Is NFKB1 p.Ile826Val (c.2476A>G) pathogenic?

NFKB1 p.Ile826Val (c.2476A>G) is classified Uncertain significance in NFKB1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-16). AlphaMissense: likely benign (0.0897); Ultra-rare (popmax 0.0312%, eas); Associated with Inborn genetic diseases.

What condition is associated with NFKB1 p.Ile826Val (c.2476A>G)?

NFKB1 p.Ile826Val (c.2476A>G) is associated with Inborn genetic diseases (ClinVar).

How common is NFKB1 p.Ile826Val (c.2476A>G) in the general population?

NFKB1 p.Ile826Val (c.2476A>G) is ultra-rare (popmax 0.0312%, eas) (gnomAD).

What do computational predictors say about NFKB1 p.Ile826Val (c.2476A>G)?

AlphaMissense predicts likely benign (score 0.0897) — an in-silico prediction, not a clinical call.

NFKB1 p.Ile826Val

c.2476A>G · rs761606059 · VCV2123670

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0897 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0312%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0897	likely benign
REVEL	0.016	strongly benign-leaning
SaProt	LLR -5.37	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP -2.5, phastCons 0.99
Regional constraint	o/e 0.73	unconstrained · MANE · 19 kb · p 5.5e-11 · regional, not allelic
Overall
CADD	11.12	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM I825V vs ClinVar I826V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0312% East Asian · 14/44,892 alleles

Filtering AF 0.0188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0151%

Overall 0.000868% 14/1,613,824 alleles · ultra-rare exomes 13/1,461,606 · genomes 1/152,218 · 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: NFKB1
Protein: p.Ile826Val
Coding: c.2476A>G
MANE Select: NM_003998
dbSNP: rs761606059
Type: single nucleotide variant
Location: chr4:102612490 (GRCh38)
Gene constraint: LOEUF 0.178 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.84 · 15 PDB
Residue 825 UniProt numbering: the death domain; the 'interaction with cflar' region

Full NFKB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NFKB1 p.Ala495Val Uncertain significance ★★ ⚠ same condition
NFKB1 p.Ala837Val Uncertain significance ★★ ⚠ same condition
NFKB1 p.Arg231Cys Uncertain significance ★★ ⚠ same condition
NFKB1 p.Arg614Cys Uncertain significance ★★ ⚠ same condition
NFKB1 p.Arg614His Uncertain significance ★★ ⚠ same condition
NFKB1 p.Asn846Ser Uncertain significance ★★ ⚠ same condition
NFKB1 p.Asp519Asn Uncertain significance ★★ ⚠ same condition
NFKB1 p.Asp677Asn 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/nfkb1-p-ile826val (accessed [today's date]).

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