HCN4 (Q9Y3Q4) variants and mutations
HCN4 (also known as Q9Y3Q4) is a human protein-coding gene encoding a potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 protein. Its hyperpolarization-activated current contributes substantially to spontaneous diastolic depolarization in sinoatrial-node pacemaker cells. Pathogenic variants can cause sinus bradycardia, conduction abnormalities, and in some families left-ventricular noncompaction. This analysis covers 2,147 HCN4 variants and mutations. Of these, 84% have computational variant effect predictions. Disease context includes sick sinus syndrome 2, autosomal dominant, atrial fibrillation, and heart failure. Example HCN4 variants include M1V, D2E, and D2V.
Variant analysis overview
- Gene: HCN4
- Protein: Q9Y3Q4
- UniProt accession: Q9Y3Q4
- Organism: Homo sapiens
- Variants analyzed: 2147
- Variant scope: all variants
- Completed: 2026-08-18
Variant and mutation evidence
- Variant composition: 1,642 unspecified-consequence records; 4 stop lost; 1 stop retained variant; 149 synonymous variants; 298 missense variants; 34 frameshift variants; 7 in-frame deletions; 11 stop-gained variants; 1 substitution
- Prediction scores: 1,803 variants have prediction scores (84% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: sick sinus syndrome 2, autosomal dominant, atrial fibrillation, heart failure, Brugada syndrome 8, angina pectoris, cardiac arrhythmia, Abnormality of the cardiovascular system, atrial flutter, familial sick sinus syndrome, Left ventricular noncompaction cardiomyopathy, sinoatrial node disorder, congestive heart failure.
Protein structure and variant hotspots
- Protein features: 6 transmembrane segments; 11 binding sites; 4 post-translational modification sites.
- Structural context: 117 variants have structural context.
- PTM context: 10 variants overlap post-translational modification sites.
Data sources
Evidence in this analysis draws on EBI Proteins Variation, UniProt, gnomAD v4, EuropePMC, 3D Hotspot Analysis, Interaction Network Analysis, Protein Data Bank, AlphaFold DB, gnomAD constraint, Open Targets, ClinGen, MaveDB, LitVar.
Notable HCN4 variants
Examples include M1V, D2E, D2V, D2Y, K3M, K3N, K3R, K3T. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- M1V (p.Met1Val), rs1453814089, ClinGen CA393099307, ClinVar RCV002638285, MetaLR 0.90, MetaSVM 1.08, Uncertain significance, Brugada syndrome 8
- D2E (p.Asp2Glu), rs1230881569, ClinGen CA393099289, ClinVar RCV001881873, ClinVar RCV002370458, REVEL 0.38, MetaLR 0.82, Uncertain significance, Cardiovascular phenotype; Brugada syndrome 8
- D2V (p.Asp2Val), gnomAD rs2043139906, REVEL 0.62, MetaLR 0.91
- D2Y (p.Asp2Tyr), rs2549080787, ClinGen CA393099293, ClinVar RCV002343062, REVEL 0.60, MetaLR 0.93, Uncertain significance, Cardiovascular phenotype
- K3M (p.Lys3Met), rs1267513363, ClinGen CA393099282, ClinVar RCV003506251, TOPMed rs1267513363, REVEL 0.39, MetaLR 0.84, Uncertain significance, Brugada syndrome 8
- K3N (p.Lys3Asn), Ensembl rs2043139851, REVEL 0.39, MetaLR 0.80
