Is IRAK2 p.Arg485Pro (c.1454G>C) pathogenic?

IRAK2 p.Arg485Pro (c.1454G>C) is classified Uncertain significance in IRAK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-24). AlphaMissense: ambiguous (0.4225); Ultra-rare (popmax 0.0181%, nfe).

How common is IRAK2 p.Arg485Pro (c.1454G>C) in the general population?

IRAK2 p.Arg485Pro (c.1454G>C) is ultra-rare (popmax 0.0181%, nfe) (gnomAD).

What do computational predictors say about IRAK2 p.Arg485Pro (c.1454G>C)?

AlphaMissense predicts ambiguous (score 0.4225) — an in-silico prediction, not a clinical call.

IRAK2 p.Arg485Pro

c.1454G>C · VCV3861206

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4225 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0181%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4225	ambiguous
REVEL	0.305	indeterminate
SaProt	LLR -9.28	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.4	GERP 1.5, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 77 kb · p 0.88 · regional, not allelic
Overall
CADD	24.5	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 0.0181% European (non-Finnish) · 213/1,179,728 alleles

Filtering AF 0.016% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0152%

Overall 0.0143% 231/1,612,780 alleles · ultra-rare exomes 215/1,460,572 · genomes 16/152,208 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0181%	5,539
Remaining individualsnot grpmax-eligible	0.0176%	5,675
African / African-American	0.00934%	10,703

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: IRAK2
Protein: p.Arg485Pro
Coding: c.1454G>C
MANE Select: NM_001570
Type: single nucleotide variant
Location: chr3:10234640 (GRCh38)
Gene constraint: LOEUF 0.962 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76 · 1 PDB
Residue 485: the protein kinase domain

Full IRAK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IRAK2 p.Arg485Cys Uncertain significance ★ ⚠ same residue
IRAK2 p.Leu392Val Benign ★★ same type
IRAK2 p.Ala152Thr Uncertain significance ★ ⚠ same type
IRAK2 p.Ala192Thr Uncertain significance ★ ⚠ same type
IRAK2 p.Ala451Ser Uncertain significance ★ ⚠ same type
IRAK2 p.Ala477Thr Uncertain significance ★ ⚠ same type
IRAK2 p.Ala573Ser Uncertain significance ★ ⚠ same type
IRAK2 p.Ala601Val 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/irak2-p-arg485pro (accessed [today's date]).

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