# NM_003998.4(NFKB1):c.2476A>G (p.Ile826Val)

https://sugi.bio/variant/nfkb1-p-ile826val

## Summary

**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.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs761606059 · 2 submitters · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.0312%, eas)

## For patients & families {#patients}

This is a change in the NFKB1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to Inborn genetic diseases.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [NFKB1](https://sugi.bio/atlas/gene/NFKB1/) |
| Protein change (HGVS p.) | p.Ile826Val |
| Coding change (HGVS c.) | c.2476A>G |
| MANE Select transcript | [NM_003998](https://www.ncbi.nlm.nih.gov/nuccore/NM_003998) |
| dbSNP | [rs761606059](https://www.ncbi.nlm.nih.gov/snp/rs761606059/) |
| Variant type | single nucleotide variant |
| Location | chr4:102612490-102612490 (GRCh38) |
| ClinVar | [VCV2123670](https://www.ncbi.nlm.nih.gov/clinvar/variation/2123670/) |

**All HGVS expressions:** `LRG_1316:g.116162A>G`, `LRG_1316t1:c.2476A>G`, `NC_000004.11:g.103533647A>G`, `NC_000004.12:g.102612490A>G`, `NG_050628.1:g.116162A>G`, `NM_001165412.2:c.2473A>G`, `NM_001319226.2:c.2473A>G`, `NM_001382625.1:c.2476A>G`, `NM_001382626.1:c.2476A>G`, `NM_001382627.1:c.2473A>G`, `NM_001382628.1:c.2434A>G`, `NM_003998.3:c.2476A>G`, `NM_003998.4:c.2476A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0897)
- REVEL 0.016 (strongly benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.372 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 2.644, GERP -2.52, phastCons 0.993 — highly conserved (differs from AlphaMissense)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **I825V** vs ClinVar **I826V**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 11.12**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.73** across the covering region of the MANE Select transcript (102,597,538–102,616,591), spanning 19,053 bp. Chi-square p 5.5e-11. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0312%** (eas) · FAF95 0.0188% · FAF99 0.0151% · 14/44,892 in the highest group · 14/1,613,824 alleles overall — ultra-rare (popmax 0.0312%, eas).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**NFKB1** population constraint: LOEUF 0.178, pLI 1, missense-Z 3.9758. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **immunodeficiency, common variable, 12** — Definitive (AD)

## Protein context {#protein}

Residue **825** lies in the death domain; the 'interaction with cflar' region.

AlphaFold model confidence (whole protein): pLDDT 73.84, 45% of residues very-high.

**15 experimental structure(s)** (PDB): [1MDI](https://www.rcsb.org/structure/1MDI), [1MDJ](https://www.rcsb.org/structure/1MDJ), [1MDK](https://www.rcsb.org/structure/1MDK), [1NFI](https://www.rcsb.org/structure/1NFI), [1SVC](https://www.rcsb.org/structure/1SVC), [2DBF](https://www.rcsb.org/structure/2DBF) — incl. mutant structure 1MDI.

## What this gene does {#gene-function}

*Describes the biological roles of NFKB1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** NFKB1's established molecular role includes transcription cis-regulatory region binding. p.Ile826Val falls in the death domain. In Reactome, NFKB1 is annotated in disease pathway(s) including **HCMV Early Events**, **IkBA variant leads to EDA-ID**.

**Disease mechanism (Reactome):** NFKB1 loss or alteration is curated in [HCMV Early Events](https://reactome.org/content/detail/R-HSA-9609690), [IkBA variant leads to EDA-ID](https://reactome.org/content/detail/R-HSA-5603029), [Purinergic signaling in leishmaniasis infection](https://reactome.org/content/detail/R-HSA-9660826).

