# NM_001793.6(CDH3):c.1508G>A (p.Arg503His)

https://sugi.bio/variant/cdh3-p-arg503his

## Summary

**CDH3 p.Arg503His (c.1508G>A)** is classified **Pathogenic/Likely pathogenic** in CDH3 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-13). AlphaMissense: likely benign (0.2673); Very rare (popmax 0.00333%, amr); Associated with CDH3-related disorder.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs121434542 · 5 submitters · 4 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00333%, amr)

## For patients & families {#patients}

This is a change in the CDH3 gene that is considered likely disease-causing, submitted by 5 submitters, and is linked to CDH3-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 | [CDH3](https://sugi.bio/atlas/gene/CDH3/) |
| Protein change (HGVS p.) | p.Arg503His |
| Coding change (HGVS c.) | c.1508G>A |
| MANE Select transcript | [NM_001793](https://www.ncbi.nlm.nih.gov/nuccore/NM_001793) |
| dbSNP | [rs121434542](https://www.ncbi.nlm.nih.gov/snp/rs121434542/) |
| Variant type | single nucleotide variant |
| Location | chr16:68685288-68685288 (GRCh38) |
| ClinVar | [VCV17639](https://www.ncbi.nlm.nih.gov/clinvar/variation/17639/) |

**All HGVS expressions:** `NC_000016.10:g.68685288G>A`, `NC_000016.9:g.68719191G>A`, `NG_009096.1:g.46041G>A`, `NM_001317195.3:c.1508G>A`, `NM_001317196.2:c.1343G>A`, `NM_001793.6:c.1508G>A`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — AlphaMissense predicts likely-benign.

- AlphaMissense **likely benign** (0.2673) — ⚠ discordant with the pathogenic call
- REVEL 0.624 (indeterminate)
- SaProt LLR -11.113 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL makes no call
- Conservation: phyloP 11.756, GERP 2.07, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 29.2**. 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** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00333%** (amr) · FAF95 0.000553% · FAF99 0.000207% · 2/59,994 in the highest group · 9/1,613,988 alleles overall — very rare (popmax 0.00333%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00333% | 29,997 |
| European (non-Finnish) | 0.000593% | 168,572 |

*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}

**CDH3** population constraint: LOEUF 0.823, pLI 5.7123e-12, missense-Z 0.71843. *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)

## Protein context {#protein}

Residue **503** lies in a UniProt-annotated variant site (in hjmd); the cadherin 4 domain.

AlphaFold model confidence (whole protein): pLDDT 76.71, 46% of residues very-high.

**19 experimental structure(s)** (PDB): [4OY9](https://www.rcsb.org/structure/4OY9), [4ZML](https://www.rcsb.org/structure/4ZML), [4ZMN](https://www.rcsb.org/structure/4ZMN), [4ZMO](https://www.rcsb.org/structure/4ZMO), [4ZMP](https://www.rcsb.org/structure/4ZMP), [4ZMQ](https://www.rcsb.org/structure/4ZMQ).

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

*Describes the biological roles of CDH3 (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}

CDH3 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Adherens junctions interactions](https://reactome.org/content/detail/R-HSA-418990) | curated |
| [Developmental Lineage of Mammary Gland Myoepithelial Cells](https://reactome.org/content/detail/R-HSA-9927432) | curated |

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

**Biological process:** retina homeostasis, positive regulation of keratinocyte proliferation, hair cycle process, negative regulation of transforming growth factor beta receptor signaling pathway, keratinization, positive regulation of insulin-like growth factor receptor signaling pathway.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-13.

**Submitter consensus:** conflicting (4 Pathogenic, 1 Likely pathogenic).

**Submission history:** 5 submissions (2002–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Pathogenic | criteria provided, single submitter | clinical testing | 2017-01-01 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2002-11-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-10-23 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2022-05-13 |
| Genetics Laboratory, Great Ormond Street Hospital NHS Foundation Trust, North Thames Genomic Laboratory Hub | Likely pathogenic | criteria provided, single submitter | clinical testing | 2026-02-13 |

## Associated conditions {#conditions}

[CDH3-related disorder](https://sugi.bio/atlas/disease/cdh3-related-disorder/), [retinal disorder](https://sugi.bio/atlas/disease/retinal-disorder/), [congenital hypotrichosis with juvenile macular dystrophy](https://sugi.bio/atlas/disease/congenital-hypotrichosis-with-juvenile-macular-dystrophy/), [inherited retinal dystrophy](https://sugi.bio/atlas/disease/inherited-retinal-dystrophy/).

**Reported phenotype names (ClinVar):** CDH3-related disorder, Congenital hypotrichosis with juvenile macular dystrophy, not provided, Retinal dystrophy, Retinal disorder, CDH3-related condition, Inherited retinal dystrophy, none provided, HYPOTRICHOSIS WITH CONE-ROD DYSTROPHY, Retinal disorders.

## Similar variants {#similar}

Related CDH3 variant pages (same residue, condition, or type): [CDH3 p.Arg503Cys](/variant/cdh3-p-arg503cys), [CDH3 c.1796-2A>G](/variant/cdh3-c-1796-minus-2a-g), [CDH3 p.Arg103Ter](/variant/cdh3-p-arg103ter), [CDH3 p.Arg221Ter](/variant/cdh3-p-arg221ter), [CDH3 p.Glu708Ter](/variant/cdh3-p-glu708ter), [CDH3 p.Trp362Ter](/variant/cdh3-p-trp362ter), [CDH3 p.Val205Met](/variant/cdh3-p-val205met), [CDH3 p.Ala150Thr](/variant/cdh3-p-ala150thr).

### 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 17639). 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.*