Is IRAK2 p.Pro306Arg (c.917C>G) pathogenic?

IRAK2 p.Pro306Arg (c.917C>G) is classified Uncertain significance in IRAK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-27). AlphaMissense: likely benign (0.0906); Very rare (popmax 0.00935%, afr).

How common is IRAK2 p.Pro306Arg (c.917C>G) in the general population?

IRAK2 p.Pro306Arg (c.917C>G) is very rare (popmax 0.00935%, afr) (gnomAD).

What do computational predictors say about IRAK2 p.Pro306Arg (c.917C>G)?

AlphaMissense predicts likely benign (score 0.0906) — an in-silico prediction, not a clinical call.

IRAK2 p.Pro306Arg

c.917C>G · rs1457176323 · VCV2570065

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0906 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00935%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0906	likely benign
REVEL	0.16	moderately benign-leaning
SaProt	LLR -9.30	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 0.8	GERP -2.7
Regional constraint	o/e 0.99	unconstrained · MANE · 77 kb · p 0.88 · regional, not allelic
Overall
CADD	15.71	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 0.00935% African / African-American · 7/74,898 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.000682% 11/1,613,536 alleles · very rare exomes 9/1,461,432 · genomes 2/152,104 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00935%	10,700
Remaining individualsnot grpmax-eligible	0.0064%	15,617

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.Pro306Arg
Coding: c.917C>G
MANE Select: NM_001570
dbSNP: rs1457176323
Type: single nucleotide variant
Location: chr3:10219693 (GRCh38)
Gene constraint: LOEUF 0.962 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76 · 1 PDB
Residue 306: the protein kinase domain

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

Similar variants

IRAK2 p.Pro306Ala Uncertain significance ★ ⚠ same residue
IRAK2 p.Pro306Ser 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

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-pro306arg (accessed [today's date]).

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