### Pathways affected {#pathways}

NFKB1 participates in **30 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [HCMV Early Events](https://reactome.org/content/detail/R-HSA-9609690) | curated |
| ⚕ [IkBA variant leads to EDA-ID](https://reactome.org/content/detail/R-HSA-5603029) | curated |
| ⚕ [Purinergic signaling in leishmaniasis infection](https://reactome.org/content/detail/R-HSA-9660826) | curated |
| ⚕ [SARS-CoV-1 activates/modulates innate immune responses](https://reactome.org/content/detail/R-HSA-9692916) | curated |
| [Activation of NF-kappaB in B cells](https://reactome.org/content/detail/R-HSA-1169091) | curated |
| [Activation of STAT3 by cadherin engagement](https://reactome.org/content/detail/R-HSA-9958825) | curated |
| [CD209 (DC-SIGN) signaling](https://reactome.org/content/detail/R-HSA-5621575) | curated |
| [CLEC7A (Dectin-1) signaling](https://reactome.org/content/detail/R-HSA-5607764) | curated |
| [CLEC7A/inflammasome pathway](https://reactome.org/content/detail/R-HSA-5660668) | curated |
| [DEx/H-box helicases activate type I IFN and inflammatory cytokines production ](https://reactome.org/content/detail/R-HSA-3134963) | curated |
| [Downstream TCR signaling](https://reactome.org/content/detail/R-HSA-202424) | curated |
| [FCERI mediated NF-kB activation](https://reactome.org/content/detail/R-HSA-2871837) | curated |
| [Interleukin-1 processing](https://reactome.org/content/detail/R-HSA-448706) | curated |
| [Interleukin-1 signaling](https://reactome.org/content/detail/R-HSA-9020702) | curated |
| [MAP3K8 (TPL2)-dependent MAPK1/3 activation](https://reactome.org/content/detail/R-HSA-5684264) | curated |
| [NF-kB is activated and signals survival](https://reactome.org/content/detail/R-HSA-209560) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [PKMTs methylate histone lysines](https://reactome.org/content/detail/R-HSA-3214841) | curated |
| [RIP-mediated NFkB activation via ZBP1](https://reactome.org/content/detail/R-HSA-1810476) | curated |
| [Regulated proteolysis of p75NTR](https://reactome.org/content/detail/R-HSA-193692) | curated |
| [Regulation of NFE2L2 gene expression](https://reactome.org/content/detail/R-HSA-9818749) | curated |
| [Regulation of PD-L1(CD274) transcription](https://reactome.org/content/detail/R-HSA-9909649) | curated |
| [Senescence-Associated Secretory Phenotype (SASP)](https://reactome.org/content/detail/R-HSA-2559582) | curated |
| [TAK1-dependent IKK and NF-kappa-B activation  ](https://reactome.org/content/detail/R-HSA-445989) | curated |
| [TRAF6 mediated NF-kB activation](https://reactome.org/content/detail/R-HSA-933542) | curated |
| [The NLRP3 inflammasome](https://reactome.org/content/detail/R-HSA-844456) | curated |
| [Transcriptional Regulation by VENTX](https://reactome.org/content/detail/R-HSA-8853884) | curated |
| [Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells](https://reactome.org/content/detail/R-HSA-9860927) | curated |
| [Somatic hypermutation of immunoglobulin genes](https://reactome.org/content/detail/R-HSA-9938024) | electronic |
| [Transcriptional regulation of white adipocyte differentiation](https://reactome.org/content/detail/R-HSA-381340) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** transcription cis-regulatory region binding, RNA polymerase II transcription regulatory region sequence-specific DNA binding, RNA polymerase II cis-regulatory region sequence-specific DNA binding, DNA-binding transcription factor activity, RNA polymerase II-specific, DNA-binding transcription repressor activity, RNA polymerase II-specific, DNA-binding transcription activator activity, RNA polymerase II-specific.

**Biological process:** negative regulation of transcription by RNA polymerase II, regulation of transcription by RNA polymerase II, canonical NF-kappaB signal transduction, negative regulation of gene expression, positive regulation of macrophage derived foam cell differentiation, positive regulation of cholesterol efflux.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-16.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2023–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-08-15 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-12-16 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not provided, none provided.

## Similar variants {#similar}

Related NFKB1 variant pages (same residue, condition, or type): [NFKB1 p.Ala495Val](/variant/nfkb1-p-ala495val), [NFKB1 p.Ala837Val](/variant/nfkb1-p-ala837val), [NFKB1 p.Arg231Cys](/variant/nfkb1-p-arg231cys), [NFKB1 p.Arg614Cys](/variant/nfkb1-p-arg614cys), [NFKB1 p.Arg614His](/variant/nfkb1-p-arg614his), [NFKB1 p.Asn846Ser](/variant/nfkb1-p-asn846ser), [NFKB1 p.Asp519Asn](/variant/nfkb1-p-asp519asn), [NFKB1 p.Asp677Asn](/variant/nfkb1-p-asp677asn).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 2123670). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*