HIF1A (Hypoxia-inducible factor 1-alpha) variants and mutations
HIF1A (also known as Hypoxia-inducible factor 1-alpha) is a human protein-coding gene encoding a hypoxia-inducible factor 1-alpha protein. When oxygen falls, its stabilization activates transcriptional programs that increase glycolysis, angiogenesis, erythropoietic support, and other adaptations to hypoxia. Persistent HIF-1 signaling can help tumors survive oxygen-poor environments and contributes to ischemic and inflammatory disease biology. This analysis covers 1,105 HIF1A variants and mutations. Of these, 74% have computational variant effect predictions. Disease context includes Enchondromatosis, breast ductal adenocarcinoma, and colorectal adenocarcinoma. Example HIF1A variants include M1?, E2V, and E2G.
Variant analysis overview
- Gene: HIF1A
- Protein: Hypoxia-inducible factor 1-alpha
- UniProt accession: Q16665
- Organism: Homo sapiens
- Variants analyzed: 1105
- Variant scope: all variants
- Completed: 2026-07-30
Variant and mutation evidence
- Variant composition: 908 unspecified-consequence records; 112 missense variants; 58 synonymous variants; 4 in-frame deletions; 4 splice-region variants; 11 frameshift variants; 1 stop-gained variants; 1 protein altering variant; 5 substitution
- Prediction scores: 814 variants have prediction scores (74% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: Enchondromatosis, breast ductal adenocarcinoma, colorectal adenocarcinoma, kidney neoplasm, brain glioblastoma, lymphoid neoplasm, bile duct carcinoma, ovarian endometrioid adenocarcinoma with squamous differentiation, endometrial endometrioid adenocarcinoma, carcinoma of liver and intrahepatic biliary tract, Maffucci syndrome, neurodegenerative disease.
Protein structure and variant hotspots
- Protein features: 4 domains; 13 post-translational modification sites.
- Structural context: 362 variants have structural context.
- PTM context: 18 variants overlap post-translational modification sites.
Data sources
Evidence in this analysis draws on EBI Proteins Variation, UniProt, gnomAD v4, EuropePMC, Interaction Network Analysis, Protein Data Bank, AlphaFold DB, gnomAD constraint, Open Targets, MaveDB, LitVar.
Notable HIF1A variants
Examples include M1?, E2V, E2G, E2A, E2E, E2D, G3D, G3S. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- M1?, cosmic curated COSV60189
- E2V (p.Glu2Val), gnomAD 14-61695809-A-T, REVEL 0.19, CADD 22.40
- E2G (p.Glu2Gly), gnomAD 14-61695809-A-G, REVEL 0.14, CADD 22.70
- E2A (p.Glu2Ala), gnomAD 14-61695809-A-C, REVEL 0.10, CADD 22.40
- E2E (p.Glu2Glu), rs1566556739, gnomAD 14-61695810-G-A, CADD 21.60
- E2D (p.Glu2Asp), gnomAD 14-61695810-G-T, REVEL 0.07, CADD 21.30
- G3D (p.Gly3Asp), 1000Genomes rs547805630, ExAC rs547805630, gnomAD rs547805630, REVEL 0.10, CADD 21.70
- G3S (p.Gly3Ser), ExAC rs763159088, TOPMed rs763159088, gnomAD rs763159088, REVEL 0.06, CADD 21.70
- G3V (p.Gly3Val), gnomAD 14-61695812-G-T, REVEL 0.10, CADD 21.50
- G3G (p.Gly3Gly), rs1427567704, gnomAD 14-61695813-C-A, CADD 21.50
- A4D (p.Ala4Asp), TOPMed rs1253716282, gnomAD rs1253716282, REVEL 0.14, CADD 21.90
- A4T (p.Ala4Thr), cosmic curated COSV60191, REVEL 0.17, CADD 22.00
- A4S (p.Ala4Ser), gnomAD 14-61695814-G-T, REVEL 0.14, CADD 21.40
- A4V (p.Ala4Val), gnomAD 14-61695815-C-T, REVEL 0.09, CADD 22.10
