rs587782951 — JPH2 Thr161Lys

Pathogenic missense variant in junctophilin-2 that disrupts sarcoplasmic reticulum coupling and calcium signaling, causing hypertrophic cardiomyopathy with high age-dependent penetrance

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JPH2 Thr161Lys — When the Heart's Calcium Bridge Breaks

Your heart muscle relies on millisecond-precise calcium pulses to contract and relax in perfect rhythm. The junctophilin-2 protein, encoded by JPH2, is the structural bridge that makes this possible — a molecular tether clamping the plasma membrane and sarcoplasmic reticulum together so that the electrical signal arriving at the cell surface is faithfully translated into a calcium surge inside the cell. rs58778295111 rs587782951
This single-nucleotide variant at chromosome 20q13.12 replaces threonine-161 with lysine, subtly but consequentially altering this coupling machinery. The result is hypertrophic cardiomyopathy (HCM) — the most common inherited cardiac disorder and a leading cause of sudden cardiac death in young people.

The Mechanism

The JPH2 protein contains eight MORN (membrane occupation and recognition nexus) motifs at its N-terminus that anchor it to the plasma membrane, and a C-terminal transmembrane domain that inserts into the sarcoplasmic reticulum22 sarcoplasmic reticulum
the cell's internal calcium store membrane. Between them, the joining region spans the narrow junctional gap between the two membranes, holding them ~10–15 nm apart — a distance perfectly calibrated for calcium channel coupling.

The Thr161Lys substitution falls in the joining region, replacing a neutral polar amino acid (threonine) with a positively charged lysine. Studies in patient-derived iPSC cardiomyocytes show this disrupts protein localization and calcium inactivation kinetics33 disrupts protein localization and calcium inactivation kinetics, producing a slower time constant of calcium current decay. The consequence: the action potential lingers longer at each beat, calcium handling is dysregulated across millions of cardiomyocytes, and the myocardium hypertrophies — thickening its walls in an attempt to compensate for impaired pump efficiency. Early afterdepolarizations (EADs) arising from this prolonged repolarization create the substrate for lethal arrhythmias.

The Evidence

JPH2 was established as an HCM disease gene in 2007, when Landstrom et al. screened 388 unrelated HCM patients44 Landstrom et al. screened 388 unrelated HCM patients
Landstrom AP et al. J Mol Cell Cardiol 2007 and identified three novel JPH2 missense mutations (S101R, Y141H, S165F) absent in 1,000 control alleles. Each mutation caused protein reorganization, disrupted calcium signaling, and increased cardiomyocyte size — establishing a direct causal chain.

The Thr161Lys variant specifically was characterized in a Finnish founder-effect setting. Vanninen et al. 201855 Vanninen et al. 2018
Vanninen SUM et al. PLoS One 2018;13(9):e0203422 followed 26 heterozygous carriers across 9 families and found penetrance of 71% by age 60 and 100% by age 80 — unusually high for a single-gene cardiac variant. Clinical features included left ventricular hypertrophy, third-degree AV block, and end-stage systolic heart failure in a subset of carriers; co-segregation confirmed in 6 of 9 families. This variant is classified as pathogenic in ClinVar (VCV000155800), supported by multiple independent submissions.

The mechanism was further characterized in iPSC-derived cardiomyocytes: Valtonen et al. 202366 Valtonen et al. 2023
Biomedicines 2023;11(6):1558 showed Thr161Lys cardiomyocytes display significantly enlarged cell bodies, disrupted sarcomeric organization, prolonged action potentials at 50% and 90% repolarization, and spontaneous phase-3 early afterdepolarizations — recapitulating the patient arrhythmia phenotype at the cellular level.

Across a broader JPH2 landscape, Parker et al. 202377 Parker et al. 2023
Trends Cardiovasc Med 2023;33(1):1-10 systematically reviewed 61 JPH2 variant carriers and found 47% developed HCM, 18% DCM, and 14% experienced arrhythmia or sudden cardiac death — underscoring the high clinical stakes of JPH2 pathogenic variants as a class.

Practical Implications

Heterozygous carriers of the Thr161Lys variant face near-certain lifetime risk of HCM. The high age-dependent penetrance means that a carrier who is asymptomatic in their 30s may not yet have developed disease, making regular surveillance essential. HCM in JPH2 carriers has a distinctive phenotype: left ventricular hypertrophy combined with risk of high-grade conduction block and arrhythmia, which distinguishes it from sarcomeric HCM caused by MYH7 or MYBPC3 mutations. Early identification enables lifestyle risk reduction (avoiding competitive sports), pharmacologic management of symptoms, and implantable cardioverter-defibrillator consideration in high-risk individuals.

First-degree relatives of a carrier have a 50% probability of inheriting the variant and require cascade genetic testing regardless of current symptoms.

Interactions

JPH2 does not have established interactions with other HCM-associated genes of the type seen with sarcomeric compound heterozygosity (e.g. MYBPC3 + MYH7). However, disease expression may be modulated by variants in genes that regulate calcium handling, including RYR2 (ryanodine receptor) and CASQ2 (calsequestrin), which together with JPH2 form the junctional calcium signaling complex. These interactions are mechanistically plausible but not yet characterized in carriers of Thr161Lys specifically.

Genotype Interpretations

What each possible genotype means for this variant.

GG Non-Carrier Normal

No JPH2 Thr161Lys variant detected

You carry two copies of the reference G allele at rs587782951, meaning you do not carry the JPH2 Thr161Lys pathogenic variant. This variant is extremely rare — the T allele is found in approximately 0.0005% of European ancestry individuals in large population databases, and is essentially absent in all other ancestral groups. The absence of this variant is the expected result for the overwhelming majority of people.

TT Homozygous Homozygous

Homozygous for JPH2 Thr161Lys — extremely rare, severe HCM expected

You carry two copies of the T allele at rs587782951. Homozygosity for this pathogenic variant is exceptionally rare — the T allele frequency is approximately 0.000005 in European populations, making homozygous TT essentially theoretical in population databases. Based on what is known about JPH2 loss-of-function in animal models (embryonic cardiac arrest in homozygous knockout mice) and the severe phenotype of homozygous JPH2 loss-of-function variants in humans (neonatal dilated cardiomyopathy), severe early-onset cardiomyopathy would be expected. Immediate cardiological assessment is required.

GT Carrier Carrier

Carrier of the JPH2 Thr161Lys pathogenic variant — high-penetrance HCM risk

The JPH2 Thr161Lys variant disrupts junctophilin-2's role in coupling plasma membrane L-type calcium channels to ryanodine receptors in the sarcoplasmic reticulum. In iPSC-derived cardiomyocytes from Thr161Lys carriers, the variant prolongs action potential duration and generates spontaneous early afterdepolarizations — a mechanism for the arrhythmia vulnerability seen clinically. The hypertrophic phenotype arises as the myocardium remodels in response to chronic calcium mishandling.

Because this is an autosomal dominant variant, each of your first-degree biological relatives (parents, siblings, children) has a 50% chance of having inherited the same variant. Cascade testing of relatives is the single highest-impact clinical action following a positive result.

HCM caused by JPH2 is typically distinguished from sarcomeric HCM (MYH7, MYBPC3) by its higher propensity for conduction disease and the extreme age-dependent penetrance. Clinical management follows HCM guidelines but must account for this specific phenotypic profile — particularly the arrhythmia burden.