NKX2-1 (Homeobox protein Nkx-2.1) variants and mutations
NKX2-1 (also known as Homeobox protein Nkx-2.1) is a human protein-coding gene encoding a homeobox protein Nkx-2.1 protein. It controls developmental and tissue-specific gene programs in lung, thyroid, and basal ganglia. Haploinsufficiency causes brain-lung-thyroid syndrome, variably combining chorea or developmental movement disorder, neonatal respiratory disease, and thyroid dysfunction. This analysis covers 1,196 NKX2-1 variants and mutations. Of these, 36% have computational variant effect predictions. Disease context includes brain-lung-thyroid syndrome, Benign familial chorea, and choreatic disease. Example NKX2-1 variants include M1?, S2L, and M3I.
Variant analysis overview
- Gene: NKX2-1
- Protein: Homeobox protein Nkx-2.1
- UniProt accession: P43699
- Organism: Homo sapiens
- Variants analyzed: 1196
- Variant scope: all variants
- Completed: 2026-08-20
Variant and mutation evidence
- Variant composition: 882 unspecified-consequence records; 1 stop lost; 90 synonymous variants; 198 missense variants; 7 in-frame deletions; 5 stop-gained variants; 9 frameshift variants; 2 in-frame insertions; 1 splice-region variants; 1 substitution
- Prediction scores: 434 variants have prediction scores (36% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: brain-lung-thyroid syndrome, Benign familial chorea, choreatic disease, hereditary disease, neurodegenerative disease, thyroid gland follicular carcinoma, NKX2-1 related choreoathetosis and congenital hypothyroidism with or without pul, thyroid cancer, nonmedullary, 1, non-small cell lung carcinoma, Abnormality of the skeletal system, gastric carcinoma, congenital hypothyroidism.
Protein structure and variant hotspots
- Protein features: 1 post-translational modification sites.
- PTM context: 7 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, MaveDB, LitVar.
Notable NKX2-1 variants
Examples include M1?, S2L, M3I, M3R, M3V, S4N, K6N, K6T. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- M1?, NCI-TCGA Cosmic COSV6138, cosmic curated COSV61388, cosmic curated COSV61389, Variant assessed as somatic; high impact.
- S2L (p.Ser2Leu), Ensembl rs2139412807
- M3I (p.Met3Ile), TOPMed rs1461014578, gnomAD rs1461014578, cosmic curated COSV10888
- M3R (p.Met3Arg), cosmic curated COSV10466
- M3V (p.Met3Val), gnomAD rs1159598878
- S4N (p.Ser4Asn), cosmic curated COSV10582, TOPMed rs1210385877
- K6N (p.Lys6Asn), gnomAD rs1415723316
- K6T (p.Lys6Thr), rs2502636519, ClinGen CA389461896, ClinVar RCV002684645, Uncertain significance, Inborn genetic diseases
- H7P (p.His7Pro), rs1881229890, ClinGen CA389461868, ClinVar RCV002702105, TOPMed rs1881229890, AlphaMissense 0.69, MetaLR 0.42, Uncertain significance, Inborn genetic diseases
- H7Q (p.His7Gln), rs758847127, ClinGen CA389461852, ClinVar RCV002690795, ClinVar RCV005445675, AlphaMissense 0.77, MetaLR 0.29, Uncertain significance, Inborn genetic diseases; not provided
- H7Y (p.His7Tyr), gnomAD rs1190397986
- T8A (p.Thr8Ala), ExAC rs750626194, gnomAD rs750626194
- T8M (p.Thr8Met), NCI-TCGA Cosmic COSV6138, cosmic curated COSV61388, NCI-TCGA Cosmic COSV6139, ExAC rs765587544, Variant assessed as somatic; moderate impact.
- T8R (p.Thr8Arg), cosmic curated COSV61390, ExAC rs765587544, gnomAD rs765587544
- P10A (p.Pro10Ala), ExAC rs762169593, gnomAD rs762169593
- P10L (p.Pro10Leu), NCI-TCGA Cosmic COSV6138, cosmic curated COSV61387, Variant assessed as somatic; moderate impact.
- F11L (p.Phe11Leu), cosmic curated COSV61390
- S12L (p.Ser12Leu), NCI-TCGA Cosmic COSV6138, cosmic curated COSV61387, Variant assessed as somatic; moderate impact.
