# NM_016366.3(CABP2):c.482del (p.Phe161fs)

https://sugi.bio/variant/cabp2-p-phe161fs

## Summary

**CABP2 p.Phe161fs (c.482del)** is classified **Likely pathogenic** in CABP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-20). Ultra-rare (popmax 0.016%, afr); Associated with autosomal recessive nonsyndromic hearing loss 93.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs368437370 · 1 submitter · 1 linked condition · ultra-rare (popmax 0.016%, afr)

## For patients & families {#patients}

This is a change in the CABP2 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to autosomal recessive nonsyndromic hearing loss 93.

*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/0022645/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CABP2](https://sugi.bio/atlas/gene/CABP2/) |
| Protein change (HGVS p.) | p.Phe161fs |
| Coding change (HGVS c.) | c.482del |
| MANE Select transcript | [NM_016366](https://www.ncbi.nlm.nih.gov/nuccore/NM_016366) |
| dbSNP | [rs368437370](https://www.ncbi.nlm.nih.gov/snp/rs368437370/) |
| Variant type | Deletion |
| Location | chr11:67520058-67520058 (GRCh38) |
| ClinVar | [VCV1324001](https://www.ncbi.nlm.nih.gov/clinvar/variation/1324001/) |

**All HGVS expressions:** `NC_000011.10:g.67520059del`, `NC_000011.9:g.67287530del`, `NG_032982.1:g.8371del`, `NM_001318496.2:c.500del`, `NM_016366.3:c.482del`

## 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 3.216, GERP -0.356, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.299, pLI 1.0077e-08. *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.
- CADD: **PHRED 34.0**. 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.*
- 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.
- Population frequency (gnomAD v4.1): grpmax **0.016%** (afr) · FAF95 0.00921% · FAF99 0.00722% · 12/74,922 in the highest group · 13/1,612,188 alleles overall — ultra-rare (popmax 0.016%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.016% | 6,243 |
| European (non-Finnish) | 8.48e-05% | 1,179,686 |

*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}

**CABP2** population constraint: LOEUF 1.299, pLI 1.0077e-08, missense-Z -0.18317; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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):

- **nonsyndromic genetic hearing loss** — Definitive (AR)

## Protein context {#protein}

Residue **161** lies in a UniProt-annotated variant site (in dfnb93); the ef-hand 3 domain.

AlphaFold model confidence (whole protein): pLDDT 68.93, 13% of residues very-high.

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

*Describes the biological roles of CABP2 (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.*


### Pathways affected {#pathways}

CABP2 participates in **1 Reactome pathway** (⚕ = disease pathway):

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

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-10-20.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Revvity Omics, Revvity | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-10-20 |

## Associated conditions {#conditions}

[autosomal recessive nonsyndromic hearing loss 93](https://sugi.bio/atlas/disease/autosomal-recessive-nonsyndromic-hearing-loss-93/).

**Reported phenotype names (ClinVar):** Autosomal recessive nonsyndromic hearing loss 93, Deafness, autosomal recessive 93.

## Similar variants {#similar}

Related CABP2 variant pages (same residue, condition, or type): [CABP2 c.637+1G>T](/variant/cabp2-c-637-plus-1g-t), [CABP2 p.Met1Ile](/variant/cabp2-p-met1ile), [CABP2 p.Pro43Ser](/variant/cabp2-p-pro43ser), [CABP2 p.Tyr48Ser](/variant/cabp2-p-tyr48ser), [CABP2 p.Arg63Gln](/variant/cabp2-p-arg63gln), [CABP2 p.Arg94Gln](/variant/cabp2-p-arg94gln), [CABP2 c.490-8C>A](/variant/cabp2-c-490-minus-8c-a), [CABP2 p.Ile197Thr](/variant/cabp2-p-ile197thr).

### 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 1324001). 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.*