Is RIOK2 p.Arg276Ser (c.826C>A) pathogenic?

RIOK2 p.Arg276Ser (c.826C>A) is classified Uncertain significance in RIOK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: likely pathogenic (0.9842); No allele count reported in gnomAD v4.1 (AN 1,600,854).

How common is RIOK2 p.Arg276Ser (c.826C>A) in the general population?

RIOK2 p.Arg276Ser (c.826C>A) is no allele count reported in gnomAD v4.1 (AN 1,600,854) (gnomAD).

What do computational predictors say about RIOK2 p.Arg276Ser (c.826C>A)?

AlphaMissense predicts likely pathogenic (score 0.9842) — an in-silico prediction, not a clinical call.

RIOK2 p.Arg276Ser

c.826C>A · VCV4154665

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9842 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,600,854)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9842	likely pathogenic · top 8% in RIOK2
REVEL	0.45	indeterminate
SaProt	LLR -13.43	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.9	GERP 4.5, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 20 kb · p 0.0011 · regional, not allelic
Overall
CADD	26.8	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

No allele count reported in gnomAD v4.1 (AN 1,600,854). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: RIOK2
Protein: p.Arg276Ser
Coding: c.826C>A
MANE Select: NM_018343
Type: single nucleotide variant
Location: chr5:97168806 (GRCh38)
Gene constraint: LOEUF 1.009 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.80 · 10 PDB
Residue 276: an α-helix

Full RIOK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RIOK2 p.Arg276Cys Uncertain significance ★ ⚠ same residue
RIOK2 p.Arg276His Uncertain significance ★ same residue
RIOK2 p.Ala185Ser Uncertain significance ★ ⚠ same type
RIOK2 p.Ala302Val Uncertain significance ★ ⚠ same type
RIOK2 p.Ala490Thr Uncertain significance ★ ⚠ same type
RIOK2 p.Arg155Cys Uncertain significance ★ ⚠ same type
RIOK2 p.Arg463Ser Uncertain significance ★ ⚠ same type
RIOK2 p.Arg520Gln 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/riok2-p-arg276ser (accessed [today's date]).

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