Is RIOX2 p.Pro341Thr (c.1021C>A) pathogenic?

RIOX2 p.Pro341Thr (c.1021C>A) is classified Uncertain significance in RIOX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-12). AlphaMissense: likely pathogenic (0.5664); Ultra-rare (popmax 0.0154%, sas).

How common is RIOX2 p.Pro341Thr (c.1021C>A) in the general population?

RIOX2 p.Pro341Thr (c.1021C>A) is ultra-rare (popmax 0.0154%, sas) (gnomAD).

What do computational predictors say about RIOX2 p.Pro341Thr (c.1021C>A)?

AlphaMissense predicts likely pathogenic (score 0.5664) — an in-silico prediction, not a clinical call.

RIOX2 p.Pro341Thr

c.1021C>A · rs147454535 · VCV3154481

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5664 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0154%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5664	likely pathogenic
REVEL	0.429	indeterminate
SaProt	LLR -8.88	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; 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	25.3	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 0.0154% South Asian · 14/91,046 alleles

Filtering AF 0.0092% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00735%

Overall 0.00254% 41/1,613,682 alleles · ultra-rare exomes 39/1,461,678 · genomes 2/152,004 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0154%	6,503
European (non-Finnish)	0.00229%	43,701

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.Pro341Thr
Coding: c.1021C>A
MANE Select: NM_153182
dbSNP: rs147454535
Type: single nucleotide variant
Location: chr3:97949883 (GRCh38)
Gene constraint: LOEUF 0.978 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.76 · 3 PDB
Residue 341: an α-helix

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

Similar variants

RIOX2 p.Pro341Ser Uncertain significance ★ ⚠ same residue
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

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-pro341thr (accessed [today's date]).

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