# NM_006384.4(CIB1):c.564G>A (p.Lys188=)

https://sugi.bio/variant/cib1-p-lys188

## Summary

**CIB1 p.Lys188= (c.564G>A)** is classified **Likely benign** in CIB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-13). Absent from gnomAD v4.1.

**At a glance:** Likely benign · review: Single submitter · 1 submitter · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CIB1 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 | [CIB1](https://sugi.bio/atlas/gene/CIB1/) |
| Protein change (HGVS p.) | p.Lys188= |
| Coding change (HGVS c.) | c.564G>A |
| MANE Select transcript | [NM_006384](https://www.ncbi.nlm.nih.gov/nuccore/NM_006384) |
| Variant type | single nucleotide variant |
| Location | chr15:90230496-90230496 (GRCh38) |
| ClinVar | [VCV4797923](https://www.ncbi.nlm.nih.gov/clinvar/variation/4797923/) |

**All HGVS expressions:** `NC_000015.10:g.90230496C>T`, `NC_000015.9:g.90773728C>T`, `NM_001277764.2:c.684G>A`, `NM_006384.4:c.564G>A`, `NR_102427.1:n.750G>A`, `NR_102428.1:n.616G>A`

## 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 1.756, GERP 0.477, phastCons 1 — weakly conserved position
- CADD: **PHRED 13.56**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.29 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **188** lies in a UniProt-annotated variant site (in ev3; absence of cib1 protein in homozygous patient cells); 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.


### 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 benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-07-13.

**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 | 2025-07-13 |

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

## Similar variants {#similar}

Related CIB1 variant pages (same residue, condition, or type): [CIB1 p.Ala184Pro](/variant/cib1-p-ala184pro), [CIB1 p.Ala66Thr](/variant/cib1-p-ala66thr), [CIB1 p.Arg113His](/variant/cib1-p-arg113his), [CIB1 p.Arg143Gln](/variant/cib1-p-arg143gln), [CIB1 p.Arg143Trp](/variant/cib1-p-arg143trp), [CIB1 p.Arg72Gln](/variant/cib1-p-arg72gln), [CIB1 p.Asn155Asp](/variant/cib1-p-asn155asp), [CIB1 p.Asn169Ser](/variant/cib1-p-asn169ser).

### 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 4797923). 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.*