Is NFKB2 p.Pro757= (c.2271C>T) pathogenic?

NFKB2 p.Pro757= (c.2271C>T) is classified Likely benign in NFKB2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-06-20). Ultra-rare (popmax 0.0227%, afr); Associated with immunodeficiency, common variable, 10.

What condition is associated with NFKB2 p.Pro757= (c.2271C>T)?

NFKB2 p.Pro757= (c.2271C>T) is associated with immunodeficiency, common variable, 10 (ClinVar).

How common is NFKB2 p.Pro757= (c.2271C>T) in the general population?

NFKB2 p.Pro757= (c.2271C>T) is ultra-rare (popmax 0.0227%, afr) (gnomAD).

NFKB2 p.Pro757=

c.2271C>T · rs370993988 · VCV1147269

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, afr)

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	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -5	GERP -2.9
Overall
CADD	0.199	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0227% African / African-American · 17/74,882 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0119%

Overall 0.00112% 18/1,613,358 alleles · ultra-rare exomes 10/1,461,276 · genomes 8/152,082 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0227%	4,405
Admixed American	0.00167%	59,988

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.Pro757=
Coding: c.2271C>T
MANE Select: NM_001322934
dbSNP: rs370993988
Type: single nucleotide variant
Location: chr10:102401496 (GRCh38)
Gene constraint: LOEUF 0.308 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 75.94 · 11 PDB
Residue 757: a UniProt-annotated variant site (in truncated form eb308); a UniProt-annotated variant site (in truncated form p80ht); a UniProt-annotated variant site (in truncated form lb40)

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-pro757 (accessed [today's date]).

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