NKX2-5 (Homeobox protein Nkx-2.5) variants and mutations
NKX2-5 (also known as Homeobox protein Nkx-2.5) is a human protein-coding gene encoding a homeobox protein Nkx-2.5 protein. It specifies myocardial lineages and maintains genes needed for adult conduction and contractile function. Heterozygous pathogenic variants can cause congenital heart defects, especially atrial septal defects, often with progressive conduction disease. This analysis covers 920 NKX2-5 variants and mutations. Of these, 84% have computational variant effect predictions. Disease context includes Atrial septal defect - atrioventricular conduction defects, atrial septal defect 7, and Tetralogy of Fallot. Example NKX2-5 variants include M1K, S4G, and S4N.
Variant analysis overview
- Gene: NKX2-5
- Protein: Homeobox protein Nkx-2.5
- UniProt accession: P52952
- Organism: Homo sapiens
- Variants analyzed: 920
- Variant scope: all variants
- Completed: 2026-08-22
Variant and mutation evidence
- Variant composition: 603 unspecified-consequence records; 149 synonymous variants; 135 missense variants; 12 frameshift variants; 9 in-frame deletions; 3 in-frame insertions; 1 protein altering variant; 6 stop-gained variants; 2 stop retained variant; 7 stop lost; 1 splice-region variants; 4 substitution
- Prediction scores: 775 variants have prediction scores (84% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: Atrial septal defect - atrioventricular conduction defects, atrial septal defect 7, Tetralogy of Fallot, atrial septal defect, hypothyroidism, congenital, nongoitrous, 5, ventricular septal defect 3, hypoplastic left heart syndrome 2, conotruncal heart malformations, Abnormality of the cardiovascular system, atrial fibrillation, congenital heart disease, neurodegenerative disease.
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 NKX2-5 variants
Examples include M1K, S4G, S4N, P5R, P5S, P5T, A6G, A6T. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- M1K (p.Met1Lys), rs1761447434, ClinGen CA362163892, ClinVar RCV004518926, MetaLR 0.92, MetaSVM 0.50, Uncertain significance, Cardiovascular phenotype
- S4G (p.Ser4Gly), rs1270909226, ClinGen CA362163872, ClinVar RCV003509233, TOPMed rs1270909226, REVEL 0.69, CADD 28.20, Uncertain significance, Atrial septal defect 7
- S4N (p.Ser4Asn), TOPMed rs1341734909, gnomAD rs1341734909, REVEL 0.58, CADD 26.40
- P5R (p.Pro5Arg), rs2480080911, ClinGen CA362163861, ClinVar RCV003090716, ClinVar RCV003358081, REVEL 0.68, CADD 27.00, Uncertain significance, Atrial septal defect 7; Cardiovascular phenotype
- P5S (p.Pro5Ser), rs769233111, ClinGen CA3563864, ClinVar RCV000702042, ClinVar RCV002388316, REVEL 0.54, CADD 23.10, Uncertain significance, Hypothyroidism, congenital, nongoitrous, 5; Ventricular septal defect 3; Hypopla
- P5T (p.Pro5Thr), ExAC rs769233111, TOPMed rs769233111, gnomAD rs769233111, Uncertain significance
- A6G (p.Ala6Gly), Ensembl rs1561621781, REVEL 0.21, CADD 22.50
- A6T (p.Ala6Thr), ExAC rs780812253, gnomAD rs780812253, REVEL 0.26, CADD 20.40
- L7P (p.Leu7Pro), UniProt VAR 038212, Pathogenic, in ASD7