- S14F (p.Ser14Phe), NCI-TCGA Cosmic COSV6138, cosmic curated COSV61389, Variant assessed as somatic; moderate impact.
- S14Y (p.Ser14Tyr), NCI-TCGA Cosmic COSV6138, cosmic curated COSV61389, Variant assessed as somatic; moderate impact.
- I16T (p.Ile16Thr), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- L17F (p.Leu17Phe), cosmic curated COSV61390
- S18C (p.Ser18Cys), Ensembl rs2139412719
- S18N (p.Ser18Asn), gnomAD rs1333571433
- P19F (p.Pro19Phe), cosmic curated COSV61390
- P19L (p.Pro19Leu), cosmic curated COSV61390
- P19T (p.Pro19Thr), cosmic curated COSV61388, ExAC rs776752141, TOPMed rs776752141, gnomAD rs776752141, Uncertain significance, not provided
- L20P (p.Leu20Pro), ExAC rs764140949, gnomAD rs764140949
- E21* (p.Glu21Ter), Ensembl rs2139412687
- E21A (p.Glu21Ala), cosmic curated COSV10526
- E21Q (p.Glu21Gln), Ensembl rs2139412687
- S23C (p.Ser23Cys), Ensembl rs2139412680
- S23N (p.Ser23Asn), cosmic curated COSV10888, gnomAD rs1269165387
- Y24F (p.Tyr24Phe), TOPMed rs1198235940
- K25N (p.Lys25Asn), NCI-TCGA Cosmic COSV1007, cosmic curated COSV10070, NCI-TCGA Cosmic COSV6138, cosmic curated COSV61388, Variant assessed as somatic; moderate impact.
- K25R (p.Lys25Arg), ExAC rs774163179, gnomAD rs774163179
- K26E (p.Lys26Glu), TOPMed rs1881227170
- V27L (p.Val27Leu), cosmic curated COSV61390, ESP rs140051139
- V27M (p.Val27Met), ESP rs140051139
- G28S (p.Gly28Ser), Ensembl rs1881226858
- G28V (p.Gly28Val), rs1050246022, ClinGen CA258878685, ClinVar RCV001915119, TOPMed rs1050246022, AlphaMissense 0.22, MetaLR 0.35, Uncertain significance, Inborn genetic diseases; not provided
- M29I (p.Met29Ile), NCI-TCGA Cosmic COSV6138, cosmic curated COSV61389, Variant assessed as somatic; moderate impact.
- M29K (p.Met29Lys), gnomAD rs1440785591
- M29T (p.Met29Thr), gnomAD rs1440785591
- E30G (p.Glu30Gly), Ensembl rs2139412619
- E30K (p.Glu30Lys), cosmic curated COSV10647
- E30V (p.Glu30Val), Ensembl rs2139412619
- G31S (p.Gly31Ser), TOPMed rs1881226119
- G32C (p.Gly32Cys), gnomAD rs1392451343
- G32D (p.Gly32Asp), Ensembl rs2139412580
- G32S (p.Gly32Ser), gnomAD rs1392451343
- G33A (p.Gly33Ala), TOPMed rs200134608, gnomAD rs200134608, Uncertain significance
- G33D (p.Gly33Asp), TOPMed rs200134608, gnomAD rs200134608, Uncertain significance
- G33S (p.Gly33Ser), NCI-TCGA Cosmic COSV1007, cosmic curated COSV10070, Variant assessed as somatic; moderate impact.
