Is NFKB2 p.Pro709Thr (c.2125C>A) pathogenic?

NFKB2 p.Pro709Thr (c.2125C>A) is classified Uncertain significance in NFKB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-27). AlphaMissense: likely benign (0.067); Very rare (popmax 0.00335%, amr); Associated with immunodeficiency, common variable, 10.

What condition is associated with NFKB2 p.Pro709Thr (c.2125C>A)?

NFKB2 p.Pro709Thr (c.2125C>A) is associated with immunodeficiency, common variable, 10 (ClinVar).

How common is NFKB2 p.Pro709Thr (c.2125C>A) in the general population?

NFKB2 p.Pro709Thr (c.2125C>A) is very rare (popmax 0.00335%, amr) (gnomAD).

What do computational predictors say about NFKB2 p.Pro709Thr (c.2125C>A)?

AlphaMissense predicts likely benign (score 0.067) — an in-silico prediction, not a clinical call.

NFKB2 p.Pro709Thr

c.2125C>A · rs761599377 · VCV1981661

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.067 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00335%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency, common variable, 10

Computational evidence

Protein change
AlphaMissense	0.067	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	LLR -7.86	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.3	GERP 0.85, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 1,325 bp · p 0.00043 · regional, not allelic
Overall
CADD	17.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00335% Admixed American · 2/59,690 alleles

Filtering AF 0.000556% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000208%

Overall 0.000124% 2/1,611,254 alleles · very rare exomes 2/1,458,950 · genomes 0/152,304 · joint denominator

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.Pro709Thr
Coding: c.2125C>A
MANE Select: NM_001322934
dbSNP: rs761599377
Type: single nucleotide variant
Location: chr10:102401233 (GRCh38)
Gene constraint: LOEUF 0.308 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 75.94 · 11 PDB
Residue 709: the 'disordered' region; 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.Pro709Ser 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-pro709thr (accessed [today's date]).

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