- L7V (p.Leu7Val), TOPMed rs1277858223, gnomAD rs1277858223, REVEL 0.26, CADD 18.30
- T8A (p.Thr8Ala), gnomAD rs1485780506
- T8M (p.Thr8Met), cosmic curated COSV61298, ExAC rs768954078, TOPMed rs768954078, gnomAD rs768954078, REVEL 0.59, AlphaMissense 0.34
- T8R (p.Thr8Arg), rs768954078, ClinGen CA362163844, ClinVar RCV003620755, AlphaMissense 0.34, MetaLR 0.92, Uncertain significance, Atrial septal defect 7
- F12S (p.Phe12Ser), rs1085307815, ClinGen CA362163821, ClinVar RCV000489523, Ensembl rs1085307815, AlphaMissense 1.00, MetaLR 0.92, Uncertain significance, not provided
- F12V (p.Phe12Val), gnomAD rs1363368305, REVEL 0.93, CADD 29.60
- V14A (p.Val14Ala), 1000Genomes rs2113906894, REVEL 0.85, CADD 28.90
- K15I (p.Lys15Ile), rs387906773, ClinGen CA212677, ClinVar RCV000023020, UniProt VAR 038213, AlphaMissense 0.97, MetaLR 0.90, Pathogenic, Atrial septal defect 7
- D16A (p.Asp16Ala), rs17052019, UniProt VAR 049581, Ensembl rs17052019, AlphaMissense 0.99, MetaLR 0.93
- D16N (p.Asp16Asn), rs750904275, ClinGen CA3563857, ClinVar RCV001967393, ExAC rs750904275, REVEL 0.62, CADD 24.50, Uncertain significance, Atrial septal defect 7
- I17V (p.Ile17Val), TOPMed rs1176053334, gnomAD rs1176053334, REVEL 0.68, CADD 23.60
- N19S (p.Asn19Ser), UniProt VAR 038214, Pathogenic, in ASD7
- L20P (p.Leu20Pro), rs1471444031, ClinGen CA362163769, ClinVar RCV000621382, ClinVar RCV003619711, REVEL 0.72, CADD 25.10, Uncertain significance, Atrial septal defect 7; Cardiovascular phenotype
- E21D (p.Glu21Asp), 1000Genomes rs2277923, ESP rs2277923, ExAC rs2277923, TOPMed rs2277923, Benign, in TOF and ASD7
- E21Q (p.Glu21Gln), rs104893904, ClinGen CA214394, cosmic curated COSV61298, ClinVar RCV000009574, REVEL 0.78, CADD 25.10, Conflicting interpretations, Cardiovascular phenotype; not specified; not provided
- Q22E (p.Gln22Glu), rs764389026, ClinGen CA3563855, ClinVar RCV003620428, ClinVar RCV004374323, REVEL 0.48, CADD 22.90, Uncertain significance, Cardiovascular phenotype; Atrial septal defect 7
- Q22K (p.Gln22Lys), rs764389026, ClinGen CA362163759, ClinVar RCV002248048, ExAC rs764389026, REVEL 0.66, CADD 23.10, Likely pathogenic, Atrial septal defect 7
- Q22P (p.Gln22Pro), rs201442000, ClinGen CA132260566, ClinVar RCV000542359, ClinVar RCV000786392, REVEL 0.82, CADD 24.00, Uncertain significance, not provided; Atrial septal defect 7; Ventricular septal defect 3
- Q22R (p.Gln22Arg), rs201442000, ClinGen CA206627, cosmic curated COSV61299, ClinVar RCV000193266, REVEL 0.65, CADD 23.60, Uncertain significance, Cardiovascular phenotype; not specified; not provided
- Q23H (p.Gln23His), gnomAD rs1761443946, REVEL 0.20, CADD 16.10
- Q23K (p.Gln23Lys), TOPMed rs1761444032, REVEL 0.33, CADD 21.40
- Q24R (p.Gln24Arg), ExAC rs751398261, TOPMed rs751398261, gnomAD rs751398261, REVEL 0.34, CADD 22.40
- R25C (p.Arg25Cys), rs28936670, ClinGen CA120055, cosmic curated COSV61298, ClinVar RCV000009572, REVEL 0.35, CADD 23.20, Conflicting interpretations, Cardiovascular phenotype; not specified; not provided
- R25L (p.Arg25Leu), ExAC rs762957966, gnomAD rs762957966, REVEL 0.28, CADD 19.00, Uncertain significance, Atrial septal defect 7