- G33V (p.Gly33Val), rs200134608, ClinGen CA258878671, ClinVar RCV002883520, ClinVar RCV003777883, AlphaMissense 0.47, MetaLR 0.21, Uncertain significance, not provided; Inborn genetic diseases
- L34I (p.Leu34Ile), rs201631950, ClinGen CA7158568, ClinVar RCV000861436, ClinVar RCV001109019, AlphaMissense 0.13, MetaLR 0.60, Conflicting interpretations, Brain-lung-thyroid syndrome; Benign hereditary chorea; not provided
- L34P (p.Leu34Pro), Ensembl rs2139412547
- G35R (p.Gly35Arg), cosmic curated COSV10442, TOPMed rs1367492025, gnomAD rs1367492025
- A36G (p.Ala36Gly), gnomAD rs1474322770
- A36S (p.Ala36Ser), Ensembl rs1881224424, Uncertain significance
- A36T (p.Ala36Thr), Ensembl rs1881224424, Uncertain significance, NKX2-1-Related Disorders
- A36V (p.Ala36Val), gnomAD rs1474322770
- P37L (p.Pro37Leu), Ensembl rs2139412510
- P37S (p.Pro37Ser), 1000Genomes rs182071645, ExAC rs182071645, gnomAD rs182071645
- P37T (p.Pro37Thr), 1000Genomes rs182071645, ExAC rs182071645, gnomAD rs182071645
- L38P (p.Leu38Pro), cosmic curated COSV10526, Uncertain significance, not provided
- A39E (p.Ala39Glu), rs1004953614, ClinGen CA258878650, ClinVar RCV003044295, TOPMed rs1004953614, AlphaMissense 0.17, MetaLR 0.26, Uncertain significance, not provided
- A39G (p.Ala39Gly), TOPMed rs1004953614, gnomAD rs1004953614, Uncertain significance
- A39V (p.Ala39Val), rs1004953614, NCI-TCGA Cosmic COSV1007, cosmic curated COSV10070, TOPMed rs1004953614, AlphaMissense 0.17, MetaLR 0.26, Uncertain significance
- A40E (p.Ala40Glu), Ensembl rs2139412475
- A40G (p.Ala40Gly), Ensembl rs2139412475
- A40T (p.Ala40Thr), TOPMed rs1215035228, gnomAD rs1215035228
- A40V (p.Ala40Val), Ensembl rs2139412475
- Y41D (p.Tyr41Asp), TOPMed rs1881222714, gnomAD rs1881222714
- Y41H (p.Tyr41His), TOPMed rs1881222714, gnomAD rs1881222714
- R42S (p.Arg42Ser), gnomAD rs1271885366
- Q43* (p.Gln43Ter), cosmic curated COSV61389, Ensembl rs2139412451
- G44D (p.Gly44Asp), TOPMed rs1293120962, gnomAD rs1293120962
- G44V (p.Gly44Val), TOPMed rs1293120962, gnomAD rs1293120962
- A46V (p.Ala46Val), gnomAD rs1341967476
- A47G (p.Ala47Gly), Ensembl rs2139412410
- A47P (p.Ala47Pro), ExAC rs758796327, gnomAD rs758796327
- A47S (p.Ala47Ser), ExAC rs758796327, gnomAD rs758796327
- A47T (p.Ala47Thr), ExAC rs758796327, gnomAD rs758796327
- A47V (p.Ala47Val), Ensembl rs2139412410
- P48L (p.Pro48Leu), cosmic curated COSV61388, ExAC rs750787733, TOPMed rs750787733, gnomAD rs750787733, Uncertain significance
- P48Q (p.Pro48Gln), ExAC rs750787733, TOPMed rs750787733, gnomAD rs750787733, Uncertain significance, Inborn genetic diseases
- P48R (p.Pro48Arg), ExAC rs750787733, TOPMed rs750787733, gnomAD rs750787733, Uncertain significance
- P48S (p.Pro48Ser), Ensembl rs2139412400
- P49Q (p.Pro49Gln), Ensembl rs2139412378
- P49S (p.Pro49Ser), Ensembl rs61997695, REVEL 0.59, CADD 28.30
- T50A (p.Thr50Ala), TOPMed rs1328452630, gnomAD rs1328452630
- T50I (p.Thr50Ile), Ensembl rs2139412357
- T50P (p.Thr50Pro), TOPMed rs1328452630, gnomAD rs1328452630, Uncertain significance, not provided
- A51G (p.Ala51Gly), TOPMed rs909780517, gnomAD rs909780517
