rs10918594 — NOS1AP

Regulatory variant upstream of NOS1AP (CAPON) associated with QT interval prolongation via altered nNOS-mediated cardiac repolarization; the G allele extends QTc by ~3.6 ms per copy

See your personal result for NOS1AP

Upload your DNA data to find out which genotype you carry and what it means for you.

Upload your DNA data

Works with 23andMe, AncestryDNA, and other DNA test exports. Results in under 60 seconds.

NOS1AP and the QT Interval — A Common Variant in the Heart's Electrical Timing

The QT interval11 QT interval
the time between the start of ventricular depolarization and the end of repolarization, measured on an electrocardiogram is one of medicine's most important cardiac biomarkers. A prolonged QTc interval predisposes to torsades de pointes22 torsades de pointes
a dangerous polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation and sudden cardiac death. Genetics account for roughly 30% of QTc variation in the population — and the NOS1AP gene harbors one of the strongest common genetic contributors ever discovered.

NOS1AP (also called CAPON — Carboxy-terminal PDZ ligand of Neuronal nitric Oxide synthase) encodes an adaptor protein that physically binds to neuronal nitric oxide synthase (nNOS). Though originally studied in the brain, nNOS is expressed in cardiac myocytes where it plays a key role in modulating calcium handling and action potential duration.

The Mechanism

nNOS in cardiomyocytes inhibits the L-type calcium channel33 L-type calcium channel
the main inward calcium current that drives and prolongs cardiac contraction and activates the delayed rectifier potassium current. Together, these effects accelerate ventricular repolarization — shortening the action potential and therefore the QT interval. NOS1AP/CAPON interacts with nNOS and modulates the efficiency of this signaling cascade.

rs10918594 is a C>G variant located upstream of NOS1AP, approximately 55 kb from a second functional SNP in the same gene (rs10494366, r²=0.63, D′=0.89). Neither SNP is a coding variant — they sit in regulatory or non-coding sequence and have no known functional effect on the protein itself. Instead, they appear to tag a causal regulatory variant that alters NOS1AP expression in cardiac tissue. Direct evidence supports this interpretation: analysis of NOS1AP RNA levels in human right ventricular tissue44 analysis of NOS1AP RNA levels in human right ventricular tissue
cardiac samples from 17 patients undergoing pacemaker lead extraction found that CC homozygotes (major allele) had lower NOS1AP expression than GG minor homozygotes. Lower NOS1AP expression correlates with shorter QTc — meaning the G allele raises NOS1AP/CAPON expression, which amplifies nNOS signaling and paradoxically reduces nNOS's ability to shorten the action potential. The net effect is prolonged repolarization.

The Evidence

The original discovery came from the landmark Rotterdam Study55 Rotterdam Study
a prospective population-based cohort of 3,761 individuals aged ≥55 years in the Netherlands. The rs10918594 G allele (31% frequency in this European cohort) was associated with a 3.6-ms increase in QTc per additional allele copy (95% CI 2.7–4.4; P=6.9×10⁻¹⁷) — a highly significant genome-wide association replicated across dozens of subsequent studies. GG homozygotes averaged 7.2 ms longer QTc than CC homozygotes.

Replication in the Diabetes Heart Study66 Diabetes Heart Study
European-American families with and without type 2 diabetes confirmed and extended the finding. Minor homozygotes had QT intervals 12.5 ms longer than major homozygotes overall (P=1.5×10⁻⁶). Critically, the effect was stronger among diabetic individuals (13.9-ms difference), suggesting that diabetic cardiomyopathy creates a permissive background in which NOS1AP-dependent calcium dysregulation is amplified.

Beyond QTc prolongation, NOS1AP variation is associated with sudden cardiac death (SCD) risk77 NOS1AP variation is associated with sudden cardiac death (SCD) risk
in 233 SCD cases over 11.9 years of follow-up in the Rotterdam Study — and this SCD association appears to be at least partially independent of the effect on QT duration, suggesting NOS1AP influences arrhythmia susceptibility through mechanisms beyond simple QT prolongation.

NOS1AP has also emerged as a genetic modifier of congenital Long QT syndrome (LQTS)88 genetic modifier of congenital Long QT syndrome (LQTS)
inherited channelopathies caused by loss-of-function mutations in KCNQ1, KCNH2, and SCN5A. Among LQTS patients, G allele carriers had higher rates of life-threatening cardiac events (24.8% vs 17.8%), and the variant independently predicted arrhythmia risk beyond QTc alone — meaning NOS1AP genotyping adds prognostic information on top of standard clinical assessment in these patients.

