Is IKBKB p.Pro326= (c.978T>G) pathogenic?

IKBKB p.Pro326= (c.978T>G) is classified Likely benign in IKBKB (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-13). Ultra-rare (popmax 0.033%, mid); Associated with severe combined immunodeficiency due to IKK2 deficiency.

What condition is associated with IKBKB p.Pro326= (c.978T>G)?

IKBKB p.Pro326= (c.978T>G) is associated with severe combined immunodeficiency due to IKK2 deficiency (ClinVar).

How common is IKBKB p.Pro326= (c.978T>G) in the general population?

IKBKB p.Pro326= (c.978T>G) is ultra-rare (popmax 0.033%, mid) (gnomAD).

IKBKB p.Pro326=

Q: How is Combined immunodeficiency due to IKBKB deficiency inherited?

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

c.978T>G · rs755619006 · VCV2828148

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Conditions

severe combined immunodeficiency due to IKK2 deficiency

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 -1.4	GERP -3.8
Overall
CADD	2.127	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.000205% 3/1,461,872 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
European (non-Finnish)	8.47e-05%	1,180,018

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: IKBKB
Protein: p.Pro326=
Coding: c.978T>G
MANE Select: NM_001556
dbSNP: rs755619006
Type: single nucleotide variant
Location: chr8:42316757 (GRCh38)
Gene constraint: LOEUF 0.472 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 87.09 · 5 PDB
Residue 326: a β-strand

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

Disease context

severe combined immunodeficiency due to IKK2 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Combined immunodeficiency due to IKBKB deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

IKBKB p.Arg286Ter Pathogenic ★★ same condition
IKBKB p.Val203Ile Pathogenic ★★ ⚠ same condition
IKBKB p.Ala132Val Uncertain significance ★★ ⚠ same condition
IKBKB p.Ala422Thr Uncertain significance ★★ ⚠ same condition
IKBKB p.Ala454Thr Uncertain significance ★★ ⚠ same condition
IKBKB p.Ala702Thr Uncertain significance ★★ ⚠ same condition
IKBKB p.Arg105Trp Uncertain significance ★★ ⚠ same condition
IKBKB p.Arg419Gly 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/ikbkb-p-pro326 (accessed [today's date]).

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