- A4A (p.Ala4Ala), gnomAD 14-61695816-C-G, CADD 21.70
- G5D (p.Gly5Asp), TOPMed rs1471152502, gnomAD rs1471152502, REVEL 0.07, CADD 21.80
- G5S (p.Gly5Ser), Ensembl rs2044106465, REVEL 0.07, CADD 20.90
- p.Gly5 Ala7del, rs754951963, gnomAD 14-61695810-GGGCG, CADD 21.30
- G5C (p.Gly5Cys), gnomAD 14-61695817-G-T, REVEL 0.17, CADD 20.80
- G5G (p.Gly5Gly), gnomAD 14-61695819-C-A, CADD 19.00
- G6C (p.Gly6Cys), gnomAD 14-61695820-G-T, REVEL 0.15, CADD 22.10
- G6D (p.Gly6Asp), gnomAD 14-61695821-G-A, REVEL 0.08, CADD 21.60
- G6G (p.Gly6Gly), gnomAD 14-61695822-C-T, CADD 21.00
- G6S (p.Gly6Ser), rs1449589520, gnomAD 14-61697902-G-A, CADD 16.60, SIFT 0.10
- G6E (p.Gly6Glu), gnomAD 14-61697909-G-A, CADD 8.70, SIFT 0.18
- G6R (p.Gly6Arg), gnomAD 14-61697953-G-C, CADD 15.50, SIFT 0.02
- G6V (p.Gly6Val), gnomAD 14-61697954-G-T, CADD 20.00, SIFT 0.02
- A7T (p.Ala7Thr), gnomAD rs1396364190, REVEL 0.06, CADD 21.00
- A7S (p.Ala7Ser), gnomAD 14-61695823-G-T, REVEL 0.04, CADD 20.70
- A7E (p.Ala7Glu), gnomAD 14-61695824-C-A, REVEL 0.06, CADD 19.70
- A7A (p.Ala7Ala), gnomAD 14-61695825-G-T, CADD 18.90
- N8K (p.Asn8Lys), Ensembl rs2044106582, REVEL 0.07, CADD 20.60
- N8H (p.Asn8His), gnomAD 14-61695826-A-C, REVEL 0.07, CADD 21.60
- N8I (p.Asn8Ile), gnomAD 14-61695827-A-T, REVEL 0.10, CADD 20.70
- N8S (p.Asn8Ser), gnomAD 14-61695827-A-G, REVEL 0.05, CADD 21.10
- N8N (p.Asn8Asn), gnomAD 14-61695828-C-T, CADD 21.00
- N8D (p.Asn8Asp), rs1053985430, gnomAD 14-61697878-A-G, CADD 13.10
- N8T (p.Asn8Thr), rs2044134416, gnomAD 14-61697879-A-C, CADD 4.45
- D9H (p.Asp9His), rs752063685, ExAC rs752063685, TOPMed rs752063685, gnomAD rs752063685, REVEL 0.07, CADD 21.90, Variant assessed as somatic; moderate impact.
- D9N (p.Asp9Asn), ExAC rs752063685, TOPMed rs752063685, gnomAD rs752063685, REVEL 0.09, CADD 22.00
- D9del (p.Asp9del), rs1306188430, gnomAD 14-61695826-AACG-, CADD 21.20
- D9Y (p.Asp9Tyr), gnomAD 14-61695829-G-T, REVEL 0.20, CADD 21.80
- D9G (p.Asp9Gly), gnomAD 14-61695830-A-G, REVEL 0.12, CADD 22.30
- D9E (p.Asp9Glu), gnomAD 14-61695831-C-G, REVEL 0.09, CADD 21.00
- D9D (p.Asp9Asp), gnomAD 14-61695831-C-T, CADD 21.30
- K10E (p.Lys10Glu), Ensembl rs2140112009, REVEL 0.17, CADD 22.30
- K10N (p.Lys10Asn), cosmic curated COSV10811, NCI-TCGA Cosmic COSV6018, cosmic curated COSV60188, REVEL 0.18, CADD 20.90, Variant assessed as somatic; moderate impact.
- K11I (p.Lys11Ile), Ensembl rs2044106654, MetaLR 0.15, MetaSVM -0.86
- K11R (p.Lys11Arg), gnomAD 14-61695836-A-G, REVEL 0.06, CADD 22.40
- K11K (p.Lys11Lys), gnomAD 14-61695837-A-G, CADD 22.60
- K12N (p.Lys12Asn), Ensembl rs943135091
- K12E (p.Lys12Glu), gnomAD 14-61695838-A-G, REVEL 0.13, CADD 23.60
- K12R (p.Lys12Arg), gnomAD 14-61695839-A-G, REVEL 0.07, CADD 22.50
- K12K (p.Lys12Lys), gnomAD 14-61720382-G-A, CADD 14.50
- I13M (p.Ile13Met), gnomAD rs1334800559, REVEL 0.08, CADD 20.00
- I13V (p.Ile13Val), TOPMed rs2044412573, REVEL 0.09, CADD 18.30, Uncertain significance, not specified
- I13I (p.Ile13Ile), gnomAD 14-61697940-C-A, CADD 9.97
- I13K (p.Ile13Lys), gnomAD 14-61697945-T-A, CADD 18.40, SIFT 0.22
- S14I (p.Ser14Ile), gnomAD rs1381507939, REVEL 0.37, CADD 28.40
- S14R (p.Ser14Arg), NCI-TCGA Cosmic COSV6019, cosmic curated COSV60190, MetaLR 0.38, MetaSVM -0.18, Variant assessed as somatic; moderate impact.