- A51T (p.Ala51Thr), TOPMed rs1049229039, gnomAD rs1049229039
- A51V (p.Ala51Val), cosmic curated COSV61387, TOPMed rs909780517, gnomAD rs909780517
- A52D (p.Ala52Asp), 1000Genomes rs2139412321
- A52P (p.Ala52Pro), rs1594407218, ClinGen CA389461125, ClinVar RCV002853493, Ensembl rs1594407218, AlphaMissense 0.10, MetaLR 0.37, Uncertain significance, Inborn genetic diseases
- A52T (p.Ala52Thr), Ensembl rs1594407218, Uncertain significance
- A52V (p.Ala52Val), 1000Genomes rs2139412321
- M53I (p.Met53Ile), rs566702552, ClinGen CA7158558, ClinVar RCV002883519, ClinVar RCV003777882, AlphaMissense 0.31, MetaLR 0.36, Uncertain significance, not provided; Inborn genetic diseases
- M53K (p.Met53Lys), Ensembl rs2139412303
- M53R (p.Met53Arg), Ensembl rs2139412303
- M53V (p.Met53Val), TOPMed rs1881219340
- Q54* (p.Gln54Ter), rs2139412296, ClinGen CA389461099, ClinVar RCV002511775, ClinVar RCV003336768, Pathogenic
- Q54K (p.Gln54Lys), cosmic curated COSV61389
- Q55* (p.Gln55Ter), Ensembl rs2139412273
- Q55H (p.Gln55His), rs1234556444, ClinGen CA389461080, ClinVar RCV003296136, ClinVar RCV005102656, AlphaMissense 0.21, MetaLR 0.50, Uncertain significance, Inborn genetic diseases; not provided
- H56L (p.His56Leu), gnomAD rs1421473238
- H56P (p.His56Pro), gnomAD rs1421473238
- H56Q (p.His56Gln), Ensembl rs2139412262
- A57P (p.Ala57Pro), Ensembl rs2139412253
- A57T (p.Ala57Thr), NCI-TCGA Cosmic COSV6138, cosmic curated COSV61388, Ensembl rs2139412253, Variant assessed as somatic; moderate impact.
- A57V (p.Ala57Val), Ensembl rs2139412246
- V58A (p.Val58Ala), gnomAD rs1453510112
- V58E (p.Val58Glu), gnomAD rs1453510112
- V58G (p.Val58Gly), gnomAD rs1453510112
- V58L (p.Val58Leu), rs1332287438, ClinGen CA389461048, ClinVar RCV002027640, gnomAD rs1332287438, AlphaMissense 0.10, MetaLR 0.12, Uncertain significance, Inborn genetic diseases
- V58M (p.Val58Met), rs1332287438, gnomAD rs1332287438, AlphaMissense 0.10, MetaLR 0.12, Uncertain significance
- G59E (p.Gly59Glu), gnomAD rs1488542462, Uncertain significance, not provided
- G59R (p.Gly59Arg), gnomAD rs1195377434
- H60P (p.His60Pro), Ensembl rs2139412200
- H60Y (p.His60Tyr), cosmic curated COSV10466, Ensembl rs2139412207
- H61L (p.His61Leu), TOPMed rs996353352, gnomAD rs996353352
- H61P (p.His61Pro), TOPMed rs996353352, gnomAD rs996353352
- H61Q (p.His61Gln), gnomAD rs1439191961, Uncertain significance
- H61R (p.His61Arg), TOPMed rs996353352, gnomAD rs996353352
- G62R (p.Gly62Arg), Ensembl rs2139412166
- G62S (p.Gly62Ser), Ensembl rs2139412166, REVEL 0.21, CADD 22.40
- A63P (p.Ala63Pro), ExAC rs751469975, TOPMed rs751469975, gnomAD rs751469975
- A63S (p.Ala63Ser), ExAC rs751469975, TOPMed rs751469975, gnomAD rs751469975
- A63T (p.Ala63Thr), ExAC rs751469975, TOPMed rs751469975, gnomAD rs751469975
- A63V (p.Ala63Val), Ensembl rs2139412152
- V64A (p.Val64Ala), Ensembl rs2139412137
- V64F (p.Val64Phe), Ensembl rs2139412140
- V64I (p.Val64Ile), Ensembl rs2139412140
- T65P (p.Thr65Pro), Ensembl rs2139412126
- A66P (p.Ala66Pro), cosmic curated COSV10606, Ensembl rs2139412117
- A66T (p.Ala66Thr), cosmic curated COSV61389, Ensembl rs2139412117, REVEL 0.28, CADD 24.20, Uncertain significance, NKX2-1-Related Disorders