Drug-induced QT prolongation99 Drug-induced QT prolongation
a major cause of drug withdrawal and black-box warnings across multiple drug classes is also modified by NOS1AP variants. The G allele was associated with increased risk of amiodarone-induced ventricular arrhythmia. The Rotterdam Study specifically showed that G allele carriers had a significantly potentiated QTc-prolonging response to verapamil (a calcium channel blocker) — consistent with the mechanistic role of NOS1AP in L-type calcium channel regulation.

A systematic meta-analysis published in 20191010 systematic meta-analysis published in 2019
pooling data across multiple cohorts confirmed that the NOS1AP QTc association is particularly strong in women and in patients with diabetes mellitus, and that the sudden death association is significant in Caucasian populations.

Practical Actions

For carriers of one or two G alleles, the primary concern is QTc prolongation. A QTc above 450 ms in men or 460 ms in women is considered borderline prolonged; above 500 ms substantially elevates arrhythmia risk. NOS1AP's 3.6-ms-per-allele effect is modest in isolation — GG homozygotes average about 7 ms longer QTc — but the clinical stakes rise when other QT-prolonging factors stack on top.

Key risks to manage: certain medications (including many antiarrhythmics, antibiotics, antipsychotics, and antihistamines) prolong the QT interval independently, and G allele carriers face an amplified combined effect. Electrolyte disturbances — particularly hypokalemia and hypomagnesemia — further extend the QT interval and lower the threshold for torsades de pointes. Diabetics with G alleles face a compounded risk because both diabetic autonomic neuropathy and NOS1AP variants independently prolong QTc.

Interactions

The two principal NOS1AP SNPs — rs10918594 and rs10494366 — are in moderate linkage disequilibrium (r²=0.63) and are typically co-inherited. Their combined effects have not been formally quantified in a compound-genotype analysis, but given their shared locus and similar effect sizes, they likely tag the same functional regulatory variant rather than act through independent mechanisms.

Interaction with rs12143842 (and its proxy rs16847549), a neighboring NOS1AP variant, was the strongest SCD signal in the Rotterdam Study follow-up analysis. In the congenital LQTS context, NOS1AP G allele carriers with KCNQ1 variants also showed elevated risk — suggesting the NOS1AP-nNOS pathway compounds with the primary channelopathy.

Drug Interactions

amiodarone increased_toxicity literature
verapamil increased_toxicity literature

Genotype Interpretations

What each possible genotype means for this variant.

CC Typical Repolarization Normal

Normal cardiac repolarization at this locus

You carry two copies of the C allele at rs10918594, the common variant associated with lower NOS1AP expression in cardiac tissue and shorter QTc duration. About 48% of people of European descent share this genotype. Your NOS1AP/CAPON signaling does not add to QT interval prolongation at this locus — your baseline cardiac repolarization timing falls within the typical range for this gene's contribution.

CG Moderately Extended QTc Intermediate

One G allele adds approximately 3.6 ms to QTc interval

You carry one copy of the G allele at rs10918594. This is associated with higher NOS1AP expression in cardiac tissue and a corresponding ~3.6 ms increase in QTc interval compared to CC carriers (Rotterdam Study, P=6.9×10⁻¹⁷). About 43% of people of European descent share this heterozygous genotype. On its own, a single G allele is unlikely to push your QTc into a clinically prolonged range — but it does mean that additional QT-prolonging factors (certain drugs, electrolyte disturbances, diabetes) will have a larger combined effect than they would in CC carriers.

GG Extended QTc Risk High Risk

Two G alleles add ~7 ms to QTc; meaningful drug and electrolyte sensitivity

The 7-ms QTc increment from GG genotype is meaningful in context. Most individuals have QTc in the 360–440 ms range. A 7-ms shift can push borderline QTc values into the prolonged range, and its significance multiplies when other QTc-prolonging factors are present. Drug-induced QT prolongation — one of the most common causes of drug withdrawal — is substantially amplified by GG genotype, particularly with amiodarone and verapamil. The Rotterdam Study showed a statistically significant interaction between NOS1AP G allele and verapamil QTc effect, suggesting that NOS1AP's role in L-type calcium channel regulation is the mechanistic nexus.

The SCD data from the Rotterdam Study are more nuanced: rs10918594 itself did not reach significance for SCD in the primary analysis, but the closely linked rs12143842 (via rs16847549) showed the strongest SCD signal when analysis was restricted to witnessed events. Given the near-perfect LD between these variants, the SCD association at this locus should be viewed as real but imprecisely localized to the specific causal variant. For LQTS patients, the additive arrhythmia risk from G alleles is well-established and has been replicated across independent cohorts.