# NM_152750.5(CDHR3):c.1316del (p.Pro439fs)

https://sugi.bio/variant/cdhr3-p-pro439fs

## Summary

**CDHR3 p.Pro439fs (c.1316del)** is classified **Uncertain significance** in CDHR3 (ClinVar, Single submitter, 2 submitters). Rare (popmax 0.951%, eas).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs201638418 · 2 submitters · rare (popmax 0.951%, eas)

## For patients & families {#patients}

This is a change in the CDHR3 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 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 | [CDHR3](https://sugi.bio/atlas/gene/CDHR3/) |
| Protein change (HGVS p.) | p.Pro439fs |
| Coding change (HGVS c.) | c.1316del |
| MANE Select transcript | [NM_152750](https://www.ncbi.nlm.nih.gov/nuccore/NM_152750) |
| dbSNP | [rs201638418](https://www.ncbi.nlm.nih.gov/snp/rs201638418/) |
| Variant type | Deletion |
| Location | chr7:106015196-106015196 (GRCh38) |
| ClinVar | [VCV1294432](https://www.ncbi.nlm.nih.gov/clinvar/variation/1294432/) |

**All HGVS expressions:** `NC_000007.13:g.105655648del`, `NC_000007.14:g.106015202del`, `NM_001301161.2:c.1052del`, `NM_152750.5:c.1316del`

## 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 3.982, GERP 4.26, phastCons 0.959 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.087, pLI 2.6956e-20. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 10 of 19**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 23.1**. 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 **0.951%** (eas) · FAF95 0.876% · FAF99 0.847% · 426/44,806 in the highest group · 657/1,609,176 alleles overall — rare (popmax 0.951%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.951% | 105 |
| Finnish (not grpmax-eligible) | 0.182% | 550 |
| Remaining individuals (not grpmax-eligible) | 0.0321% | 3,118 |
| South Asian | 0.0134% | 7,464 |
| European (non-Finnish) | 0.00671% | 14,910 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00339% | 29,478 |
| African / African-American | 0.00267% | 37,410 |
| Admixed American | 0.00168% | 59,544 |

*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}

**CDHR3** population constraint: LOEUF 1.087, pLI 2.6956e-20, missense-Z 0.67832. *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 **439** lies in the cadherin 4 domain.

AlphaFold model confidence (whole protein): pLDDT 78.08, 38% of residues very-high.

**3 experimental structure(s)** (PDB): [6PPO](https://www.rcsb.org/structure/6PPO), [6PSF](https://www.rcsb.org/structure/6PSF), [7KNV](https://www.rcsb.org/structure/7KNV).

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2013); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Santos-Cortez Lab, University of Colorado School of Medicine | Uncertain significance | no assertion criteria provided | research | 2013-02-01 |
| Breakthrough Genomics, Breakthrough Genomics | Uncertain significance | criteria provided, single submitter | not provided |  |

**Reported phenotype names (ClinVar):** Susceptibility to nonsyndromic otitis media, not provided, none provided.

## Similar variants {#similar}

Related CDHR3 variant pages (same residue, condition, or type): [CDHR3 p.Pro439Thr](/variant/cdhr3-p-pro439thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 1294432). 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.*