- A66V (p.Ala66Val), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- A67P (p.Ala67Pro), ExAC rs762924398, gnomAD rs762924398
- A67S (p.Ala67Ser), ExAC rs762924398, gnomAD rs762924398
- A67T (p.Ala67Thr), ExAC rs762924398, gnomAD rs762924398
- Y68D (p.Tyr68Asp), rs2502635487, ClinGen CA389460938, ClinVar RCV002692658, Uncertain significance, Inborn genetic diseases
- Y68F (p.Tyr68Phe), cosmic curated COSV10943
- Y68S (p.Tyr68Ser), Ensembl rs2139412091
- H69L (p.His69Leu), Ensembl rs1881215365
- H69N (p.His69Asn), cosmic curated COSV10818
- H69P (p.His69Pro), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- H69Q (p.His69Gln), TOPMed rs1312450089, gnomAD rs1312450089, Likely benign
- H69R (p.His69Arg), Ensembl rs1881215365
- M70L (p.Met70Leu), TOPMed rs926485528
- M70R (p.Met70Arg), gnomAD rs1443393688, Uncertain significance, not specified
- T71K (p.Thr71Lys), cosmic curated COSV10888
- T71M (p.Thr71Met), Ensembl rs2139412038
- T71R (p.Thr71Arg), Ensembl rs2139412038
- T71S (p.Thr71Ser), cosmic curated COSV10888
- A72E (p.Ala72Glu), NCI-TCGA Cosmic COSV1007, cosmic curated COSV10070, NCI-TCGA Cosmic COSV6138, Variant assessed as somatic; moderate impact.
- A72G (p.Ala72Gly), 1000Genomes rs546402304, TOPMed rs546402304
- A72V (p.Ala72Val), cosmic curated COSV61387, 1000Genomes rs546402304, TOPMed rs546402304, Uncertain significance, Inborn genetic diseases
- A73G (p.Ala73Gly), Ensembl rs2139412001
- A73V (p.Ala73Val), cosmic curated COSV10742, NCI-TCGA Cosmic COSV6138, Ensembl rs2139412001, Variant assessed as somatic; moderate impact.
- G74A (p.Gly74Ala), ExAC rs761461360, TOPMed rs761461360, gnomAD rs761461360
- G74E (p.Gly74Glu), rs761461360, ClinGen CA389460853, ClinVar RCV003442643, cosmic curated COSV61387, AlphaMissense 0.15, MetaLR 0.36, Uncertain significance, not provided
- G74R (p.Gly74Arg), cosmic curated COSV10742
- V75G (p.Val75Gly), ExAC rs768162492, gnomAD rs768162492
- V75L (p.Val75Leu), rs776161318, ClinGen CA389460849, ClinVar RCV001934888, ExAC rs776161318, AlphaMissense 0.35, MetaLR 0.70, Uncertain significance, not provided
- V75M (p.Val75Met), ExAC rs776161318, TOPMed rs776161318, gnomAD rs776161318, Uncertain significance
- P76L (p.Pro76Leu), TOPMed rs1396450644
- P76S (p.Pro76Ser), rs746531863, ClinGen CA7158547, ClinVar RCV001777103, ExAC rs746531863, AlphaMissense 0.13, MetaLR 0.20, Uncertain significance, not provided
- P76T (p.Pro76Thr), ExAC rs746531863, TOPMed rs746531863, gnomAD rs746531863, Uncertain significance
- Q77* (p.Gln77Ter), rs1052071927, ClinGen CA389460831, ClinVar RCV003322243, AlphaMissense 0.39, MetaLR 0.41, Pathogenic
- Q77E (p.Gln77Glu), TOPMed rs1052071927, gnomAD rs1052071927
- Q77H (p.Gln77His), Ensembl rs1881212683
- Q77K (p.Gln77Lys), TOPMed rs1052071927, gnomAD rs1052071927
- Q77L (p.Gln77Leu), Ensembl rs2139411941
- Q77P (p.Gln77Pro), Ensembl rs2139411941
- L78F (p.Leu78Phe), Ensembl rs970449088
- L78H (p.Leu78His), Ensembl rs2139411918
Public NKX2-1 analysis runs
- NKX2-1 analysis run — NKX2-1 (1,196 variants) — completed 2026-08-20