# NM_002230.4(JUP):c.2176A>G (p.Ile726Val)

https://sugi.bio/variant/jup-p-ile726val

## Summary

**JUP p.Ile726Val (c.2176A>G)** is classified **Uncertain significance** in JUP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-13). AlphaMissense: likely benign (0.0582); Very rare (popmax 0.00133%, afr); Associated with arrhythmogenic right ventricular dysplasia 12.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00133%, afr)

## For patients & families {#patients}

This is a change in the JUP gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to arrhythmogenic right ventricular dysplasia 12.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | No data available |
| Diagnostic panels | JUP is a diagnostic-grade gene on 10 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024880/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [JUP](https://sugi.bio/atlas/gene/JUP/) |
| Protein change (HGVS p.) | p.Ile726Val |
| Coding change (HGVS c.) | c.2176A>G |
| MANE Select transcript | [NM_002230](https://www.ncbi.nlm.nih.gov/nuccore/NM_002230) |
| Variant type | single nucleotide variant |
| Location | chr17:41755806-41755806 (GRCh38) |
| ClinVar | [VCV4791897](https://www.ncbi.nlm.nih.gov/clinvar/variation/4791897/) |

**All HGVS expressions:** `LRG_401:g.35907A>G`, `LRG_401t1:c.2176A>G`, `LRG_401t2:c.2176A>G`, `NC_000017.10:g.39912058T>C`, `NC_000017.11:g.41755806T>C`, `NG_009090.2:g.35907A>G`, `NM_001352773.2:c.2176A>G`, `NM_001352774.2:c.2176A>G`, `NM_001352775.2:c.2176A>G`, `NM_001352776.2:c.2176A>G`, `NM_001352777.2:c.2176A>G`, `NM_002230.4:c.2176A>G`, `NM_021991.4:c.2176A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0582)
- REVEL 0.085 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.667 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 2.347, GERP 1.43, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 14.04**. 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 0.84** across the covering region of the MANE Select transcript (41,755,747–41,771,854), spanning 16,107 bp. Chi-square p 5.2e-07. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **0.00133%** (afr) · 1/74,994 in the highest group · 2/1,460,842 alleles overall — very rare (popmax 0.00133%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00133% | 74,994 |
| European (non-Finnish) | 8.48e-05% | 1,179,494 |

*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}

**JUP** population constraint: LOEUF 0.533, pLI 0.74487, missense-Z 2.0603. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 80.88, 64% of residues very-high.

**1 experimental structure(s)** (PDB): [3IFQ](https://www.rcsb.org/structure/3IFQ).

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

*Describes the biological roles of JUP (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:** JUP's established molecular role includes transcription coactivator activity.


### Pathways affected {#pathways}

JUP participates in **20 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Adherens junctions interactions](https://reactome.org/content/detail/R-HSA-418990) | curated |
| [CDC42 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013148) | curated |
| [Degradation of CDH1](https://reactome.org/content/detail/R-HSA-9766229) | curated |
| [Formation of the cornified envelope](https://reactome.org/content/detail/R-HSA-6809371) | curated |
| [Keratinization](https://reactome.org/content/detail/R-HSA-6805567) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [RHOA GTPase cycle](https://reactome.org/content/detail/R-HSA-8980692) | curated |
| [RHOB GTPase cycle](https://reactome.org/content/detail/R-HSA-9013026) | curated |
| [RHOC GTPase cycle](https://reactome.org/content/detail/R-HSA-9013106) | curated |
| [RHOH GTPase cycle](https://reactome.org/content/detail/R-HSA-9013407) | curated |
| [RHOJ GTPase cycle](https://reactome.org/content/detail/R-HSA-9013409) | curated |
| [RHOQ GTPase cycle](https://reactome.org/content/detail/R-HSA-9013406) | curated |
| [Regulation of CDH1 Function](https://reactome.org/content/detail/R-HSA-9764561) | curated |
| [Regulation of CDH1 posttranslational processing and trafficking to plasma membrane](https://reactome.org/content/detail/R-HSA-9768727) | curated |
| [VEGFR2 mediated vascular permeability](https://reactome.org/content/detail/R-HSA-5218920) | curated |
| [Activation of STAT3 by cadherin engagement](https://reactome.org/content/detail/R-HSA-9958825) | electronic |
| [CDH11 homotypic and heterotypic interactions](https://reactome.org/content/detail/R-HSA-9833576) | electronic |
| [Regulation of CDH11 function](https://reactome.org/content/detail/R-HSA-9762292) | electronic |
| [Regulation of CDH19 Expression and Function](https://reactome.org/content/detail/R-HSA-9764302) | electronic |
| [SRC activates STAT3 in a quantitative manner, through Cadherin-11 (CDH11), RAC1 and gp130 (IL6ST)](https://reactome.org/content/detail/R-HSA-9958810) | electronic |

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

**Molecular function:** transcription coactivator activity, protein phosphatase binding, alpha-catenin binding, cadherin binding, cell adhesion molecule binding, cytoskeletal protein-membrane anchor activity.

**Biological process:** positive regulation of cell-matrix adhesion, desmosome assembly, cell migration, regulation of cell population proliferation, positive regulation of protein import into nucleus, negative regulation of blood vessel endothelial cell migration.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-10-13.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-10-13 |

## Associated conditions {#conditions}

[arrhythmogenic right ventricular dysplasia 12](https://sugi.bio/atlas/disease/arrhythmogenic-right-ventricular-dysplasia-12/), [Naxos disease](https://sugi.bio/atlas/disease/naxos-disease/).

**Reported phenotype names (ClinVar):** Arrhythmogenic right ventricular dysplasia 12, Naxos disease, ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 12, CARDIOMYOPATHY, ARRHYTHMOGENIC RIGHT VENTRICULAR, WITH SKIN, HAIR, AND NAIL ABNORMALITIES, KERATOSIS PALMOPLANTARIS WITH ARRHYTHMOGENIC CARDIOMYOPATHY, MAL DE NAXOS, PALMOPLANTAR KERATODERMA WITH ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY AND WOOLLY HAIR, WOOLLY HAIR, PALMOPLANTAR KERATODERMA, AND CARDIAC ABNORMALITIES.

## Similar variants {#similar}

Related JUP variant pages (same residue, condition, or type): [JUP p.Ile726=](/variant/jup-p-ile726), [JUP c.1773+3G>A](/variant/jup-c-1773-plus-3g-a), [JUP c.468+4T>C](/variant/jup-c-468-plus-4t-c), [JUP c.707+5C>A](/variant/jup-c-707-plus-5c-a), [JUP c.*1026G>A](/variant/jup-c-star-1026g-a), [JUP c.*1136C>T](/variant/jup-c-star-1136c-t), [JUP c.*413C>T](/variant/jup-c-star-413c-t), [JUP c.*771G>C](/variant/jup-c-star-771g-c).

### 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 2026-07-14); 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 4791897). 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.*