Location: chr3:97967320 (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-arg92trp (accessed [today's date]).

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