Is NFKB2 p.Pro681= (c.2043G>A) pathogenic?

NFKB2 p.Pro681= (c.2043G>A) is classified Likely benign in NFKB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-06-04). Very rare (popmax 0.00401%, afr); Associated with immunodeficiency, common variable, 10.

What condition is associated with NFKB2 p.Pro681= (c.2043G>A)?

NFKB2 p.Pro681= (c.2043G>A) is associated with immunodeficiency, common variable, 10 (ClinVar).

How common is NFKB2 p.Pro681= (c.2043G>A) in the general population?

NFKB2 p.Pro681= (c.2043G>A) is very rare (popmax 0.00401%, afr) (gnomAD).

NFKB2 p.Pro681=

c.2043G>A · rs757196237 · VCV1142726

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00401%, 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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.7	GERP -3.9
Overall
CADD	4.99	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00401% African / African-American · 3/74,898 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000805% 13/1,613,908 alleles · very rare exomes 12/1,461,766 · genomes 1/152,142 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,966
Admixed American	0.00167%	59,982
Remaining individualsnot grpmax-eligible	0.0016%	62,474
European (non-Finnish)	0.000678%	147,498

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.Pro681=
Coding: c.2043G>A
MANE Select: NM_001322934
dbSNP: rs757196237
Type: single nucleotide variant
Location: chr10:102401021 (GRCh38)
Gene constraint: LOEUF 0.308 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 75.94 · 11 PDB
Residue 681: an α-helix; a UniProt-annotated variant site (in truncated form eb308); a UniProt-annotated variant site (in truncated form p80ht)

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.Pro681Leu 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
NFKB2 p.Ala475Val 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-pro681 (accessed [today's date]).

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