- S26N (p.Ser26Asn), gnomAD rs1375476320, REVEL 0.23, CADD 18.80
- S26R (p.Ser26Arg), rs2113906717, ClinGen CA362163729, ClinVar RCV004493269, REVEL 0.20, CADD 16.90, Uncertain significance, Cardiovascular phenotype
- A28T (p.Ala28Thr), rs1279595214, ClinGen CA362163723, ClinVar RCV000703980, ClinVar RCV003165900, REVEL 0.28, CADD 22.20, Conflicting interpretations, Cardiovascular phenotype; Atrial septal defect 7
- A29T (p.Ala29Thr), rs1554093718, ClinGen CA362163717, ClinVar RCV000617626, Ensembl rs1554093718, AlphaMissense 0.09, MetaLR 0.69, Uncertain significance, Cardiovascular phenotype
- A30D (p.Ala30Asp), rs1425683417, ClinGen CA362163708, ClinVar RCV000820710, TOPMed rs1425683417, REVEL 0.37, CADD 22.50, Uncertain significance, Atrial septal defect 7
- A30S (p.Ala30Ser), cosmic curated COSV61298, TOPMed rs1304644050, gnomAD rs1304644050, REVEL 0.18, CADD 14.50, Uncertain significance, Cardiovascular phenotype; Atrial septal defect 7
- A30T (p.Ala30Thr), rs1304644050, ClinGen CA362163711, cosmic curated COSV61299, ClinVar RCV001858880, REVEL 0.20, CADD 16.20, Uncertain significance, Atrial septal defect 7; Cardiovascular phenotype
- G31R (p.Gly31Arg), rs1360215151, ClinGen CA362163705, cosmic curated COSV10733, ClinVar RCV001208962, REVEL 0.15, CADD 19.00, Uncertain significance, Atrial septal defect 7; Cardiovascular phenotype
- G31V (p.Gly31Val), ExAC rs769355297, gnomAD rs769355297
- E32D (p.Glu32Asp), rs776310516, ClinGen CA3563847, ClinVar RCV001061180, ClinVar RCV006556972, REVEL 0.35, CADD 13.10, Uncertain significance, Atrial septal defect 7; Conotruncal heart malformations; Hypothyroidism, congeni
- E32K (p.Glu32Lys), 1000Genomes rs552617433, ExAC rs552617433, REVEL 0.34, CADD 22.00
- L33F (p.Leu33Phe), rs1048146799, ClinGen CA132260474, ClinVar RCV003360656, ClinVar RCV006472440, AlphaMissense 0.11, MetaLR 0.83, Uncertain significance, Cardiovascular phenotype; Atrial septal defect 7
- S34P (p.Ser34Pro), rs2480080381, ClinGen CA362163687, ClinVar RCV002442246, Uncertain significance, Cardiovascular phenotype
- A35T (p.Ala35Thr), rs2480080369, ClinGen CA362163683, ClinVar RCV003944383, Uncertain significance, NKX2-5-related disorder
- A35V (p.Ala35Val), ExAC rs768386936, TOPMed rs768386936, REVEL 0.23, CADD 20.30
- R36C (p.Arg36Cys), gnomAD rs1172036454, REVEL 0.51, CADD 26.20, Uncertain significance, Atrial septal defect 7
- R36H (p.Arg36His), rs948440843, ClinGen CA362163674, ClinVar RCV002644261, REVEL 0.26, CADD 22.60, Uncertain significance, Atrial septal defect 7
- R36L (p.Arg36Leu), Ensembl rs948440843, REVEL 0.31, CADD 22.50, Uncertain significance, Atrial septal defect 7
- E38K (p.Glu38Lys), TOPMed rs1302984436, REVEL 0.36, CADD 22.80
- E38Q (p.Glu38Gln), TOPMed rs1302984436
- A39E (p.Ala39Glu), TOPMed rs1234717083, gnomAD rs1234717083, REVEL 0.24, CADD 23.80, Uncertain significance
- A39G (p.Ala39Gly), rs1234717083, ClinGen CA362163656, ClinVar RCV001203285, TOPMed rs1234717083, REVEL 0.30, CADD 22.80, Uncertain significance, Atrial septal defect 7
- A39T (p.Ala39Thr), Ensembl rs1761440143
