# NM_002230.4(JUP):c.297G>A (p.Ser99=)

https://sugi.bio/variant/jup-p-ser99

## Summary

**JUP p.Ser99= (c.297G>A)** is classified **Conflicting classifications of pathogenicity** in JUP (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-01-20). Rare (popmax 0.165%, mid); Associated with Cardiovascular phenotype.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs200976464 · 10 submitters · 3 linked conditions · rare (popmax 0.165%, mid)

## For patients & families {#patients}

This is a change in the JUP gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 10 submitters, and is linked to Cardiovascular phenotype.

*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 | [JUP](https://sugi.bio/atlas/gene/JUP/) |
| Protein change (HGVS p.) | p.Ser99= |
| Coding change (HGVS c.) | c.297G>A |
| MANE Select transcript | [NM_002230](https://www.ncbi.nlm.nih.gov/nuccore/NM_002230) |
| dbSNP | [rs200976464](https://www.ncbi.nlm.nih.gov/snp/rs200976464/) |
| Variant type | single nucleotide variant |
| Location | chr17:41769589-41769589 (GRCh38) |
| ClinVar | [VCV45848](https://www.ncbi.nlm.nih.gov/clinvar/variation/45848/) |

**All HGVS expressions:** `LRG_401:g.22124G>A`, `LRG_401t1:c.297G>A`, `LRG_401t2:c.297G>A`, `NC_000017.10:g.39925841C>T`, `NC_000017.11:g.41769589C>T`, `NG_009090.2:g.22124G>A`, `NM_001352773.2:c.297G>A`, `NM_001352774.2:c.297G>A`, `NM_001352775.2:c.297G>A`, `NM_001352776.2:c.297G>A`, `NM_001352777.2:c.297G>A`, `NM_002230.3:c.297G>A`, `NM_002230.4:c.297G>A`, `NM_021991.4:c.297G>A`

## 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 0.24) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -13.462, GERP -4.67 — fast-evolving / accelerated position
- CADD: **PHRED 2.155**. 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 **0.24**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.24**, donor gain **0.00**.
- Pangolin: Δ**0.26** (gain), gain 0.26 / 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 **0.165%** (mid) · FAF95 0.0971% · FAF99 0.0904% · 10/6,044 in the highest group · 885/1,605,758 alleles overall — rare (popmax 0.165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.212% | 472 |
| Middle Eastern (grpmax) | 0.165% | 604 |
| Admixed American | 0.118% | 845 |
| South Asian | 0.115% | 868 |
| Remaining individuals (not grpmax-eligible) | 0.0547% | 1,830 |
| European (non-Finnish) | 0.0509% | 1,965 |
| African / African-American | 0.00667% | 15,002 |
| East Asian | 0.00449% | 22,272 |
| Finnish (not grpmax-eligible) | 0.00159% | 62,998 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

Residue **99** lies in a modified residue (phosphoserine).

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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-20.

**Submitter consensus:** conflicting (5 Likely benign, 3 Benign, 2 Uncertain significance, 1 Likely Benign).

**Submission history:** 11 submissions (2015–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Likely benign | criteria provided, single submitter | clinical testing | 2015-12-04 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2021-10-09 |
| Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Likely benign | criteria provided, single submitter | clinical testing | 2025-04-09 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-20 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2020-11-01 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2015-03-03 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2016-10-25 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Likely Benign | criteria provided, single submitter | clinical testing | 2025-04-08 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-27 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, not specified, Arrhythmogenic right ventricular dysplasia 12, Naxos disease, not provided, 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, CARDIOMYOPATHY, ARRHYTHMOGENIC RIGHT VENTRICULAR, WITH SKIN, HAIR, AND NAIL ABNORMALITIES.

## Similar variants {#similar}

Related JUP variant pages (same residue, condition, or type): [JUP p.Ser99Leu](/variant/jup-p-ser99leu), [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.-1G>A](/variant/jup-c-minus-1g-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).

### 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 2026-10-14); 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 45848). 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.*