# NM_001278.5(CHUK):c.450A>C (p.Ile150=)

https://sugi.bio/variant/chuk-p-ile150

## Summary

**CHUK p.Ile150= (c.450A>C)** is classified **Likely benign** in CHUK (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-01). Very rare (popmax 0.000339%, nfe).

**At a glance:** Likely benign · review: Single submitter · rsID rs375635899 · 1 submitter · very rare (popmax 0.000339%, nfe)

## For patients & families {#patients}

This is a change in the CHUK gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*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 | [CHUK](https://sugi.bio/atlas/gene/CHUK/) |
| Protein change (HGVS p.) | p.Ile150= |
| Coding change (HGVS c.) | c.450A>C |
| MANE Select transcript | [NM_001278](https://www.ncbi.nlm.nih.gov/nuccore/NM_001278) |
| dbSNP | [rs375635899](https://www.ncbi.nlm.nih.gov/snp/rs375635899/) |
| Variant type | single nucleotide variant |
| Location | chr10:100220612-100220612 (GRCh38) |
| ClinVar | [VCV2807759](https://www.ncbi.nlm.nih.gov/clinvar/variation/2807759/) |

**All HGVS expressions:** `NC_000010.10:g.101980369T>G`, `NC_000010.11:g.100220612T>G`, `NG_028023.1:g.13976A>C`, `NG_028023.2:g.13984A>C`, `NM_001278.5:c.450A>C`, `NM_001320928.2:c.450A>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 3.515, GERP -0.51, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 10.5**. 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.*
- 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 **0.000339%** (nfe) · FAF95 7.9e-05% · FAF99 5.4e-05% · 4/1,178,304 in the highest group · 4/1,612,092 alleles overall — very rare (popmax 0.000339%, nfe).

*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}

**CHUK** population constraint: LOEUF 0.61, pLI 0.3913, missense-Z 2.0823. *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):

- **Bartsocas-Papas syndrome 2** — Moderate (AR)

## Protein context {#protein}

Residue **150** lies in the protein kinase domain.

AlphaFold model confidence (whole protein): pLDDT 84.41, 60% of residues very-high.

**5 experimental structure(s)** (PDB): [3BRT](https://www.rcsb.org/structure/3BRT), [5EBZ](https://www.rcsb.org/structure/5EBZ), [5TQW](https://www.rcsb.org/structure/5TQW), [5TQX](https://www.rcsb.org/structure/5TQX), [5TQY](https://www.rcsb.org/structure/5TQY).

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

*Describes the biological roles of CHUK (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:** CHUK's established molecular role includes protein kinase activity. p.Ile150= falls in the protein kinase domain. In Reactome, CHUK is annotated in disease pathway(s) including **Constitutive Signaling by AKT1 E17K in Cancer**, **IKBKB deficiency causes SCID**.

**Disease mechanism (Reactome):** CHUK loss or alteration is curated in [Constitutive Signaling by AKT1 E17K in Cancer](https://reactome.org/content/detail/R-HSA-5674400), [IKBKB deficiency causes SCID](https://reactome.org/content/detail/R-HSA-5602636), [IKBKG deficiency causes anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) (via TLR)](https://reactome.org/content/detail/R-HSA-5603027).

