# NM_020433.5(JPH2):c.1728C>G (p.Pro576=)

https://sugi.bio/variant/jph2-p-pro576

## Summary

**JPH2 p.Pro576= (c.1728C>G)** is classified **Benign** in JPH2 (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-02-04). Common (popmax 25.6%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Cardiovascular phenotype.

**At a glance:** Benign · review: Multiple submitters · rsID rs74352869 · 13 submitters · 3 linked conditions · common (popmax 25.6%, afr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the JPH2 gene that is classified as benign — not considered disease-causing, submitted by 13 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 | [JPH2](https://sugi.bio/atlas/gene/JPH2/) |
| Protein change (HGVS p.) | p.Pro576= |
| Coding change (HGVS c.) | c.1728C>G |
| MANE Select transcript | [NM_020433](https://www.ncbi.nlm.nih.gov/nuccore/NM_020433) |
| dbSNP | [rs74352869](https://www.ncbi.nlm.nih.gov/snp/rs74352869/) |
| Variant type | single nucleotide variant |
| Location | chr20:44115947-44115947 (GRCh38) |
| ClinVar | [VCV137609](https://www.ncbi.nlm.nih.gov/clinvar/variation/137609/) |

**All HGVS expressions:** `LRG_394:g.76632C>G`, `LRG_394t1:c.1728C>G`, `NC_000020.10:g.42744587G>C`, `NC_000020.11:g.44115947G>C`, `NG_031867.1:g.76632C>G`, `NM_020433.5:c.1728C>G`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 25.6%, afr) — too common for a highly-penetrant pathogenic allele.

- **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 (below), not from a missing predictor score.
- Conservation: phyloP 0.007, GERP -3.42 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 0.959**. 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 **25.6%** (afr) · FAF95 25.3% · FAF99 25.1% · 18,993/74,256 in the highest group · 337,904/1,567,210 alleles overall — common (popmax 25.6%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Amish (not grpmax-eligible) | 32.4% | 3 |
| African / African-American (grpmax) | 25.6% | 4 |
| European (non-Finnish) | 23.4% | 4 |
| Ashkenazi Jewish (not grpmax-eligible) | 23.4% | 4 |
| Finnish (not grpmax-eligible) | 22% | 5 |
| Remaining individuals (not grpmax-eligible) | 20.5% | 5 |
| Middle Eastern | 15.8% | 6 |
| Admixed American | 12.2% | 8 |
| South Asian | 8.39% | 12 |
| East Asian | 5.01% | 20 |

Amish 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}

**JPH2** population constraint: LOEUF 1.051, pLI 4.6954e-11, missense-Z -0.84463. *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):

- **hypertrophic cardiomyopathy** — Moderate (AD)
- **cardiomyopathy, dilated, 2E** — Strong (AR)
- **dilated cardiomyopathy** — Limited (AD)

## Protein context {#protein}

Residue **576** lies in the 'disordered' region; a UniProt-annotated variant site (in cmd2e; uncertain significance).

AlphaFold model confidence (whole protein): pLDDT 65.09, 37% of residues very-high.

**2 experimental structure(s)** (PDB): [7RXE](https://www.rcsb.org/structure/7RXE), [7RXQ](https://www.rcsb.org/structure/7RXQ).

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

*Describes the biological roles of JPH2 (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:** JPH2's established molecular role includes phosphatidylserine binding. p.Pro576= falls in the disordered region.


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

**Molecular function:** phosphatidylserine binding, phosphatidylinositol-4,5-bisphosphate binding, phosphatidylinositol-3,4,5-trisphosphate binding, phosphatidylinositol-5-phosphate binding, phosphatidylinositol-3-phosphate binding, phosphatidylinositol-4-phosphate binding.

**Biological process:** calcium ion homeostasis.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** unanimous (13/13 Benign).

**Submission history:** 13 submissions (2013–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-11-28 |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Benign | criteria provided, single submitter | clinical testing | 2017-07-28 |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Benign | no assertion criteria provided | clinical testing |  |
| Ambry Genetics | Benign | criteria provided, single submitter | clinical testing | 2015-06-18 |
| Eurofins Ntd Llc (ga) | Benign | criteria provided, single submitter | clinical testing | 2015-01-19 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2022-04-26 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2013-11-18 |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Benign | criteria provided, single submitter | clinical testing | 2015-09-21 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Benign | criteria provided, single submitter | clinical testing | 2014-11-24 |
| Clinical Genetics, Academic Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Benign | criteria provided, single submitter | clinical testing | 2025-04-09 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/), [hypertrophic cardiomyopathy](https://sugi.bio/atlas/disease/hypertrophic-cardiomyopathy/), [hypertrophic cardiomyopathy 17](https://sugi.bio/atlas/disease/hypertrophic-cardiomyopathy-17/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, not specified, Hypertrophic cardiomyopathy, Hypertrophic cardiomyopathy 17, not provided, AllHighlyPenetrant, none provided, HYPERTROPHIC MYOCARDIOPATHY.

## Similar variants {#similar}

Related JPH2 variant pages (same residue, condition, or type): [JPH2 p.Pro576Leu](/variant/jph2-p-pro576leu), [JPH2 p.Pro576Ser](/variant/jph2-p-pro576ser), [JPH2 p.Thr161Lys](/variant/jph2-p-thr161lys), [JPH2 c.-4T>A](/variant/jph2-c-minus-4t-a), [JPH2 c.*15A>T](/variant/jph2-c-star-15a-t), [JPH2 p.Ala181Thr](/variant/jph2-p-ala181thr), [JPH2 p.Ala194Ser](/variant/jph2-p-ala194ser), [JPH2 p.Ala214Glu](/variant/jph2-p-ala214glu).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 137609). 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.*