Is IRAK2 p.Ser217Arg (c.651C>A) pathogenic?

IRAK2 p.Ser217Arg (c.651C>A) is classified Uncertain significance in IRAK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-02). AlphaMissense: likely benign (0.3397); Ultra-rare (popmax 0.035%, amr).

How common is IRAK2 p.Ser217Arg (c.651C>A) in the general population?

IRAK2 p.Ser217Arg (c.651C>A) is ultra-rare (popmax 0.035%, amr) (gnomAD).

What do computational predictors say about IRAK2 p.Ser217Arg (c.651C>A)?

AlphaMissense predicts likely benign (score 0.3397) — an in-silico prediction, not a clinical call.

IRAK2 p.Ser217Arg

c.651C>A · VCV4679535

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3397 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.035%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3397	likely benign
REVEL	0.26	benign-leaning
SaProt	LLR -9.12	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 -8.3	GERP -3.6
Regional constraint	o/e 0.99	unconstrained · MANE · 77 kb · p 0.88 · regional, not allelic
Overall
CADD	2.013	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 0.035% Admixed American · 21/59,998 alleles

Filtering AF 0.0234% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.00316% 51/1,614,112 alleles · ultra-rare exomes 46/1,461,880 · genomes 5/152,232 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.035%	2,857
Remaining individualsnot grpmax-eligible	0.0064%	15,627
East Asian	0.00446%	22,440
European (non-Finnish)	0.00203%	49,168

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.Ser217Arg
Coding: c.651C>A
MANE Select: NM_001570
Type: single nucleotide variant
Location: chr3:10213329 (GRCh38)
Gene constraint: LOEUF 0.962 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76 · 1 PDB
Residue 217: the protein kinase domain; a binding site

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

Similar variants

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
IRAK2 p.Arg312His 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-ser217arg (accessed [today's date]).

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