# NM_006383.4(CIB2):c.483C>T (p.Asp161=)

https://sugi.bio/variant/cib2-p-asp161

## Summary

**CIB2 p.Asp161= (c.483C>T)** is classified **Likely benign** in CIB2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-01). Ultra-rare (popmax 0.0181%, nfe).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs199794998 · 3 submitters · ultra-rare (popmax 0.0181%, nfe)

## For patients & families {#patients}

This is a change in the CIB2 gene that is classified as likely benign — not considered disease-causing, submitted by 3 submitters.

*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 | [CIB2](https://sugi.bio/atlas/gene/CIB2/) |
| Protein change (HGVS p.) | p.Asp161= |
| Coding change (HGVS c.) | c.483C>T |
| MANE Select transcript | [NM_006383](https://www.ncbi.nlm.nih.gov/nuccore/NM_006383) |
| dbSNP | [rs199794998](https://www.ncbi.nlm.nih.gov/snp/rs199794998/) |
| Variant type | single nucleotide variant |
| Location | chr15:78105798-78105798 (GRCh38) |
| ClinVar | [VCV1130639](https://www.ncbi.nlm.nih.gov/clinvar/variation/1130639/) |

**All HGVS expressions:** `NC_000015.10:g.78105798G>A`, `NC_000015.9:g.78398140G>A`, `NG_033006.1:g.30738C>T`, `NM_001271888.2:c.354C>T`, `NM_001271889.2:c.336C>T`, `NM_001301224.2:c.498C>T`, `NM_006383.4:c.483C>T`, `NR_125435.2:n.691C>T`

## 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 -8.291, GERP -3.4 — fast-evolving / accelerated position
- CADD: **PHRED 1.74**. 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 (G>C, Δ0.73 donor 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 (gnomAD v4.1): grpmax **0.0181%** (nfe) · FAF95 0.016% · FAF99 0.0152% · 213/1,180,034 in the highest group · 251/1,614,204 alleles overall — ultra-rare (popmax 0.0181%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0676% | 1,480 |
| Remaining individuals (not grpmax-eligible) | 0.0224% | 4,465 |
| European (non-Finnish) (grpmax) | 0.0181% | 5,540 |
| South Asian | 0.0022% | 45,542 |
| Admixed American | 0.00167% | 60,026 |
| African / African-American | 0.00133% | 75,046 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**CIB2** population constraint: LOEUF 1.274, pLI 1.5892e-06, missense-Z 0.64344. *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):

- **Usher syndrome type 1** — Refuted (AR)
- **nonsyndromic genetic hearing loss** — Definitive (AR)

## Protein context {#protein}

Residue **161** lies in a binding site; a UniProt-annotated variant site (in dfnb48); a UniProt-annotated variant site (in dfnb48; uncertain significance); the ef-hand 3 domain; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 88.71, 68% of residues very-high.

**1 experimental structure(s)** (PDB): [8XOQ](https://www.rcsb.org/structure/8XOQ).

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

*Describes the biological roles of CIB2 (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:** CIB2's established molecular role includes magnesium ion binding. p.Asp161= falls in the ef-hand 3 domain.


### Pathways affected {#pathways}

CIB2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Sensory processing of sound by inner hair cells of the cochlea](https://reactome.org/content/detail/R-HSA-9662360) | electronic |
| [Sensory processing of sound by outer hair cells of the cochlea](https://reactome.org/content/detail/R-HSA-9662361) | electronic |

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

**Molecular function:** magnesium ion binding, calcium ion binding, protein homodimerization activity.

**Biological process:** positive regulation of cytosolic calcium ion concentration, cellular response to ATP.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-09-01.

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-03-17 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-09-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-26 |

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

## Similar variants {#similar}

Related CIB2 variant pages (same residue, condition, or type): [CIB2 p.Asp161Ala](/variant/cib2-p-asp161ala), [CIB2 p.Arg104Ter](/variant/cib2-p-arg104ter), [CIB2 p.Arg33Ter](/variant/cib2-p-arg33ter), [CIB2 p.Arg66Trp](/variant/cib2-p-arg66trp), [CIB2 c.198+3A>G](/variant/cib2-c-198-plus-3a-g), [CIB2 p.Ala108Thr](/variant/cib2-p-ala108thr), [CIB2 p.Ala76Val](/variant/cib2-p-ala76val), [CIB2 p.Arg134Gln](/variant/cib2-p-arg134gln).

### 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 1130639). 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.*