- K3R (p.Lys3Arg), rs1267513363, ClinGen CA393099283, ClinVar RCV001882222, TOPMed rs1267513363, REVEL 0.23, MetaLR 0.66, Uncertain significance, Brugada syndrome 8
- K3T (p.Lys3Thr), rs1267513363, ClinGen CA393099284, ClinVar RCV001954879, ClinVar RCV005350761, REVEL 0.38, MetaLR 0.77, Uncertain significance, Brugada syndrome 8; Cardiovascular phenotype
- P5Q (p.Pro5Gln), TOPMed rs927046568, REVEL 0.33, MetaLR 0.73
- P5S (p.Pro5Ser), rs1204027135, ClinGen CA393099272, ClinVar RCV002633482, TOPMed rs1204027135, REVEL 0.41, MetaLR 0.77, Uncertain significance, Brugada syndrome 8
- P6L (p.Pro6Leu), rs772656493, ClinGen CA7649512, ClinVar RCV001984636, ExAC rs772656493, REVEL 0.47, MetaLR 0.75, Uncertain significance, Brugada syndrome 8
- P6Q (p.Pro6Gln), rs772656493, ClinGen CA393099266, ClinVar RCV002017778, ClinVar RCV002407294, REVEL 0.43, MetaLR 0.83, Uncertain significance, Cardiovascular phenotype; Brugada syndrome 8
- P6R (p.Pro6Arg), rs772656493, ClinGen CA393099265, ClinVar RCV001054800, ClinVar RCV002409455, REVEL 0.39, MetaLR 0.80, Uncertain significance, not provided; Brugada syndrome 8; Cardiovascular phenotype
- P6S (p.Pro6Ser), rs2549080774, ClinGen CA393099267, ClinVar RCV002996881, REVEL 0.26, MetaLR 0.67, Uncertain significance, Brugada syndrome 8
- S7P (p.Ser7Pro), Ensembl rs2043139740, REVEL 0.46, MetaLR 0.85
- S7T (p.Ser7Thr), Ensembl rs2043139740, REVEL 0.39, MetaLR 0.88
- S7Y (p.Ser7Tyr), TOPMed rs1240695970, gnomAD rs1240695970, REVEL 0.55, MetaLR 0.93
- M8R (p.Met8Arg), rs749801134, ClinGen CA7649510, ClinVar RCV001942923, ClinVar RCV003382714, REVEL 0.63, MetaLR 0.87, Uncertain significance, Cardiovascular phenotype; Brugada syndrome 8
- M8T (p.Met8Thr), rs749801134, ClinGen CA393099254, ClinVar RCV001939916, ExAC rs749801134, REVEL 0.58, MetaLR 0.87, Uncertain significance, Brugada syndrome 8
- M8V (p.Met8Val), rs1595837779, ClinGen CA393099257, ClinVar RCV002637090, Ensembl rs1595837779, REVEL 0.39, MetaLR 0.84, Uncertain significance, Brugada syndrome 8
- R9H (p.Arg9His), rs1045593470, gnomAD rs1045593470, REVEL 0.63, MetaLR 0.95, Variant assessed as somatic; moderate impact.
- R9P (p.Arg9Pro), gnomAD rs1045593470, REVEL 0.74, MetaLR 0.95
- K10Q (p.Lys10Gln), Ensembl rs2043139648, Uncertain significance, Cardiovascular phenotype
- K10R (p.Lys10Arg), Ensembl rs2151228793, REVEL 0.42, MetaLR 0.84
- R11P (p.Arg11Pro), rs2549080759, ClinGen CA393099234, ClinVar RCV003833986, Uncertain significance, Brugada syndrome 8
- R11Q (p.Arg11Gln), NCI-TCGA Cosmic COSV9998, REVEL 0.50, MetaLR 0.94, Variant assessed as somatic; moderate impact.
- L12F (p.Leu12Phe), rs1247194443, ClinGen CA393099230, ClinVar RCV002685869, TOPMed rs1247194443, REVEL 0.51, MetaLR 0.93, Uncertain significance, Brugada syndrome 8
- Y13C (p.Tyr13Cys), Ensembl rs2043139583, REVEL 0.69, MetaLR 0.94, Uncertain significance, Cardiovascular phenotype
- Y13H (p.Tyr13His), gnomAD rs1438584059, REVEL 0.58, MetaLR 0.94
- L15F (p.Leu15Phe), rs2043139568, ClinGen CA393099208, ClinVar RCV003615375, TOPMed rs2043139568, REVEL 0.49, MetaLR 0.95, Uncertain significance, Brugada syndrome 8