### Pathways affected {#pathways}

CHUK participates in **31 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by AKT1 E17K in Cancer](https://reactome.org/content/detail/R-HSA-5674400) | curated |
| ⚕ [IKBKB deficiency causes SCID](https://reactome.org/content/detail/R-HSA-5602636) | curated |
| ⚕ [IKBKG deficiency causes anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) (via TLR)](https://reactome.org/content/detail/R-HSA-5603027) | curated |
| ⚕ [IkBA variant leads to EDA-ID](https://reactome.org/content/detail/R-HSA-5603029) | curated |
| ⚕ [SARS-CoV-2 activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9705671) | curated |
| [AKT phosphorylates targets in the cytosol](https://reactome.org/content/detail/R-HSA-198323) | curated |
| [CLEC7A (Dectin-1) signaling](https://reactome.org/content/detail/R-HSA-5607764) | curated |
| [Dectin-1 mediated noncanonical NF-kB signaling](https://reactome.org/content/detail/R-HSA-5607761) | curated |
| [Downstream TCR signaling](https://reactome.org/content/detail/R-HSA-202424) | curated |
| [ER-Phagosome pathway](https://reactome.org/content/detail/R-HSA-1236974) | curated |
| [FCERI mediated NF-kB activation](https://reactome.org/content/detail/R-HSA-2871837) | curated |
| [IKK complex recruitment mediated by RIP1](https://reactome.org/content/detail/R-HSA-937041) | curated |
| [IRAK1 recruits IKK complex](https://reactome.org/content/detail/R-HSA-937039) | curated |
| [IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation](https://reactome.org/content/detail/R-HSA-975144) | 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 |
| [Modulation of host responses by IFN-stimulated genes](https://reactome.org/content/detail/R-HSA-9909505) | curated |
| [NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10](https://reactome.org/content/detail/R-HSA-933543) | curated |
| [NIK-->noncanonical NF-kB signaling](https://reactome.org/content/detail/R-HSA-5676590) | curated |
| [NOD1/2 Signaling Pathway](https://reactome.org/content/detail/R-HSA-168638) | curated |
| [PKR-mediated signaling](https://reactome.org/content/detail/R-HSA-9833482) | curated |
| [RIP-mediated NFkB activation via ZBP1](https://reactome.org/content/detail/R-HSA-1810476) | curated |
| [Regulation of NF-kappa B signaling](https://reactome.org/content/detail/R-HSA-9758274) | curated |
| [Regulation of TNFR1 signaling](https://reactome.org/content/detail/R-HSA-5357905) | curated |
| [SLC15A4:TASL-dependent IRF5 activation](https://reactome.org/content/detail/R-HSA-9860276) | curated |
| [TAK1-dependent IKK and NF-kappa-B activation  ](https://reactome.org/content/detail/R-HSA-445989) | curated |
| [TICAM1, RIP1-mediated IKK complex recruitment](https://reactome.org/content/detail/R-HSA-168927) | curated |
| [TNFR1-induced NF-kappa-B signaling pathway](https://reactome.org/content/detail/R-HSA-5357956) | curated |
| [TRAF6 mediated NF-kB activation](https://reactome.org/content/detail/R-HSA-933542) | 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 |
| [Activation of NF-kappaB in B cells](https://reactome.org/content/detail/R-HSA-1169091) | electronic |

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

**Molecular function:** protein kinase activity, protein serine/threonine kinase activity, IkappaB kinase activity, identical protein binding, protein homodimerization activity, protein heterodimerization activity.

**Biological process:** canonical NF-kappaB signal transduction, positive regulation of interferon-alpha production, tumor necrosis factor-mediated signaling pathway, toll-like receptor 4 signaling pathway, non-canonical NF-kappaB signal transduction, positive regulation of canonical NF-kappaB signal transduction.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-09-01.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-09-01 |

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

## Similar variants {#similar}

Related CHUK variant pages (same residue, condition, or type): [CHUK p.Arg365Gln](/variant/chuk-p-arg365gln), [CHUK p.Arg424Cys](/variant/chuk-p-arg424cys), [CHUK p.Arg563Cys](/variant/chuk-p-arg563cys), [CHUK p.Arg563His](/variant/chuk-p-arg563his), [CHUK p.Gln226Pro](/variant/chuk-p-gln226pro), [CHUK p.Gly346Arg](/variant/chuk-p-gly346arg), [CHUK p.His520Arg](/variant/chuk-p-his520arg), [CHUK p.Lys512Arg](/variant/chuk-p-lys512arg).

### 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 2807759). 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.*