Is NFKB2 p.Arg548Pro (c.1643G>C) pathogenic?

NFKB2 p.Arg548Pro (c.1643G>C) is classified Uncertain significance in NFKB2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-23). AlphaMissense: ambiguous (0.5572); Very rare (popmax 0.00133%, afr); Associated with immunodeficiency, common variable, 10.

What condition is associated with NFKB2 p.Arg548Pro (c.1643G>C)?

NFKB2 p.Arg548Pro (c.1643G>C) is associated with immunodeficiency, common variable, 10 (ClinVar).

How common is NFKB2 p.Arg548Pro (c.1643G>C) in the general population?

NFKB2 p.Arg548Pro (c.1643G>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about NFKB2 p.Arg548Pro (c.1643G>C)?

AlphaMissense predicts ambiguous (score 0.5572) — an in-silico prediction, not a clinical call.

NFKB2 p.Arg548Pro

c.1643G>C · rs201353619 · VCV2158075

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5572 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

immunodeficiency, common variable, 10

Computational evidence

Protein change
AlphaMissense	0.5572	ambiguous
REVEL	0.338	indeterminate
SaProt	LLR -11.71	damaging
Splicing
SpliceAI	Δ0.21	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 7	GERP -4, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 1,079 bp · p 0.0022 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,924 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000744% 12/1,613,836 alleles · very rare exomes 9/1,461,678 · genomes 3/152,158 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,924
European (non-Finnish)	0.000932%	107,274

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.Arg548Pro
Coding: c.1643G>C
MANE Select: NM_001322934
dbSNP: rs201353619
Type: single nucleotide variant
Location: chr10:102400336 (GRCh38)
Gene constraint: LOEUF 0.308 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 75.94 · 11 PDB
Residue 548: 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.Arg548Gln Uncertain significance ★ ⚠ same residue
NFKB2 p.Arg548_Leu556del Uncertain significance ★★ same residue
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

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-arg548pro (accessed [today's date]).

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