- P16L (p.Pro16Leu), rs2043139529, ClinGen CA393099199, ClinVar RCV001204912, ClinVar RCV002339516, REVEL 0.76, MetaLR 0.95, Uncertain significance, Cardiovascular phenotype; Brugada syndrome 8
- P16S (p.Pro16Ser), TOPMed rs969545699, gnomAD rs969545699, REVEL 0.55, MetaLR 0.90
- Q17H (p.Gln17His), Ensembl rs867043389, REVEL 0.48, MetaLR 0.91
- Q18E (p.Gln18Glu), rs2549080745, ClinGen CA393099185, ClinVar RCV002790251, REVEL 0.29, MetaLR 0.76, Uncertain significance, Brugada syndrome 8
- Q18P (p.Gln18Pro), rs2549080743, ClinGen CA393099182, ClinVar RCV004118409, ClinVar RCV005059281, Uncertain significance, Cardiovascular phenotype; Brugada syndrome 8
- V19A (p.Val19Ala), gnomAD rs1358888636, REVEL 0.37, MetaLR 0.81
- V19L (p.Val19Leu), rs915677456, ClinGen CA272700678, ClinVar RCV003506476, Ensembl rs915677456, REVEL 0.30, MetaLR 0.73, Uncertain significance, Brugada syndrome 8
- V19M (p.Val19Met), Ensembl rs915677456, REVEL 0.39, MetaLR 0.78, Uncertain significance
- G20R (p.Gly20Arg), gnomAD rs868149827, REVEL 0.69, MetaLR 0.97
- G20W (p.Gly20Trp), gnomAD rs868149827, REVEL 0.69, MetaLR 0.97
- A21D (p.Ala21Asp), Ensembl rs867522153, REVEL 0.22, MetaLR 0.72, Uncertain significance
- A21V (p.Ala21Val), rs867522153, ClinGen CA393099155, ClinVar RCV003384163, ClinVar RCV005104261, REVEL 0.29, MetaLR 0.72, Uncertain significance, Brugada syndrome 8; Cardiovascular phenotype
- K22E (p.Lys22Glu), Ensembl rs1595837744, REVEL 0.34, MetaLR 0.82
- K22N (p.Lys22Asn), Ensembl rs867204798, REVEL 0.40, MetaLR 0.88
- A23E (p.Ala23Glu), ExAC rs781573072, gnomAD rs781573072, REVEL 0.47, MetaLR 0.87
- A23S (p.Ala23Ser), Ensembl rs868045953, REVEL 0.42, MetaLR 0.86, Uncertain significance
- A23T (p.Ala23Thr), rs868045953, ClinGen CA393099145, ClinVar RCV000678925, Ensembl rs868045953, REVEL 0.40, MetaLR 0.88, Uncertain significance, Brugada syndrome 8
- A23V (p.Ala23Val), ExAC rs781573072, gnomAD rs781573072, REVEL 0.39, MetaLR 0.88
- W24C (p.Trp24Cys), gnomAD rs1479330429, REVEL 0.39, MetaLR 0.73
- I25F (p.Ile25Phe), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- I25M (p.Ile25Met), rs1022550194, ClinGen CA393099117, ClinVar RCV003297363, Uncertain significance, Cardiovascular phenotype
- M26I (p.Met26Ile), gnomAD rs1265363121, REVEL 0.33, MetaLR 0.82
- M26L (p.Met26Leu), TOPMed rs1172106722, REVEL 0.24, MetaLR 0.80, Uncertain significance
- M26T (p.Met26Thr), rs2549080723, ClinGen CA393099110, ClinVar RCV003615261, REVEL 0.40, MetaLR 0.78, Uncertain significance, Brugada syndrome 8
- M26V (p.Met26Val), rs1172106722, ClinGen CA393099114, ClinVar RCV003121312, ClinVar RCV003396893, REVEL 0.24, MetaLR 0.78, Uncertain significance, not specified; Brugada syndrome 8
- D27H (p.Asp27His), rs2549080722, ClinGen CA393099102, ClinVar RCV002419153, ClinVar RCV003614134, REVEL 0.43, MetaLR 0.87, Uncertain significance, Cardiovascular phenotype; Brugada syndrome 8
- D27N (p.Asp27Asn), NCI-TCGA TCGA novel, REVEL 0.38, MetaLR 0.78, Variant assessed as somatic; moderate impact.
