IKBKG

Chr XX-linkedXLRXLD

inhibitor of nuclear factor kappa B kinase regulatory subunit gamma

Also known as: AMCBX1, EDAID1, FIP-3, FIP3, Fip3p, IKK-gamma, IKKAP1, IKKG

NCBI Gene: 8517 ENSG00000269335 UniProt: Q9Y6K9 OMIM: 300248

This gene encodes the regulatory subunit of the IKK complex that phosphorylates inhibitors of NF-kappaB, leading to NF-kappaB activation and downstream regulation of inflammation, immunity, and cell survival pathways. X-linked mutations cause incontinentia pigmenti, hypohidrotic ectodermal dysplasia with immunodeficiency, primary immunodeficiencies, and systemic autoinflammatory disease through disrupted NF-kappaB signaling. Inheritance patterns include both X-linked dominant (incontinentia pigmenti) and X-linked recessive forms depending on the specific condition.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes the regulatory subunit of the inhibitor of kappaB kinase (IKK) complex, which activates NF-kappaB resulting in activation of genes involved in inflammation, immunity, cell survival, and other pathways. Mutations in this gene result in incontinentia pigmenti, hypohidrotic ectodermal dysplasia, and several other types of immunodeficiencies. A pseudogene highly similar to this locus is located in an adjacent region of the X chromosome. [provided by RefSeq, Mar 2016]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismX-linked/XLR/XLDLOEUF 1.374 OMIM phenotypes

Clinical Summary— IKBKG

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Gene-Disease Validity (ClinGen)

incontinentia pigmenti · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.08) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

53 unique Pathogenic / Likely Pathogenic· 80 VUS of 208 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — IKBKG

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.37LOEUF

pLI 0.085

Z-score 1.08

OE 0.45 (0.18–1.37)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.03Z-score

OE missense 0.99 (0.79–1.24)

53 obs / 53.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.45 (0.18–1.37)

0≤0.351.4

Missense OE?0.99 (0.79–1.24)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 2 / 4.5Missense obs/exp: 53 / 53.6Syn Z: 0.30

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveIKBKG-related incontinentia pigmentiLOFmonoallelic_X_heterozygous

definitiveIKBKG-related ectodermal dysplasia and immunodeficiencyLOFXLR

This gene — mechanism propensity

0.74top 25%

GOF

0.5953th %ile

LOF

0.3067th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF62% of P/LP variants are LoF · ClinGen HI: Sufficient evidence for dosage pathogenicity

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

208 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic33

Likely Pathogenic20

VUS80

Likely Benign33

Benign14

Conflicting6

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	24	2	7	0	33
Likely Pathogenic	9	10	1	0	20
VUS	2	65	10	3	80
Likely Benign	0	4	14	15	33
Benign	0	1	12	1	14
Conflicting	—				6
Total	35	82	44	19	186

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

83 pathogenic / likely-pathogenic (of 99) ClinVar copy-number / structural variants overlap IKBKG — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →