JPH3

Chr 16AD

junctophilin 3

Also known as: CAGL237, HDL2, JP-3, JP3, TNRC22

NCBI Gene: 57338ENSG00000154118UniProt: Q8WXH2

The protein forms junctional membrane complexes that link the plasma membrane with the endoplasmic reticulum in brain neurons, providing structural foundation for cross-talk between cell surface and intracellular calcium release channels. CAG/CTG repeat expansions (40-59 repeats) in the 3' UTR cause Huntington disease-like 2 through a loss-of-function mechanism, inherited in an autosomal dominant pattern. The protein is brain-specific and functions in neurons involved in motor coordination and memory.

Summary from RefSeq, OMIM, UniProt, Mechanism
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Primary Disease Associations & Inheritance

Huntington disease-like 2MIM #606438
AD
0
Active trials
8
Pubs (1 yr)
5
P/LP submissions
0%
P/LP missense
0.20
LOEUF· LoF intol.
Multiple*
Mechanism· predicted
Clinical Summary— JPH3
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
5 unique Pathogenic / Likely Pathogenic· 76 VUS of 100 total submissions
Explore recent and relevant literature in Research Assistant →
📖
GeneReview available — JPH3
Authoritative clinical overview · Recommended first read
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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
0.20LOEUF
pLI 0.999
Z-score 4.29
OE 0.04 (0.01–0.20)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint
-0.32Z-score
OE missense 1.04 (0.97–1.12)
511 obs / 491.1 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.04 (0.01–0.20)
0≤0.351.4
Missense OE1.04 (0.97–1.12)
0≤0.61.4
Synonymous OE1.43
0≤1.21.6
LoF obs/exp: 1 / 23.4Missense obs/exp: 511 / 491.1Syn Z: -5.09
DN
0.4289th %ile
GOF
0.5072th %ile
LOF
0.76top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · LOEUF 0.20
GOF1 literature citation

Literature Evidence

GOFOur results suggest that the pathogenic mechanism of HDL2 is multifactorial, involving both a toxic gain of function of JPH3 RNA and a toxic loss of JPH3 expression.PMID:22367996

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

100 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5
VUS76
Likely Benign15
Benign3
Conflicting1
5
Pathogenic
76
VUS
15
Likely Benign
3
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
5
0
5
Likely Pathogenic
0
0
0
0
0
VUS
1
68
7
0
76
Likely Benign
0
4
1
10
15
Benign
0
0
0
3
3
Conflicting
—1
Total1721313100

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

JPH3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Huntington disease-like 2: insight into neurodegeneration from an African disease.
Krause A et al.·Nat Rev Neurol
2024Review
Junctophilin 3 (JPH3) expansion mutations causing Huntington disease like 2 (HDL2) are common in South African patients with African ancestry and a Huntington disease phenotype.
Krause A et al.·Am J Med Genet B Neuropsychiatr Genet
2015Cohort
Common and Founder Mutations for Monogenic Traits in Sub-Saharan African Populations.
Krause A et al.·Annu Rev Genomics Hum Genet
2018Review
Clinical and Molecular Findings of Intermediate Allele Carriers in the HTT Gene from the Mexican Mestizo Population.
Ramírez-García MÁ et al.·Neurodegener Dis
2022
Investigations of Huntington's Disease and Huntington's Disease-Like Syndromes in Indian Choreatic Patients.
Kaur J et al.·J Huntingtons Dis
2020Cohort
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients