Is IKBKB p.Val727= (c.2181G>A) pathogenic?

IKBKB p.Val727= (c.2181G>A) is classified Likely benign in IKBKB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-13). Absent from gnomAD v4.1; Associated with severe combined immunodeficiency due to IKK2 deficiency.

What condition is associated with IKBKB p.Val727= (c.2181G>A)?

IKBKB p.Val727= (c.2181G>A) is associated with severe combined immunodeficiency due to IKK2 deficiency (ClinVar).

How common is IKBKB p.Val727= (c.2181G>A) in the general population?

IKBKB p.Val727= (c.2181G>A) is absent from gnomAD v4.1 (gnomAD).

IKBKB p.Val727=

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.2181G>A · VCV3645653

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

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	<0.2	all four deltas below 0.2 · G>T here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.6	GERP 1.7, phastCons 1
Overall
CADD	8.088	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: IKBKB
Protein: p.Val727=
Coding: c.2181G>A
MANE Select: NM_001556
Type: single nucleotide variant
Location: chr8:42329190 (GRCh38)
Gene constraint: LOEUF 0.472 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 87.09 · 5 PDB
Residue 727: 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.Val727fs Uncertain significance ★ same residue
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

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-val727 (accessed [today's date]).

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