Is NFKB2 p.Asp280= (c.840T>C) pathogenic?

NFKB2 p.Asp280= (c.840T>C) is classified Likely benign in NFKB2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-09). Ultra-rare (popmax 0.0164%, mid); Associated with immunodeficiency, common variable, 10.

What condition is associated with NFKB2 p.Asp280= (c.840T>C)?

NFKB2 p.Asp280= (c.840T>C) is associated with immunodeficiency, common variable, 10 (ClinVar).

How common is NFKB2 p.Asp280= (c.840T>C) in the general population?

NFKB2 p.Asp280= (c.840T>C) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

NFKB2 p.Asp280=

c.840T>C · rs199585223 · VCV739901

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

immunodeficiency, common variable, 10

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 · T>G here scores Δ0.82 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.53	GERP -2.6, phastCons 1
Overall
CADD	8.825	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00495% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00455%

Overall 0.00477% 77/1,614,040 alleles · ultra-rare exomes 70/1,461,882 · genomes 7/152,158 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
European (non-Finnish)	0.0061%	16,389
Remaining individualsnot grpmax-eligible	0.0048%	20,830
African / African-American	0.00134%	74,900

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: NFKB2
Protein: p.Asp280=
Coding: c.840T>C
MANE Select: NM_001322934
dbSNP: rs199585223
Type: single nucleotide variant
Location: chr10:102398285 (GRCh38)
Gene constraint: LOEUF 0.308 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 75.94 · 11 PDB
Residue 280: the rhd domain; an α-helix

Full NFKB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

immunodeficiency, common variable, 10 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NFKB2 p.Arg853Ter Pathogenic ★★ same condition
NFKB2 p.Asp865Gly Pathogenic/Likely pathogenic ★★ same condition
NFKB2 p.Gln871Ter Pathogenic ★★ same condition
NFKB2 c.243+3G>A Uncertain significance ★★ same condition
NFKB2 p.Ala121Thr Uncertain significance ★★ ⚠ same condition
NFKB2 p.Ala363Thr Uncertain significance ★★ ⚠ same condition
NFKB2 p.Ala475Val Uncertain significance ★★ ⚠ same condition
NFKB2 p.Ala572Thr 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/nfkb2-p-asp280 (accessed [today's date]).

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