- E28* (p.Glu28Ter), rs867068803, ClinGen CA272700586, ClinVar RCV002430347, Ensembl rs867068803, CADD 36.00, Uncertain significance
- E28G (p.Glu28Gly), rs989762782, ClinGen CA272700578, ClinVar RCV003504992, ClinVar RCV005353207, REVEL 0.39, MetaLR 0.82, Uncertain significance, Cardiovascular phenotype; Brugada syndrome 8
- E28K (p.Glu28Lys), rs867068803, ClinGen CA393099092, ClinVar RCV000532717, ClinVar RCV004527654, REVEL 0.49, MetaLR 0.82, Uncertain significance, HCN4-related disorder; Brugada syndrome 8
- E29G (p.Glu29Gly), gnomAD rs991540673, REVEL 0.27, MetaLR 0.71, Uncertain significance, Brugada syndrome 8
- E29K (p.Glu29Lys), Ensembl rs868043327, REVEL 0.33, MetaLR 0.75, Uncertain significance, Brugada syndrome 8
- E30K (p.Glu30Lys), rs786205802, ClinGen CA301954, ClinVar RCV001069920, ClinVar RCV002372064, REVEL 0.46, MetaLR 0.83, Uncertain significance, Cardiovascular phenotype; Brugada syndrome 8
- E30Q (p.Glu30Gln), rs786205802, ClinGen CA393099072, ClinVar RCV001228475, ClinVar RCV004762007, REVEL 0.43, MetaLR 0.86, Uncertain significance, not provided; Brugada syndrome 8
- D31N (p.Asp31Asn), rs757500423, ClinGen CA7649506, ClinVar RCV002027666, ClinVar RCV002372817, REVEL 0.33, MetaLR 0.81, Uncertain significance, Cardiovascular phenotype; not provided; Brugada syndrome 8
- A32V (p.Ala32Val), rs2043139122, ClinGen CA393099047, ClinVar RCV003614355, TOPMed rs2043139122, REVEL 0.21, MetaLR 0.76, Uncertain significance, Brugada syndrome 8
- E33D (p.Glu33Asp), 1000Genomes rs1486991862, gnomAD rs1486991862, REVEL 0.21, MetaLR 0.60
- E34K (p.Glu34Lys), ExAC rs751823089, gnomAD rs751823089, REVEL 0.20, MetaLR 0.72
- E35G (p.Glu35Gly), Ensembl rs2151228751, REVEL 0.31, MetaLR 0.76
- G36E (p.Gly36Glu), rs143090627, ClinGen CA180109, ClinVar RCV000153356, ClinVar RCV000619819, REVEL 0.23, MetaLR 0.22, Benign/Likely benign, Cardiovascular phenotype; not specified; not provided
- G36R (p.Gly36Arg), rs886039001, ClinGen CA10587884, ClinVar RCV000252541, ClinVar RCV002519001, REVEL 0.28, MetaLR 0.73, Uncertain significance, Brugada syndrome 8; Cardiovascular phenotype
- G36V (p.Gly36Val), rs143090627, ClinGen CA393099008, ClinVar RCV003506434, REVEL 0.23, MetaLR 0.73, Uncertain significance, Brugada syndrome 8
- A37D (p.Ala37Asp), rs2043138879, ClinGen CA393099000, ClinVar RCV003135536, ClinVar RCV003505297, REVEL 0.18, MetaLR 0.72, Uncertain significance, not provided; Brugada syndrome 8
- A37P (p.Ala37Pro), gnomAD rs1276311576, REVEL 0.22, MetaLR 0.75
- A37V (p.Ala37Val), rs2043138879, ClinGen CA393098999, ClinVar RCV002676680, TOPMed rs2043138879, REVEL 0.20, MetaLR 0.75, Uncertain significance, Brugada syndrome 8
- G38E (p.Gly38Glu), gnomAD rs1218127033, REVEL 0.28, MetaLR 0.76
- G38R (p.Gly38Arg), gnomAD rs1269475108, REVEL 0.33, MetaLR 0.73, Uncertain significance, Cardiovascular phenotype
- G39A (p.Gly39Ala), Ensembl rs2043138750, REVEL 0.26, MetaLR 0.69
- G39C (p.Gly39Cys), gnomAD rs1338572189, REVEL 0.35, MetaLR 0.74
- R40C (p.Arg40Cys), gnomAD rs1300096638, REVEL 0.37, MetaLR 0.72
- R40G (p.Arg40Gly), gnomAD rs1300096638, REVEL 0.29, MetaLR 0.66
- R40H (p.Arg40His), rs1400904747, ClinGen CA393098973, ClinVar RCV002963166, ClinVar RCV003274118, REVEL 0.26, MetaLR 0.67, Uncertain significance, Brugada syndrome 8; Cardiovascular phenotype
- D42A (p.Asp42Ala), ExAC rs765179741, REVEL 0.53, MetaLR 0.89
