Is IRAK4 p.Pro4= (c.12C>G) pathogenic?

IRAK4 p.Pro4= (c.12C>G) is classified Likely benign in IRAK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-07). Very rare (popmax 0.000509%, nfe); Associated with immunodeficiency 67.

What condition is associated with IRAK4 p.Pro4= (c.12C>G)?

IRAK4 p.Pro4= (c.12C>G) is associated with immunodeficiency 67 (ClinVar).

How common is IRAK4 p.Pro4= (c.12C>G) in the general population?

IRAK4 p.Pro4= (c.12C>G) is very rare (popmax 0.000509%, nfe) (gnomAD).

IRAK4 p.Pro4=

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.12C>G · rs1287416995 · VCV1957687

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Conditions

immunodeficiency 67

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.6	GERP -0.35
Overall
CADD	5.241	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000509% European (non-Finnish) · 6/1,179,610 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,613,236 alleles · very rare

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.Pro4=
Coding: c.12C>G
MANE Select: NM_016123
dbSNP: rs1287416995
Type: single nucleotide variant
Location: chr12:43768123 (GRCh38)
Gene constraint: LOEUF 1.175 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 84.11 · 98 PDB

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.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
IRAK4 p.Asn78Asp 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-pro4 (accessed [today's date]).

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