- A39V (p.Ala39Val), NCI-TCGA Cosmic COSV1002, cosmic curated COSV10023, TOPMed rs1234717083, gnomAD rs1234717083, Uncertain significance
- T40I (p.Thr40Ile), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- A42E (p.Ala42Glu), TOPMed rs1761439619, Uncertain significance
- A42P (p.Ala42Pro), rs113818864, ClinGen CA302112, ClinVar RCV000470357, ClinVar RCV001573768, REVEL 0.53, CADD 21.20, Likely benign, Cardiovascular phenotype; not specified; not provided
- A42T (p.Ala42Thr), rs113818864, ClinGen CA362163642, ClinVar RCV002297844, 1000Genomes rs113818864, REVEL 0.21, CADD 20.20, Uncertain significance, Atrial septal defect 7
- A42V (p.Ala42Val), rs1761439619, ClinGen CA362163639, ClinVar RCV001928843, TOPMed rs1761439619, REVEL 0.24, CADD 22.10, Uncertain significance, Atrial septal defect 7
- S45A (p.Ser45Ala), ExAC rs779548360, TOPMed rs779548360, gnomAD rs779548360, REVEL 0.45, AlphaMissense 0.21, Uncertain significance, in ASD7
- S45F (p.Ser45Phe), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact., in ASD7
- S45P (p.Ser45Pro), rs779548360, ClinGen CA132260457, cosmic curated COSV61298, ClinVar RCV002387691, AlphaMissense 0.21, MetaLR 0.81, Uncertain significance, Atrial septal defect 7; Cardiovascular phenotype
- C46R (p.Cys46Arg), Ensembl rs1761439288
- C46S (p.Cys46Ser), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- L48P (p.Leu48Pro), rs1284932088, ClinGen CA362163603, ClinVar RCV003874305, ClinVar RCV005445996, AlphaMissense 0.53, MetaLR 0.92, Uncertain significance, Cardiovascular phenotype; Atrial septal defect 7
- F51L (p.Phe51Leu), rs753937287, NCI-TCGA Cosmic COSV1002, cosmic curated COSV10023, UniProt VAR 038218, AlphaMissense 0.85, MetaLR 0.48, Pathogenic, in ASD7
- K52M (p.Lys52Met), NCI-TCGA Cosmic COSV1002, cosmic curated COSV10023, Variant assessed as somatic; moderate impact.
- K52N (p.Lys52Asn), rs1405115548, ClinGen CA362163575, ClinVar RCV002710888, Uncertain significance, Atrial septal defect 7
- K52Q (p.Lys52Gln), ExAC rs777670902, gnomAD rs777670902, REVEL 0.39, CADD 27.80
- E54* (p.Glu54Ter), NCI-TCGA Cosmic COSV6130, cosmic curated COSV61300, Variant assessed as somatic; high impact.
- E54D (p.Glu54Asp), TOPMed rs867314114, gnomAD rs867314114
- E54V (p.Glu54Val), TOPMed rs1261741680, gnomAD rs1261741680, REVEL 0.59, CADD 23.80
- A55T (p.Ala55Thr), Ensembl rs567939950, REVEL 0.20, CADD 21.60
- Y56* (p.Tyr56Ter), rs756377692, ClinGen CA362163549, ClinVar RCV002819875, Pathogenic
- Y56C (p.Tyr56Cys), rs1360861650, ClinGen CA362163552, ClinVar RCV001992802, gnomAD rs1360861650, REVEL 0.34, CADD 23.00, Uncertain significance, Atrial septal defect 7
- A57D (p.Ala57Asp), gnomAD rs1346280352, REVEL 0.17, CADD 18.10, Uncertain significance, not provided
- A57P (p.Ala57Pro), rs549161381, ClinGen CA132260439, ClinVar RCV002595959, ClinVar RCV003130847, REVEL 0.18, CADD 17.30, Uncertain significance, Cardiovascular phenotype; not provided; Atrial septal defect 7
- A57S (p.Ala57Ser), rs549161381, ClinGen CA3563838, ClinVar RCV001321197, ClinVar RCV001773641, REVEL 0.17, CADD 11.50, Conflicting interpretations, not provided; Conotruncal heart malformations; Atrial septal defect 7