- D42H (p.Asp42His), rs752597565, ClinGen CA7649502, ClinVar RCV000794785, ClinVar RCV002397582, REVEL 0.48, MetaLR 0.95, Uncertain significance, Cardiovascular phenotype; Brugada syndrome 8
- D42N (p.Asp42Asn), ExAC rs752597565, TOPMed rs752597565, gnomAD rs752597565, REVEL 0.34, MetaLR 0.94, Uncertain significance
- P43A (p.Pro43Ala), rs2549080660, ClinGen CA393098943, ClinVar RCV004521401, REVEL 0.31, MetaLR 0.62, Uncertain significance, Cardiovascular phenotype
- P43L (p.Pro43Leu), rs759329385, ClinGen CA7649500, ClinVar RCV000232608, ClinVar RCV002379006, REVEL 0.28, MetaLR 0.71, Conflicting interpretations, Cardiovascular phenotype; not provided; Brugada syndrome 8
- S44C (p.Ser44Cys), rs2043138506, ClinGen CA393098933, ClinVar RCV002385392, REVEL 0.33, MetaLR 0.66, Uncertain significance, Cardiovascular phenotype
- S44N (p.Ser44Asn), rs2151228715, ClinGen CA393098930, ClinVar RCV001865135, Ensembl rs2151228715, REVEL 0.30, MetaLR 0.74, Uncertain significance, Brugada syndrome 8
- S44R (p.Ser44Arg), rs2043138506, ClinGen CA393098936, ClinVar RCV001222910, TOPMed rs2043138506, REVEL 0.26, MetaLR 0.54, Uncertain significance, Brugada syndrome 8
- R45C (p.Arg45Cys), TOPMed rs2043138489, REVEL 0.55, MetaLR 0.90
- R45H (p.Arg45His), 1000Genomes rs1416460262, TOPMed rs1416460262, gnomAD rs1416460262, REVEL 0.46, MetaLR 0.91, Uncertain significance
- R45L (p.Arg45Leu), rs1416460262, ClinGen CA393098915, ClinVar RCV000557330, ClinVar RCV002491073, REVEL 0.57, MetaLR 0.88, Uncertain significance, not provided; Brugada syndrome 8; Sick sinus syndrome 2, autosomal dominant
- R45S (p.Arg45Ser), rs2043138489, ClinGen CA393098920, ClinVar RCV002949405, REVEL 0.45, MetaLR 0.82, Uncertain significance, Brugada syndrome 8
- R46G (p.Arg46Gly), rs2549080654, ClinGen CA393098913, ClinVar RCV003003325, REVEL 0.33, MetaLR 0.72, Uncertain significance, Brugada syndrome 8
- R46T (p.Arg46Thr), TOPMed rs1330528056, gnomAD rs1330528056, REVEL 0.28, MetaLR 0.72
- S47N (p.Ser47Asn), rs1426506590, ClinGen CA393098897, ClinVar RCV003505054, ClinVar RCV005575192, REVEL 0.53, MetaLR 0.94, Uncertain significance, Brugada syndrome 8; Cardiovascular phenotype
- S47R (p.Ser47Arg), rs2549080651, ClinGen CA393098899, ClinVar RCV002389187, REVEL 0.64, MetaLR 0.94, Uncertain significance, Cardiovascular phenotype
- I48M (p.Ile48Met), rs776352142, ClinGen CA7649499, ClinVar RCV003443648, ClinVar RCV005100082, REVEL 0.36, MetaLR 0.85, Uncertain significance, Brugada syndrome 8; not provided
- R49G (p.Arg49Gly), rs1477109893, ClinGen CA393098885, ClinVar RCV004521404, ClinVar RCV005100507, REVEL 0.53, MetaLR 0.82, Uncertain significance, Brugada syndrome 8; Cardiovascular phenotype
- R49P (p.Arg49Pro), rs2043138348, ClinGen CA393098883, ClinVar RCV003615037, AlphaMissense 0.19, MetaLR 0.79, Uncertain significance, Brugada syndrome 8
- R49Q (p.Arg49Gln), Ensembl rs2043138348, REVEL 0.25, AlphaMissense 0.19
- R51Q (p.Arg51Gln), rs1425211418, ClinGen CA393098867, ClinVar RCV001035563, ClinVar RCV002400210, REVEL 0.31, MetaLR 0.67, Uncertain significance, Cardiovascular phenotype; Brugada syndrome 8
- R51W (p.Arg51Trp), rs1555479061, ClinGen CA393098869, ClinVar RCV000647234, Ensembl rs1555479061, REVEL 0.44, MetaLR 0.83, Uncertain significance, Brugada syndrome 8
- P52L (p.Pro52Leu), Ensembl rs1297165703, REVEL 0.49, MetaLR 0.81, Uncertain significance, Brugada syndrome 8
