# NM_001257.5(CDH13):c.1749G>T (p.Pro583=)

https://sugi.bio/variant/cdh13-p-pro583

## Summary

**CDH13 p.Pro583= (c.1749G>T)** is classified **Likely benign** in CDH13 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-07-03). Very rare (popmax 0.000509%, nfe); Associated with CDH13-related disorder.

**At a glance:** Likely benign · review: No assertion criteria · rsID rs541617175 · 1 submitter · 1 linked condition · very rare (popmax 0.000509%, nfe)

## For patients & families {#patients}

This is a change in the CDH13 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to CDH13-related disorder.

*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 | [CDH13](https://sugi.bio/atlas/gene/CDH13/) |
| Protein change (HGVS p.) | p.Pro583= |
| Coding change (HGVS c.) | c.1749G>T |
| MANE Select transcript | [NM_001257](https://www.ncbi.nlm.nih.gov/nuccore/NM_001257) |
| dbSNP | [rs541617175](https://www.ncbi.nlm.nih.gov/snp/rs541617175/) |
| Variant type | single nucleotide variant |
| Location | chr16:83780035-83780035 (GRCh38) |
| ClinVar | [VCV3043561](https://www.ncbi.nlm.nih.gov/clinvar/variation/3043561/) |

**All HGVS expressions:** `NC_000016.10:g.83780035G>T`, `NC_000016.9:g.83813640G>T`, `NG_052819.1:g.1158242G>T`, `NG_052819.2:g.1158068G>T`, `NM_001220488.2:c.1890G>T`, `NM_001220489.2:c.1632G>T`, `NM_001220490.2:c.987G>T`, `NM_001257.5:c.1749G>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 0.30) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -0.24, GERP -5.45, phastCons 0.001 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 14.84**. 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 **0.30**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.30**, donor gain **0.00**.
- Pangolin: Δ**0.20** (gain), gain 0.20 / loss 0.00. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.000509%** (nfe) · FAF95 0.000183% · FAF99 0.00012% · 6/1,179,880 in the highest group · 6/1,613,806 alleles overall — very rare (popmax 0.000509%, nfe).

*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}

**CDH13** population constraint: LOEUF 0.456, pLI 0.99807, missense-Z -0.93707. *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 **583** lies in the cadherin 4 domain.

AlphaFold model confidence (whole protein): pLDDT 85.19, 61% of residues very-high.

**1 experimental structure(s)** (PDB): [2V37](https://www.rcsb.org/structure/2V37).

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

*Describes the biological roles of CDH13 (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:** CDH13's established molecular role includes low-density lipoprotein particle binding. p.Pro583= falls in the cadherin 4 domain.


### Pathways affected {#pathways}

CDH13 participates in **1 Reactome pathway** (⚕ = disease pathway):

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

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

**Molecular function:** low-density lipoprotein particle binding, cadherin binding, lipoprotein particle binding.

**Biological process:** positive regulation of endothelial cell proliferation, positive regulation of cell-matrix adhesion, sprouting angiogenesis, homophilic cell-cell adhesion, negative regulation of cell adhesion, Rho protein signal transduction.

## Clinical significance {#significance}

**Likely benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2019-07-03.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-07-03 |

## Associated conditions {#conditions}

[CDH13-related disorder](https://sugi.bio/atlas/disease/cdh13-related-disorder/).

**Reported phenotype names (ClinVar):** CDH13-related disorder, CDH13-related condition.

## Similar variants {#similar}

Related CDH13 variant pages (same residue, condition, or type): [CDH13 p.Ile585Val](/variant/cdh13-p-ile585val), [CDH13 p.Lys293Gln](/variant/cdh13-p-lys293gln), [CDH13 c.45+12327A>G](/variant/cdh13-c-45-plus-12327a-g), [CDH13 c.45+8A>G](/variant/cdh13-c-45-plus-8a-g), [CDH13 c.781+4T>A](/variant/cdh13-c-781-plus-4t-a), [CDH13 p.Asn420=](/variant/cdh13-p-asn420), [CDH13 p.Asp577=](/variant/cdh13-p-asp577), [CDH13 p.Gly261=](/variant/cdh13-p-gly261).

### 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 3043561). 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.*