- A57V (p.Ala57Val), gnomAD rs1346280352, Uncertain significance
- G58V (p.Gly58Val), rs1012750146, ClinGen CA132260438, ClinVar RCV000621821, ClinVar RCV001038484, REVEL 0.43, CADD 22.90, Conflicting interpretations, Atrial septal defect 7; Cardiovascular phenotype
- G58W (p.Gly58Trp), Ensembl rs2113906394
- P59A (p.Pro59Ala), rs387906775, ClinGen CA212680, ClinVar RCV000023024, UniProt VAR 067586, REVEL 0.52, CADD 17.80, Pathogenic, Ventricular septal defect 3
- E60K (p.Glu60Lys), rs766199339, ClinGen CA362163534, cosmic curated COSV61299, ClinVar RCV002917438, REVEL 0.29, CADD 22.10, Uncertain significance, Atrial septal defect 7
- E60Q (p.Glu60Gln), rs766199339, ClinGen CA3563837, cosmic curated COSV10023, ClinVar RCV001318738, REVEL 0.19, CADD 20.80, Conflicting interpretations, Hypothyroidism, congenital, nongoitrous, 5; Ventricular septal defect 3; Hypopla
- A61G (p.Ala61Gly), rs864321650, ClinGen CA279938, ClinVar RCV000203543, TOPMed rs864321650, AlphaMissense 0.08, MetaLR 0.64, Pathogenic, Congenital heart disease
- A61V (p.Ala61Val), rs864321650, ClinGen CA362163523, ClinVar RCV002904410, TOPMed rs864321650, REVEL 0.17, AlphaMissense 0.08, Uncertain significance, Atrial septal defect 7
- A63E (p.Ala63Glu), 1000Genomes rs530270916, ExAC rs530270916, TOPMed rs530270916, gnomAD rs530270916, REVEL 0.13, CADD 12.70, Likely benign, in ASD7
- A63S (p.Ala63Ser), NCI-TCGA Cosmic COSV6130, cosmic curated COSV61300, Variant assessed as somatic; moderate impact., in ASD7
- A63T (p.Ala63Thr), ExAC rs765129454, gnomAD rs765129454, REVEL 0.26, CADD 13.90, Uncertain significance, Atrial septal defect 7
- A63V (p.Ala63Val), rs530270916, ClinGen CA3563832, ClinVar RCV001055047, ClinVar RCV002255174, REVEL 0.47, CADD 16.80, Conflicting interpretations, Atrial septal defect 7; Conotruncal heart malformations; Ventricular septal defe
- P64R (p.Pro64Arg), ExAC rs763458137, gnomAD rs763458137, REVEL 0.10, CADD 19.20
- L66F (p.Leu66Phe), rs1202883517, ClinGen CA362163500, ClinVar RCV003131808, 1000Genomes rs1202883517, REVEL 0.28, CADD 24.10, Uncertain significance, not provided
- P67A (p.Pro67Ala), rs2480079901, ClinGen CA362163495, ClinVar RCV003360661, Uncertain significance, Cardiovascular phenotype
- P67L (p.Pro67Leu), rs2113906300, ClinGen CA362163493, ClinVar RCV001991449, Ensembl rs2113906300, AlphaMissense 0.15, MetaLR 0.51, Uncertain significance, Atrial septal defect 7
- P67S (p.Pro67Ser), rs2480079901, ClinGen CA362163494, ClinVar RCV002417069, Uncertain significance, Cardiovascular phenotype
- E68D (p.Glu68Asp), Ensembl rs2113906286
- L69P (p.Leu69Pro), UniProt VAR 038220, REVEL 0.26, CADD 22.50, Pathogenic, in ASD7
- L69R (p.Leu69Arg), rs1032793565, ClinGen CA132260410, ClinVar RCV000644445, TOPMed rs1032793565, AlphaMissense 0.14, MetaLR 0.66, Uncertain significance, Atrial septal defect 7
- L69V (p.Leu69Val), gnomAD rs1459934714, REVEL 0.22, CADD 18.40
- R70C (p.Arg70Cys), cosmic curated COSV61298, Ensembl rs2113906257, REVEL 0.28, CADD 22.40
- R70H (p.Arg70His), NCI-TCGA Cosmic COSV6129, cosmic curated COSV61299, Variant assessed as somatic; moderate impact.
