Is IKBKB p.Ser131= (c.393T>C) pathogenic?

IKBKB p.Ser131= (c.393T>C) is classified Likely benign in IKBKB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-09). Very rare (popmax 0.00136%, nfe); Associated with severe combined immunodeficiency due to IKK2 deficiency.

What condition is associated with IKBKB p.Ser131= (c.393T>C)?

IKBKB p.Ser131= (c.393T>C) is associated with severe combined immunodeficiency due to IKK2 deficiency (ClinVar).

How common is IKBKB p.Ser131= (c.393T>C) in the general population?

IKBKB p.Ser131= (c.393T>C) is very rare (popmax 0.00136%, nfe) (gnomAD).

IKBKB p.Ser131=

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.393T>C · rs200308355 · VCV1114173

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

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 -0.78	GERP -0.79, phastCons 0.01
Overall
CADD	8.169	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00136% European (non-Finnish) · 16/1,179,108 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.000992% 16/1,613,026 alleles · very rare exomes 15/1,460,806 · genomes 1/152,220 · joint denominator

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.Ser131=
Coding: c.393T>C
MANE Select: NM_001556
dbSNP: rs200308355
Type: single nucleotide variant
Location: chr8:42305191 (GRCh38)
Gene constraint: LOEUF 0.472 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 87.09 · 5 PDB
Residue 131: the protein kinase domain; an α-helix

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-ser131 (accessed [today's date]).

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