- P52R (p.Pro52Arg), rs1297165703, ClinGen CA393098857, ClinVar RCV003384153, ClinVar RCV006472601, REVEL 0.46, MetaLR 0.82, Uncertain significance, Brugada syndrome 8; Cardiovascular phenotype
- L53P (p.Leu53Pro), gnomAD rs1193737227, REVEL 0.57, MetaLR 0.92
- P54S (p.Pro54Ser), gnomAD rs2043138198, REVEL 0.32, MetaLR 0.83
- S55P (p.Ser55Pro), Ensembl rs2151228699, REVEL 0.43, MetaLR 0.85
- P56L (p.Pro56Leu), rs2549080630, ClinGen CA393098823, ClinVar RCV003070115, REVEL 0.47, MetaLR 0.90, Uncertain significance, Brugada syndrome 8
- S57F (p.Ser57Phe), rs1567802231, ClinGen CA393098816, ClinVar RCV002398866, ClinVar RCV006559272, REVEL 0.30, MetaLR 0.80, Uncertain significance, Cardiovascular phenotype; Brugada syndrome 8
- S57P (p.Ser57Pro), gnomAD rs1023219329, REVEL 0.28, MetaLR 0.79
- P58L (p.Pro58Leu), rs766148703, ClinGen CA7649498, ClinVar RCV002407481, ExAC rs766148703, REVEL 0.37, MetaLR 0.79, Uncertain significance, Cardiovascular phenotype
- P58S (p.Pro58Ser), rs1029043200, ClinGen CA272700504, ClinVar RCV001248102, ClinVar RCV002411912, REVEL 0.26, MetaLR 0.71, Uncertain significance, Cardiovascular phenotype; Brugada syndrome 8
- P58T (p.Pro58Thr), TOPMed rs1029043200, gnomAD rs1029043200, REVEL 0.19, MetaLR 0.75, Uncertain significance
- S59* (p.Ser59Ter), Ensembl rs1555479053, CADD 35.00
- S59L (p.Ser59Leu), NCI-TCGA TCGA novel, REVEL 0.31, MetaLR 0.64, Variant assessed as somatic; high impact.
- A60V (p.Ala60Val), rs2549080617, ClinGen CA393098789, ClinVar RCV003614984, REVEL 0.18, MetaLR 0.72, Uncertain significance, Brugada syndrome 8
- A62P (p.Ala62Pro), rs2151228688, ClinGen CA393098776, ClinVar RCV001933116, Ensembl rs2151228688, REVEL 0.31, MetaLR 0.75, Uncertain significance, Brugada syndrome 8; Cardiovascular phenotype
- A62V (p.Ala62Val), rs1595837637, ClinGen CA393098770, ClinVar RCV000804698, Ensembl rs1595837637, REVEL 0.24, MetaLR 0.67, Uncertain significance, Brugada syndrome 8
- G63D (p.Gly63Asp), rs1432580542, TOPMed rs1432580542, REVEL 0.32, MetaLR 0.82, Variant assessed as somatic; moderate impact.
- G63S (p.Gly63Ser), gnomAD rs1319902889, REVEL 0.18, MetaLR 0.75
- G64D (p.Gly64Asp), rs2549080606, ClinGen CA393098756, ClinVar RCV003042297, ClinVar RCV004990977, REVEL 0.26, MetaLR 0.77, Uncertain significance, Brugada syndrome 8; Cardiovascular phenotype
- T65A (p.Thr65Ala), Ensembl rs2043138008, REVEL 0.30, MetaLR 0.58
- T65M (p.Thr65Met), rs760387977, ClinGen CA7649497, ClinVar RCV001892519, ExAC rs760387977, REVEL 0.27, MetaLR 0.66, Uncertain significance, Brugada syndrome 8
- E66G (p.Glu66Gly), Ensembl rs2151228678, REVEL 0.18, MetaLR 0.71
- E66K (p.Glu66Lys), rs786205803, ClinGen CA301956, ClinVar RCV000170937, ClinVar RCV000808910, REVEL 0.21, MetaLR 0.73, Uncertain significance, not provided; Brugada syndrome 8
- E66Q (p.Glu66Gln), rs786205803, ClinGen CA393098745, ClinVar RCV001240953, TOPMed rs786205803, REVEL 0.24, MetaLR 0.71, Uncertain significance, Brugada syndrome 8
- S67Y (p.Ser67Tyr), Ensembl rs1595837618, REVEL 0.17, MetaLR 0.76
- R68G (p.Arg68Gly), rs962306052, ClinGen CA393098728, ClinVar RCV001370576, ClinVar RCV002420829, REVEL 0.18, MetaLR 0.74, Uncertain significance, Cardiovascular phenotype; Brugada syndrome 8
- R68Q (p.Arg68Gln), Ensembl rs1160213657, REVEL 0.23, MetaLR 0.70
- R68W (p.Arg68Trp), TOPMed rs962306052, gnomAD rs962306052, REVEL 0.32, MetaLR 0.79, Uncertain significance