- A71P (p.Ala71Pro), rs772542981, ClinGen CA3563828, ClinVar RCV003619378, ClinVar RCV004763754, REVEL 0.10, CADD 16.90, Conflicting interpretations, Atrial septal defect 7; not provided
- A71T (p.Ala71Thr), rs772542981, ExAC rs772542981, gnomAD rs772542981, REVEL 0.15, CADD 15.60, Uncertain significance
- G74D (p.Gly74Asp), rs201362118, UniProt VAR 069058, 1000Genomes rs201362118, ExAC rs201362118, REVEL 0.37, CADD 16.10
- G74R (p.Gly74Arg), rs1478644699, gnomAD 5-173233447-C-T, CADD 7.01
- G74G (p.Gly74Gly), rs571495972, gnomAD 5-173233463-C-T, CADD 7.35
- G74A (p.Gly74Ala), rs1451685747, gnomAD 5-173233464-C-G, CADD 12.40
- R75C (p.Arg75Cys), rs1216673146, ClinGen CA362163449, ClinVar RCV001754501, TOPMed rs1216673146, REVEL 0.33, CADD 22.80, Uncertain significance, not provided
- R75G (p.Arg75Gly), rs1216673146, ClinGen CA362163448, ClinVar RCV001907978, TOPMed rs1216673146, REVEL 0.25, CADD 20.40, Uncertain significance, Cardiovascular phenotype; Atrial septal defect 7
- R75H (p.Arg75His), rs1363174603, NCI-TCGA Cosmic COSV6129, cosmic curated COSV61298, gnomAD rs1363174603, REVEL 0.27, CADD 21.00, Uncertain significance
- R75L (p.Arg75Leu), rs1363174603, ClinGen CA362163444, ClinVar RCV001872366, gnomAD rs1363174603, REVEL 0.27, CADD 19.70, Uncertain significance, Atrial septal defect 7
- A76E (p.Ala76Glu), rs1761435522, ClinGen CA362163440, ClinVar RCV002570997, AlphaMissense 0.08, MetaLR 0.40, Uncertain significance, Atrial septal defect 7
- A76G (p.Ala76Gly), TOPMed rs1761435522
- A76T (p.Ala76Thr), NCI-TCGA TCGA novel, REVEL 0.32, CADD 13.00, Variant assessed as somatic; moderate impact.
- P77L (p.Pro77Leu), UniProt VAR 038221, REVEL 0.25, CADD 20.40, Pathogenic, in ASD7
- P77S (p.Pro77Ser), rs771593440, ClinGen CA3563825, ClinVar RCV001984543, ClinVar RCV004042122, REVEL 0.22, CADD 14.80, Uncertain significance, Atrial septal defect 7; Cardiovascular phenotype
- S78L (p.Ser78Leu), Ensembl rs1761435193
- S78P (p.Ser78Pro), ExAC rs749763672, TOPMed rs749763672, gnomAD rs749763672, REVEL 0.27, CADD 21.00
- P79Q (p.Pro79Gln), rs777921797, ClinGen CA362163424, cosmic curated COSV10023, ClinVar RCV003620481, REVEL 0.25, CADD 17.70, Uncertain significance, Cardiovascular phenotype; Atrial septal defect 7
- P79R (p.Pro79Arg), rs777921797, ClinGen CA3563821, ClinVar RCV001371618, ExAC rs777921797, REVEL 0.28, CADD 18.30, Likely benign, Atrial septal defect 7
- P79S (p.Pro79Ser), TOPMed rs1337440208, gnomAD rs1337440208, REVEL 0.28, CADD 15.40
- A80S (p.Ala80Ser), rs1761434661, ClinGen CA362163420, ClinVar RCV004518924, REVEL 0.15, CADD 9.96, Uncertain significance, Cardiovascular phenotype
- A80T (p.Ala80Thr), TOPMed rs1761434661, REVEL 0.12, CADD 13.00, Uncertain significance, Cardiovascular phenotype
- A80V (p.Ala80Val), Ensembl rs2113906096
- K81E (p.Lys81Glu), rs904474688, ClinGen CA132260367, ClinVar RCV000644447, TOPMed rs904474688, REVEL 0.33, CADD 21.10, Uncertain significance, Atrial septal defect 7
- K81N (p.Lys81Asn), gnomAD rs1172891428, REVEL 0.26, CADD 20.60
- C82S (p.Cys82Ser), 1000Genomes rs150813574, ExAC rs150813574, gnomAD rs150813574, REVEL 0.22, CADD 17.90, Uncertain significance, not provided; not specified; Atrial septal defect 7
- C82Y (p.Cys82Tyr), rs1333780727, ClinGen CA362163407, ClinVar RCV004518925, ClinVar RCV005412658, AlphaMissense 0.14, MetaLR 0.59, Uncertain significance, not provided; Cardiovascular phenotype
- A83G (p.Ala83Gly), rs1182777346, ClinGen CA362163399, ClinVar RCV001322934, ClinVar RCV002431920, REVEL 0.17, CADD 15.90, Uncertain significance, Atrial septal defect 7; Conotruncal heart malformations; Tetralogy of Fallot
