# NM_001792.5(CDH2):c.1493C>T (p.Ala498Val)

https://sugi.bio/variant/cdh2-p-ala498val

## Summary

**CDH2 p.Ala498Val (c.1493C>T)** is classified **Uncertain significance** in CDH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-27). AlphaMissense: likely benign (0.0638); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the CDH2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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 | [CDH2](https://sugi.bio/atlas/gene/CDH2/) |
| Protein change (HGVS p.) | p.Ala498Val |
| Coding change (HGVS c.) | c.1493C>T |
| MANE Select transcript | [NM_001792](https://www.ncbi.nlm.nih.gov/nuccore/NM_001792) |
| Variant type | single nucleotide variant |
| Location | chr18:27990202-27990202 (GRCh38) |
| ClinVar | [VCV4608862](https://www.ncbi.nlm.nih.gov/clinvar/variation/4608862/) |

**All HGVS expressions:** `NC_000018.10:g.27990202G>A`, `NC_000018.9:g.25570166G>A`, `NG_011959.1:g.192280C>T`, `NG_011959.2:g.191928C>T`, `NM_001308176.2:c.1400C>T`, `NM_001792.5:c.1493C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0638)
- REVEL 0.059 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -3.352 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor gain** (Δ 0.20) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 4.989, GERP -0.381, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 19.77**. 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 0.78** across the covering region of the MANE Select transcript (27,982,987–28,009,806), spanning 26,819 bp. Chi-square p 4e-09. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.04**, donor loss **0.00**, acceptor gain **0.20**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.04**, donor loss **0.00**, acceptor gain **0.20**, donor gain **0.00**.
- Pangolin: Δ**0.24** (gain), gain 0.24 / 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 **8.47e-05%** (nfe) · 1/1,179,986 in the highest group · 1/1,461,832 alleles overall — very rare (popmax 8.47e-05%, 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}

**CDH2** population constraint: LOEUF 0.336, pLI 1, missense-Z 2.8683. *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):

- **agenesis of corpus callosum, cardiac, ocular, and genital syndrome** — Definitive (AD)
- **dilated cardiomyopathy** — Limited (AD)
- **arrhythmogenic right ventricular cardiomyopathy** — Limited (AD)

## Protein context {#protein}

Residue **498** lies in the cadherin 4 domain.

AlphaFold model confidence (whole protein): pLDDT 79.68, 51% of residues very-high.

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

*Describes the biological roles of CDH2 (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:** CDH2's established molecular role includes beta-catenin binding. p.Ala498Val falls in the cadherin 4 domain.


### Pathways affected {#pathways}

CDH2 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Adherens junctions interactions](https://reactome.org/content/detail/R-HSA-418990) | curated |
| [Post-translational protein phosphorylation](https://reactome.org/content/detail/R-HSA-8957275) | curated |
| [Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)](https://reactome.org/content/detail/R-HSA-381426) | curated |
| [Regulation of MITF-M-dependent genes involved in extracellular matrix, focal adhesion and epithelial-to-mesenchymal transition](https://reactome.org/content/detail/R-HSA-9926550) | curated |
| [Myogenesis](https://reactome.org/content/detail/R-HSA-525793) | electronic |

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

**Molecular function:** beta-catenin binding, alpha-catenin binding, gamma-catenin binding.

**Biological process:** cell-cell adhesion.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-10-27.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-10-27 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related CDH2 variant pages (same residue, condition, or type): [CDH2 p.Ala21Val](/variant/cdh2-p-ala21val), [CDH2 p.Ala294Gly](/variant/cdh2-p-ala294gly), [CDH2 p.Ala299Thr](/variant/cdh2-p-ala299thr), [CDH2 p.Ala415Ser](/variant/cdh2-p-ala415ser), [CDH2 p.Ala418Ser](/variant/cdh2-p-ala418ser), [CDH2 p.Ala418Thr](/variant/cdh2-p-ala418thr), [CDH2 p.Ala610Thr](/variant/cdh2-p-ala610thr), [CDH2 p.Ala825Val](/variant/cdh2-p-ala825val).

### 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 4608862). 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.*