# NM_006383.4(CIB2):c.272T>C (p.Phe91Ser)

https://sugi.bio/variant/cib2-p-phe91ser

## Summary

**CIB2 p.Phe91Ser (c.272T>C)** is classified **Likely pathogenic** in CIB2 (ClinVar, Single submitter, 3 submitters; last evaluated 2022-01-12). AlphaMissense: likely pathogenic (0.9981); Ultra-rare (popmax 0.022%, sas); Associated with autosomal recessive nonsyndromic hearing loss 48.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs397515411 · 3 submitters · 2 linked conditions · AlphaMissense likely pathogenic · ultra-rare (popmax 0.022%, sas)

## For patients & families {#patients}

This is a change in the CIB2 gene that is considered likely disease-causing, submitted by 3 submitters, and is linked to autosomal recessive nonsyndromic hearing loss 48.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0022612/index) · [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.Phe91Ser |
| Coding change (HGVS c.) | c.272T>C |
| MANE Select transcript | [NM_006383](https://www.ncbi.nlm.nih.gov/nuccore/NM_006383) |
| dbSNP | [rs397515411](https://www.ncbi.nlm.nih.gov/snp/rs397515411/) |
| Variant type | single nucleotide variant |
| Location | chr15:78109309-78109309 (GRCh38) |
| ClinVar | [VCV39685](https://www.ncbi.nlm.nih.gov/clinvar/variation/39685/) |

**All HGVS expressions:** `NC_000015.10:g.78109309A>G`, `NC_000015.9:g.78401651A>G`, `NG_033006.1:g.27227T>C`, `NM_001271888.2:c.143T>C`, `NM_001271889.2:c.125T>C`, `NM_001301224.2:c.287T>C`, `NM_006383.4:c.272T>C`, `NR_125435.2:n.480T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9981) — concordant with the pathogenic call
- REVEL 0.73 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.266 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 10.895, GERP 1.39, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 3%** most-pathogenic-predicted substitutions in CIB2 (of 1,123 modeled).
- CADD: **PHRED 32.0**. 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 0.91** across the covering region of the MANE Select transcript (78,105,314–78,131,215), spanning 25,901 bp. Chi-square p 0.17. 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 **0.022%** (sas) · FAF95 0.0145% · FAF99 0.0121% · 20/91,036 in the highest group · 20/1,613,528 alleles overall — ultra-rare (popmax 0.022%, sas).

*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 **91** lies in the ef-hand 1 domain; a UniProt-annotated variant site (in dfnb48); a UniProt-annotated variant site (in dfnb48; decreases interaction with tmc1 and tmc2; no loss of localization to stereocilia; does not affect atp-induced calcium release); an α-helix.

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.Phe91Ser falls in the ef-hand 1 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 pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-01-12.

**Submitter consensus:** conflicting (2 Likely pathogenic, 1 Pathogenic).

**Submission history:** 3 submissions (2012–2022); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2012-11-01 |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-01-12 |
| University of Washington Center for Mendelian Genomics, University of Washington | Likely pathogenic | no assertion criteria provided | research |  |

## Associated conditions {#conditions}

[autosomal recessive nonsyndromic hearing loss 48](https://sugi.bio/atlas/disease/autosomal-recessive-nonsyndromic-hearing-loss-48/), [hearing loss, autosomal recessive](https://sugi.bio/atlas/disease/hearing-loss-autosomal-recessive/).

**Reported phenotype names (ClinVar):** Autosomal recessive nonsyndromic hearing loss 48, Hearing loss, autosomal recessive, Usher Syndrome Type 1J, Deafness, autosomal recessive 48, Deafness, autosomal recessive, Autosomal recessive nonsyndromic deafness, Rare autosomal recessive non-syndromic sensorineural deafness type DFNB, Nonsyndromic Hearing Loss, Recessive.

## Similar variants {#similar}

Related CIB2 variant pages (same residue, condition, or type): [CIB2 p.Phe91=](/variant/cib2-p-phe91), [CIB2 p.Arg66Trp](/variant/cib2-p-arg66trp), [CIB2 p.Arg66Gln](/variant/cib2-p-arg66gln), [CIB2 p.Asn118Asp](/variant/cib2-p-asn118asp), [CIB2 p.Val75Met](/variant/cib2-p-val75met), [CIB2 c.199-1G>A](/variant/cib2-c-199-minus-1g-a), [CIB2 p.Gln12Ter](/variant/cib2-p-gln12ter), [CIB2 p.Arg104Gln](/variant/cib2-p-arg104gln).

### 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 39685). 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.*