- A83T (p.Ala83Thr), rs750249799, ClinGen CA3563818, ClinVar RCV000520166, ClinVar RCV004023619, REVEL 0.25, CADD 12.40, Conflicting interpretations, Cardiovascular phenotype; Atrial septal defect 7; not provided
- A83V (p.Ala83Val), rs1182777346, NCI-TCGA Cosmic COSV6129, cosmic curated COSV61298, ClinGen CA362163398, REVEL 0.28, CADD 16.90, Uncertain significance, Cardiovascular phenotype
- S84C (p.Ser84Cys), ExAC rs764967109, gnomAD rs764967109, REVEL 0.32, CADD 22.20
- F86S (p.Phe86Ser), rs373807012, ClinGen CA3563815, ClinVar RCV002026496, ESP rs373807012, REVEL 0.49, CADD 24.20, Likely benign, Atrial septal defect 7
- P87S (p.Pro87Ser), rs1352813413, ClinGen CA362163377, ClinVar RCV002426202, ClinVar RCV003619799, REVEL 0.20, CADD 17.80, Conflicting interpretations, Cardiovascular phenotype; Atrial septal defect 7
- A88T (p.Ala88Thr), gnomAD rs1206097183, REVEL 0.22, CADD 12.00
- A89D (p.Ala89Asp), rs2113905976, ClinGen CA362163364, ClinVar RCV001865079, Ensembl rs2113905976, AlphaMissense 0.22, MetaLR 0.67, Uncertain significance, Atrial septal defect 7
- A89P (p.Ala89Pro), rs1761432750, ClinGen CA362163366, ClinVar RCV001344340, TOPMed rs1761432750, AlphaMissense 0.08, MetaLR 0.61, Uncertain significance, Atrial septal defect 7
- A89S (p.Ala89Ser), NCI-TCGA TCGA novel, REVEL 0.14, CADD 14.10, Variant assessed as somatic; moderate impact.
- A89T (p.Ala89Thr), TOPMed rs1761432750, gnomAD rs1761432750, REVEL 0.18, AlphaMissense 0.08, Uncertain significance
- P90L (p.Pro90Leu), gnomAD rs1169653363, REVEL 0.23, CADD 23.10, Uncertain significance, Cardiovascular phenotype
- P90T (p.Pro90Thr), cosmic curated COSV10023, gnomAD rs1307727464, REVEL 0.22, CADD 19.40
- A91P (p.Ala91Pro), gnomAD rs1314752131, REVEL 0.34, CADD 16.90
- F92V (p.Phe92Val), rs2480079424, ClinGen CA362163347, ClinVar RCV003078470, REVEL 0.50, CADD 23.30, Uncertain significance, Atrial septal defect 7
- Y93* (p.Tyr93Ter), rs2480079410, ClinGen CA362163335, ClinVar RCV003510652, Pathogenic
- P94A (p.Pro94Ala), NCI-TCGA Cosmic COSV1002, cosmic curated COSV10023, Variant assessed as somatic; moderate impact.
- P94S (p.Pro94Ser), rs1009994744, ClinGen CA132260347, ClinVar RCV000549035, ClinVar RCV004730979, AlphaMissense 0.09, MetaLR 0.53, Uncertain significance, Atrial septal defect 7
- R95C (p.Arg95Cys), rs1244289450, NCI-TCGA Cosmic COSV6129, cosmic curated COSV61299, gnomAD rs1244289450, REVEL 0.27, CADD 25.40, Uncertain significance, Cardiovascular phenotype
- R95G (p.Arg95Gly), rs1244289450, ClinGen CA362163327, ClinVar RCV003062839, REVEL 0.23, CADD 22.90, Uncertain significance, Atrial septal defect 7
- R95H (p.Arg95His), cosmic curated COSV10813, ExAC rs763729448, TOPMed rs763729448, gnomAD rs763729448, REVEL 0.25, CADD 23.20, Uncertain significance
- R95L (p.Arg95Leu), rs763729448, ClinGen CA3563814, ClinVar RCV001302062, ClinVar RCV002437025, REVEL 0.28, CADD 23.00, Conflicting interpretations, Cardiovascular phenotype; Atrial septal defect 7
- A96T (p.Ala96Thr), rs2480079367, ClinGen CA362163323, ClinVar RCV002437668, REVEL 0.25, CADD 17.90, Uncertain significance, Cardiovascular phenotype
- A96V (p.Ala96Val), rs760088847, ClinGen CA3563813, ClinVar RCV000798171, ExAC rs760088847, REVEL 0.16, CADD 22.70, Uncertain significance, Atrial septal defect 7
- Y97* (p.Tyr97Ter), rs2480079337, ClinGen CA362163312, ClinVar RCV003620674, ClinVar RCV004371647, Pathogenic
- S98R (p.Ser98Arg), gnomAD rs1394343969, REVEL 0.11, CADD 15.10
- S98T (p.Ser98Thr), rs2480079332, ClinGen CA362163306, ClinVar RCV003360657, Uncertain significance, Cardiovascular phenotype
- D99N (p.Asp99Asn), NCI-TCGA Cosmic COSV6129, cosmic curated COSV61298, REVEL 0.26, CADD 22.90, Variant assessed as somatic; moderate impact.
