# NM_004933.3(CDH15):c.1119C>T (p.Pro373=)

https://sugi.bio/variant/cdh15-p-pro373

## Summary

**CDH15 p.Pro373= (c.1119C>T)** is classified **Likely benign** in CDH15 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-08-30). Ultra-rare (popmax 0.0634%, amr).

**At a glance:** Likely benign · review: Single submitter · rsID rs570306656 · 1 submitter · ultra-rare (popmax 0.0634%, amr)

## For patients & families {#patients}

This is a change in the CDH15 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 | [CDH15](https://sugi.bio/atlas/gene/CDH15/) |
| Protein change (HGVS p.) | p.Pro373= |
| Coding change (HGVS c.) | c.1119C>T |
| MANE Select transcript | [NM_004933](https://www.ncbi.nlm.nih.gov/nuccore/NM_004933) |
| dbSNP | [rs570306656](https://www.ncbi.nlm.nih.gov/snp/rs570306656/) |
| Variant type | single nucleotide variant |
| Location | chr16:89190383-89190383 (GRCh38) |
| ClinVar | [VCV747497](https://www.ncbi.nlm.nih.gov/clinvar/variation/747497/) |

**All HGVS expressions:** `NC_000016.10:g.89190383C>T`, `NC_000016.9:g.89256791C>T`, `NG_012055.1:g.23629C>T`, `NM_004933.3:c.1119C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.32) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -6.209, GERP -2.75 — fast-evolving / accelerated position
- CADD: **PHRED 13.36**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.32**, donor gain **0.03**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.32**, donor gain **0.03**.
- Population frequency (gnomAD v4.1): grpmax **0.0634%** (amr) · FAF95 0.0474% · FAF99 0.0418% · 38/59,978 in the highest group · 58/1,612,852 alleles overall — ultra-rare (popmax 0.0634%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0634% | 1,578 |
| Remaining individuals (not grpmax-eligible) | 0.0192% | 5,206 |
| African / African-American | 0.00666% | 15,013 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,570 |
| South Asian | 0.0011% | 90,978 |
| European (non-Finnish) | 8.47e-05% | 1,179,967 |

*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}

**CDH15** population constraint: LOEUF 1.41, pLI 1.0184e-28, missense-Z -2.6625; ClinGen dosage — haploinsufficiency 0, 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):

- **EEM syndrome** — Definitive (AR)
- **intellectual disability** — Disputed (AD)

## Protein context {#protein}

Residue **373** lies in the cadherin 3 domain.

AlphaFold model confidence (whole protein): pLDDT 78.70, 50% of residues very-high.

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

*Describes the biological roles of CDH15 (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}

CDH15 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Adherens junctions interactions](https://reactome.org/content/detail/R-HSA-418990) | curated |
| [Myogenesis](https://reactome.org/content/detail/R-HSA-525793) | electronic |

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-08-30.

**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 | 2018-08-30 |

**Reported phenotype names (ClinVar):** not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Similar variants {#similar}

Related CDH15 variant pages (same residue, condition, or type): [CDH3 p.Asp373Asn](/variant/cdh3-p-asp373asn), [CDH3 p.Asp373Tyr](/variant/cdh3-p-asp373tyr), [CDH3 c.1796-2A>G](/variant/cdh3-c-1796-minus-2a-g), [CDH3 c.691+1G>A](/variant/cdh3-c-691-plus-1g-a), [CDH3 p.Arg103Ter](/variant/cdh3-p-arg103ter), [CDH3 p.Arg221Ter](/variant/cdh3-p-arg221ter), [CDH3 p.Arg503His](/variant/cdh3-p-arg503his), [CDH3 p.Gln299Ter](/variant/cdh3-p-gln299ter).

### 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 747497). 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.*