- S70A (p.Ser70Ala), rs2549080595, ClinGen CA393098707, ClinVar RCV002424037, Likely benign, Cardiovascular phenotype
- S70L (p.Ser70Leu), rs771533338, ClinGen CA7649495, ClinVar RCV000533863, ClinVar RCV004024149, REVEL 0.26, MetaLR 0.77, Uncertain significance, Cardiovascular phenotype; Brugada syndrome 8
- A71T (p.Ala71Thr), rs1360146681, ClinGen CA393098704, ClinVar RCV002417605, gnomAD rs1360146681, REVEL 0.27, MetaLR 0.73, Uncertain significance, Cardiovascular phenotype
- A71V (p.Ala71Val), rs1451861074, ClinGen CA393098698, ClinVar RCV002417750, ClinVar RCV003101072, REVEL 0.24, MetaLR 0.74, Uncertain significance, Cardiovascular phenotype; Brugada syndrome 8
- L72F (p.Leu72Phe), rs2043137832, ClinGen CA393098694, ClinVar RCV002047112, 1000Genomes rs2043137832, REVEL 0.30, MetaLR 0.72, Uncertain significance, Brugada syndrome 8
- L72H (p.Leu72His), rs2549080589, ClinGen CA393098692, ClinVar RCV002432581, REVEL 0.20, MetaLR 0.70, Uncertain significance, Cardiovascular phenotype
- L72V (p.Leu72Val), rs2043137832, ClinGen CA393098695, ClinVar RCV003506401, 1000Genomes rs2043137832, REVEL 0.20, MetaLR 0.75, Uncertain significance, Brugada syndrome 8
- G73A (p.Gly73Ala), TOPMed rs2043137791
- G73R (p.Gly73Arg), rs2043137805, ClinGen CA393098687, ClinVar RCV002432879, gnomAD rs2043137805, REVEL 0.30, MetaLR 0.81, Uncertain significance, Brugada syndrome 8
- A74T (p.Ala74Thr), rs2549080586, ClinGen CA393098682, ClinVar RCV003015677, REVEL 0.25, MetaLR 0.69, Uncertain significance, Brugada syndrome 8
- A75E (p.Ala75Glu), NCI-TCGA TCGA novel, REVEL 0.17, MetaLR 0.68, Variant assessed as somatic; moderate impact.
- E78K (p.Glu78Lys), gnomAD rs1464572850, REVEL 0.24, MetaLR 0.74, Uncertain significance, Cardiovascular phenotype
- G79A (p.Gly79Ala), rs1555479039, ClinGen CA393098629, ClinVar RCV000522606, Ensembl rs1555479039, REVEL 0.21, MetaLR 0.68, Uncertain significance, not provided
- G79R (p.Gly79Arg), rs2549080580, ClinGen CA393098632, ClinVar RCV003615257, REVEL 0.19, MetaLR 0.74, Uncertain significance, Brugada syndrome 8
- P80A (p.Pro80Ala), Ensembl rs1595837594, REVEL 0.25, MetaLR 0.67, Likely benign
- P80R (p.Pro80Arg), Ensembl rs2043137679, REVEL 0.22, MetaLR 0.72
- P80S (p.Pro80Ser), rs1595837594, ClinGen CA393098626, ClinVar RCV002459556, ClinVar RCV003101779, REVEL 0.22, MetaLR 0.66, Conflicting interpretations, Cardiovascular phenotype; Brugada syndrome 8
- A81G (p.Ala81Gly), Ensembl rs1595837586
- R82H (p.Arg82His), rs1170776732, ClinGen CA393098608, ClinVar RCV000619278, TOPMed rs1170776732, REVEL 0.29, MetaLR 0.66, Uncertain significance, Cardiovascular phenotype
- R82P (p.Arg82Pro), rs1170776732, ClinGen CA393098607, ClinVar RCV003613555, REVEL 0.39, MetaLR 0.69, Uncertain significance, Brugada syndrome 8
- G83D (p.Gly83Asp), ExAC rs770361300, gnomAD rs770361300, REVEL 0.21, MetaLR 0.72
- G83R (p.Gly83Arg), rs2043137577, ClinGen CA393098602, ClinVar RCV001050282, TOPMed rs2043137577, REVEL 0.27, MetaLR 0.66, Uncertain significance, Brugada syndrome 8
- G83S (p.Gly83Ser), TOPMed rs2043137577, REVEL 0.32, MetaLR 0.65, Uncertain significance, Cardiovascular phenotype
- G83V (p.Gly83Val), ExAC rs770361300, gnomAD rs770361300, REVEL 0.19, MetaLR 0.71
- A84E (p.Ala84Glu), NCI-TCGA TCGA novel, REVEL 0.29, MetaLR 0.63, Variant assessed as somatic; moderate impact.