- D99Y (p.Asp99Tyr), rs1761431105, ClinGen CA362163300, ClinVar RCV001954580, ClinVar RCV006352638, REVEL 0.21, CADD 24.00, Uncertain significance, Atrial septal defect 7; Cardiovascular phenotype
- P100A (p.Pro100Ala), rs550046293, ClinGen CA3563812, ClinVar RCV000226256, ExAC rs550046293, REVEL 0.14, CADD 16.00, Likely benign, Cardiovascular phenotype; not specified; Atrial septal defect 7
- P100L (p.Pro100Leu), rs2480079313, ClinGen CA362163291, ClinVar RCV002833755, REVEL 0.29, CADD 21.80, Uncertain significance, Atrial septal defect 7
- P100T (p.Pro100Thr), rs550046293, ClinGen CA132260336, ClinVar RCV000701268, ClinVar RCV002440511, REVEL 0.17, CADD 17.60, Conflicting interpretations, Cardiovascular phenotype; Atrial septal defect 7
- D101G (p.Asp101Gly), rs2480079285, ClinGen CA362163286, ClinVar RCV003510378, NCI-TCGA Cosmic COSV6129, REVEL 0.23, CADD 23.40, Uncertain significance, Atrial septal defect 7
- D101N (p.Asp101Asn), rs1365219269, NCI-TCGA Cosmic COSV6129, cosmic curated COSV61298, TOPMed rs1365219269, REVEL 0.31, CADD 23.20, Variant assessed as somatic; moderate impact.
- D101V (p.Asp101Val), rs2480079285, ClinGen CA362163285, ClinVar RCV002690534, Uncertain significance, Atrial septal defect 7
- D101Y (p.Asp101Tyr), TOPMed rs1365219269, gnomAD rs1365219269, REVEL 0.40, CADD 26.80
- P102Q (p.Pro102Gln), Ensembl rs1761430319, REVEL 0.18, CADD 18.50
- K104* (p.Lys104Ter), rs1761430125, ClinGen CA362163270, ClinVar RCV001058874, Ensembl rs1761430125, Pathogenic
- K104N (p.Lys104Asn), rs774878026, ClinVar RCV005405010, ExAC rs774878026, TOPMed rs774878026, REVEL 0.36, CADD 23.40, Uncertain significance, Cardiovascular phenotype
- P106L (p.Pro106Leu), rs1188239387, ClinVar RCV006588512, AlphaMissense 0.10, MetaLR 0.64, Uncertain significance, Atrial septal defect 7
- P106R (p.Pro106Arg), rs1188239387, ClinGen CA362163241, ClinVar RCV002322716, ClinVar RCV006616667, REVEL 0.19, AlphaMissense 0.10, Conflicting interpretations, Cardiovascular phenotype; Atrial septal defect 7
- P106S (p.Pro106Ser), Ensembl rs1761429871, REVEL 0.25, CADD 19.80
- P106P (p.Pro106Pro), rs770760092, gnomAD 5-173233451-G-A, CADD 14.70
- P106T (p.Pro106Thr), gnomAD 5-173233453-G-T, CADD 1.09
- R107S (p.Arg107Ser), ExAC rs771362938, gnomAD rs771362938, REVEL 0.16, CADD 15.30
- R107P (p.Arg107Pro), gnomAD 5-173233449-C-CG, CADD 2.68
- R107Q (p.Arg107Gln), rs1387273472, gnomAD 5-173233449-C-T, CADD 2.73
- R107G (p.Arg107Gly), rs1308631223, gnomAD 5-173233450-G-C, CADD 3.59
- R107R (p.Arg107Arg), gnomAD 5-173233450-G-T, CADD 3.44
Public NKX2-5 analysis runs
- NKX2-5 analysis run — NKX2-5 (920 variants) — completed 2026-08-22