# NM_006384.4(CIB1):c.461del (p.Asp154fs)

https://sugi.bio/variant/cib1-p-asp154fs

## Summary

**CIB1 p.Asp154fs (c.461del)** is classified **Likely pathogenic** in CIB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-22). Associated with Susceptibility to severe COVID-19.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the CIB1 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to Susceptibility to severe COVID-19.

*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 | [CIB1](https://sugi.bio/atlas/gene/CIB1/) |
| Protein change (HGVS p.) | p.Asp154fs |
| Coding change (HGVS c.) | c.461del |
| MANE Select transcript | [NM_006384](https://www.ncbi.nlm.nih.gov/nuccore/NM_006384) |
| Variant type | Deletion |
| Location | chr15:90231099-90231099 (GRCh38) |
| ClinVar | [VCV3256944](https://www.ncbi.nlm.nih.gov/clinvar/variation/3256944/) |

**All HGVS expressions:** `NC_000015.10:g.90231099del`, `NC_000015.9:g.90774331del`, `NM_001277764.2:c.581del`, `NM_006384.4:c.461del`, `NM_006384.4:c.461delA`, `NR_102427.1:n.647del`, `NR_102428.1:n.513del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 3.614, GERP 0.296, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.233, pLI 2.3786e-06. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 5 of 7**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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}

**CIB1** population constraint: LOEUF 1.233, pLI 2.3786e-06, missense-Z 0.07808. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **154** lies in a UniProt-annotated variant site (in ev3; absence of cib1 protein in homozygous patient cells); the ef-hand 2 domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 76.37, 0% of residues very-high.

**9 experimental structure(s)** (PDB): [1DGU](https://www.rcsb.org/structure/1DGU), [1DGV](https://www.rcsb.org/structure/1DGV), [1XO5](https://www.rcsb.org/structure/1XO5), [1Y1A](https://www.rcsb.org/structure/1Y1A), [2L4H](https://www.rcsb.org/structure/2L4H), [2L4I](https://www.rcsb.org/structure/2L4I).

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

*Describes the biological roles of CIB1 (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:** CIB1's established molecular role includes calcium ion binding. p.Asp154fs falls in the ef-hand 2 domain.


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

**Molecular function:** calcium ion binding, calcium-dependent protein kinase inhibitor activity, protein serine/threonine kinase inhibitor activity, small GTPase binding, protein-membrane adaptor activity.

**Biological process:** apoptotic process, DNA damage response, negative regulation of microtubule depolymerization, endomitotic cell cycle, negative regulation of cell population proliferation, negative regulation of neuron projection development.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-07-22.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Molecular Medicine Center, Medical University of Sofia | Likely pathogenic | criteria provided, single submitter | research | 2024-07-22 |

## Associated conditions {#conditions}

[Susceptibility to severe COVID-19](https://sugi.bio/atlas/disease/susceptibility-to-severe-covid-19/).

**Reported phenotype names (ClinVar):** Susceptibility to severe COVID-19.

## Similar variants {#similar}

Related CIB1 variant pages (same residue, condition, or type): [CIB1 p.Asp154His](/variant/cib1-p-asp154his), [CIB1 c.465+1del](/variant/cib1-c-465-plus-1del), [CIB1 p.Asp154Tyr](/variant/cib1-p-asp154tyr), [GDPGP1 p.Leu154Met](/variant/gdpgp1-p-leu154met), [CIB1 c.87-37T>G](/variant/cib1-c-87-minus-37t-g), [CIB1 c.87-36C>T](/variant/cib1-c-87-minus-36c-t), [CIB1 c.87-29_87-20del](/variant/cib1-c-87-minus-29-87-minus-20del), [CIB1 p.Asp116_Phe117insTer](/variant/cib1-p-asp116-phe117inster).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 3256944). 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.*