- A84T (p.Ala84Thr), rs1266912247, ClinGen CA393098595, ClinVar RCV003384155, TOPMed rs1266912247, REVEL 0.23, MetaLR 0.66, Uncertain significance, Cardiovascular phenotype
- A84V (p.Ala84Val), rs2151228645, ClinGen CA393098588, ClinVar RCV001870620, Ensembl rs2151228645, REVEL 0.23, MetaLR 0.71, Uncertain significance, Brugada syndrome 8
- G85D (p.Gly85Asp), gnomAD rs1397898750, REVEL 0.39, MetaLR 0.64, Uncertain significance
- G85V (p.Gly85Val), rs1397898750, ClinGen CA393098580, ClinVar RCV001309105, ClinVar RCV004034191, REVEL 0.37, MetaLR 0.60, Uncertain significance, Cardiovascular phenotype; Brugada syndrome 8
- K86* (p.Lys86Ter), rs1472909888, ClinGen CA393098576, ClinVar RCV003022401, CADD 36.00, Uncertain significance
- K86N (p.Lys86Asn), TOPMed rs1019029244, gnomAD rs1019029244, REVEL 0.24, MetaLR 0.80, Likely benign
- K86Q (p.Lys86Gln), gnomAD rs1472909888, REVEL 0.33, MetaLR 0.83
- K86R (p.Lys86Arg), rs549753996, ClinGen CA272700475, ClinVar RCV003384152, ClinVar RCV003614233, REVEL 0.25, MetaLR 0.76, Uncertain significance, Cardiovascular phenotype; Brugada syndrome 8
- S87C (p.Ser87Cys), rs866449137, ClinGen CA393098564, ClinVar RCV001322716, ClinVar RCV005911044, AlphaMissense 0.29, MetaLR 0.76, Uncertain significance, not specified; Brugada syndrome 8
- S87F (p.Ser87Phe), Ensembl rs866449137, REVEL 0.36, AlphaMissense 0.29, Uncertain significance
- S88N (p.Ser88Asn), rs1060500108, ClinGen CA16614926, ClinVar RCV000471352, gnomAD rs1060500108, REVEL 0.23, MetaLR 0.79, Uncertain significance, Brugada syndrome 8
- S88R (p.Ser88Arg), TOPMed rs1265825959, gnomAD rs1265825959, REVEL 0.28, MetaLR 0.82
- T89M (p.Thr89Met), TOPMed rs1459039632, gnomAD rs1459039632, REVEL 0.26, MetaLR 0.75, Uncertain significance, Brugada syndrome 8
- T89R (p.Thr89Arg), TOPMed rs1459039632, gnomAD rs1459039632, REVEL 0.28, MetaLR 0.75
- N90K (p.Asn90Lys), rs2043137309, ClinGen CA393098532, ClinVar RCV004118635, ClinVar RCV005099677, REVEL 0.49, MetaLR 0.93, Uncertain significance, Cardiovascular phenotype; Brugada syndrome 8
- G91R (p.Gly91Arg), rs746252218, ClinGen CA393098529, ClinVar RCV002023050, ClinVar RCV003303644, REVEL 0.59, MetaLR 0.97, Uncertain significance, Cardiovascular phenotype; Brugada syndrome 8
- G91S (p.Gly91Ser), rs746252218, ClinGen CA7649491, ClinVar RCV003615487, ClinVar RCV004634350, REVEL 0.52, MetaLR 0.97, Uncertain significance, Brugada syndrome 8; Cardiovascular phenotype
- D92G (p.Asp92Gly), rs2549080544, ClinGen CA393098517, ClinVar RCV004547271, ClinVar RCV004621955, REVEL 0.60, MetaLR 0.95, Uncertain significance, Cardiovascular phenotype; Epilepsy, idiopathic generalized, susceptibility to, 1
- D92N (p.Asp92Asn), rs2151228629, ClinGen CA393098523, ClinVar RCV002005353, Ensembl rs2151228629, REVEL 0.47, MetaLR 0.95, Uncertain significance, Brugada syndrome 8
- C93S (p.Cys93Ser), Ensembl rs1253825124
- R94K (p.Arg94Lys), Ensembl rs2151228625, REVEL 0.39, MetaLR 0.88
- R94S (p.Arg94Ser), gnomAD rs1199371021, REVEL 0.57, MetaLR 0.89
- R95L (p.Arg95Leu), gnomAD rs1321152002, REVEL 0.43, MetaLR 0.89
Public HCN4 analysis runs
- HCN4 analysis run — HCN4 (2,147 variants) — completed 2026-08-18