Is IRAK4 p.Ile26Val (c.76A>G) pathogenic?

IRAK4 p.Ile26Val (c.76A>G) is classified Uncertain significance in IRAK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-26). AlphaMissense: likely benign (0.0918); Very rare (popmax 0.00288%, nfe); Associated with immunodeficiency 67.

What condition is associated with IRAK4 p.Ile26Val (c.76A>G)?

IRAK4 p.Ile26Val (c.76A>G) is associated with immunodeficiency 67 (ClinVar).

How common is IRAK4 p.Ile26Val (c.76A>G) in the general population?

IRAK4 p.Ile26Val (c.76A>G) is very rare (popmax 0.00288%, nfe) (gnomAD).

What do computational predictors say about IRAK4 p.Ile26Val (c.76A>G)?

AlphaMissense predicts likely benign (score 0.0918) — an in-silico prediction, not a clinical call.

IRAK4 p.Ile26Val

Q: How is Transient predisposition to invasive pyogenic bacterial infection inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.76A>G · rs768548402 · VCV2142780

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0918 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00288%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency 67

Computational evidence

Protein change
AlphaMissense	0.0918	likely benign
REVEL	0.053	moderately benign-leaning
SaProt	LLR -9.04	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 6.1	GERP 2.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 19 kb · p 0.028 · regional, not allelic
Overall
CADD	19.47	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 0.00288% European (non-Finnish) · 34/1,179,460 alleles

Filtering AF 0.00208% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00217% 35/1,613,216 alleles · very rare exomes 34/1,461,006 · genomes 1/152,210 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00288%	34,690
Admixed American	0.00167%	59,916

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: IRAK4
Protein: p.Ile26Val
Coding: c.76A>G
MANE Select: NM_016123
dbSNP: rs768548402
Type: single nucleotide variant
Location: chr12:43768187 (GRCh38)
Gene constraint: LOEUF 1.175 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 84.11 · 98 PDB
Residue 26: the death domain; a UniProt-annotated variant site (no effect on inhibition of nf-kappa-b activation; no effect on interaction with myd88); an α-helix

Full IRAK4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

immunodeficiency 67 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Transient predisposition to invasive pyogenic bacterial infection (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

IRAK4 p.Ile26Thr Uncertain significance ★ ⚠ same residue
IRAK4 p.Arg183Ter Pathogenic/Likely pathogenic ★★ same condition
IRAK4 p.Gln122Ter Pathogenic ★★ same condition
IRAK4 p.Gln293Ter Pathogenic ★★ same condition
IRAK4 c.*2666G>T Uncertain significance ★★ same condition
IRAK4 c.*319A>G Uncertain significance ★★ same condition
IRAK4 p.Arg12His Uncertain significance ★★ ⚠ same condition
IRAK4 p.Arg361His Uncertain significance ★★ ⚠ same condition

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/irak4-p-ile26val (accessed [today's date]).

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