- S14G (p.Ser14Gly), gnomAD 14-61697854-A-G, CADD 9.47
- S14N (p.Ser14Asn), gnomAD 14-61697855-G-A, CADD 6.08
- S14S (p.Ser14Ser), gnomAD 14-61697856-C-T, CADD 5.55
- S14P (p.Ser14Pro), gnomAD 14-61697857-T-C, CADD 5.42
- S14A (p.Ser14Ala), gnomAD 14-61697857-T-G, CADD 2.82
- S14Y (p.Ser14Tyr), gnomAD 14-61697858-C-A, CADD 3.43
- S14F (p.Ser14Phe), rs1289925593, gnomAD 14-61697858-C-T, CADD 5.38
- S15F (p.Ser15Phe), ESP rs374224409, ExAC rs374224409, TOPMed rs374224409, gnomAD rs374224409, REVEL 0.46, CADD 29.00
- S15P (p.Ser15Pro), gnomAD 14-61720389-T-C, REVEL 0.49, MetaLR 0.41
- S15Y (p.Ser15Tyr), gnomAD 14-61720390-C-A, REVEL 0.44, MetaLR 0.44
- S15S (p.Ser15Ser), rs1042773566, gnomAD 14-61720391-T-C, CADD 12.70
- E16* (p.Glu16Ter), cosmic curated COSV60189, CADD 38.00
- E16A (p.Glu16Ala), ExAC rs778648481, gnomAD rs778648481, REVEL 0.49, CADD 29.40
- E17del (p.Glu17del), gnomAD 14-61697896-AAAG-, CADD 11.90
- E16K (p.Glu16Lys), rs1391324896, gnomAD 14-61697899-G-A, CADD 20.10, SIFT 0.00
- E16Q (p.Glu16Gln), rs1391324896, gnomAD 14-61697899-G-C, CADD 17.80, SIFT 0.00
- E16E (p.Glu16Glu), gnomAD 14-61697901-A-G, CADD 7.41
- R17C (p.Arg17Cys), TOPMed rs904387412, gnomAD rs904387412, REVEL 0.46, CADD 32.00
- R17G (p.Arg17Gly), NCI-TCGA Cosmic COSV6019, cosmic curated COSV60191, MetaLR 0.40, MetaSVM -0.19, Variant assessed as somatic; moderate impact.
- R17H (p.Arg17His), rs1163104034, cosmic curated COSV10004, TOPMed rs1163104034, gnomAD rs1163104034, REVEL 0.45, CADD 32.00, Variant assessed as somatic; moderate impact.
- R17R (p.Arg17Arg), gnomAD 14-61697866-C-A, CADD 0.53
- R17Q (p.Arg17Gln), rs559818454, gnomAD 14-61697867-G-A, CADD 2.97
- R17L (p.Arg17Leu), rs559818454, gnomAD 14-61697867-G-T, CADD 2.34
- R17P (p.Arg17Pro), gnomAD 14-61720396-G-C, REVEL 0.53, MetaLR 0.44
- R18* (p.Arg18Ter), NCI-TCGA TCGA novel, CADD 36.00, Variant assessed as somatic; high impact.
- R18Q (p.Arg18Gln), NCI-TCGA Cosmic COSV6018, cosmic curated COSV60188, TOPMed rs2044412888, gnomAD rs2044412888, REVEL 0.43, CADD 32.00, Variant assessed as somatic; moderate impact.
- R18R (p.Arg18Arg), gnomAD 14-61720398-C-A, CADD 13.30
- K19Q (p.Lys19Gln), NCI-TCGA Cosmic COSV6018, cosmic curated COSV60188, MetaLR 0.49, MetaSVM 0.17, Variant assessed as somatic; moderate impact.
- E20* (p.Glu20Ter), NCI-TCGA Cosmic COSV1043, NCI-TCGA Cosmic COSV6018, cosmic curated COSV60189, Variant assessed as somatic; high impact.
- E20K (p.Glu20Lys), cosmic curated COSV10439, MetaLR 0.51, MetaSVM 0.16
- E20G (p.Glu20Gly), gnomAD 14-61697924-A-G, CADD 14.60, SIFT 0.03
- E20D (p.Glu20Asp), gnomAD 14-61697925-A-T, CADD 11.80, SIFT 0.04
- E20E (p.Glu20Glu), gnomAD 14-61697925-A-G, CADD 9.03
- E20V (p.Glu20Val), gnomAD 14-61720405-A-T, REVEL 0.47, MetaLR 0.43
- K21M (p.Lys21Met), TOPMed rs1461259695, REVEL 0.49, AlphaMissense 0.97, Uncertain significance
- K21R (p.Lys21Arg), rs1461259695, ClinGen CA389923838, ClinVar RCV004397141, TOPMed rs1461259695, AlphaMissense 0.97, MetaLR 0.49, Uncertain significance, not specified
- K21E (p.Lys21Glu), rs771610659, gnomAD 14-61697917-A-G, CADD 14.30, SIFT 0.20
- K21I (p.Lys21Ile), gnomAD 14-61697918-A-T, CADD 17.60, SIFT 0.54
- K21K (p.Lys21Lys), gnomAD 14-61697919-A-G, CADD 10.00
- S22Y (p.Ser22Tyr), cosmic curated COSV60190
- S22P (p.Ser22Pro), gnomAD 14-61697914-T-C, CADD 17.80, SIFT 0.00
- S22* (p.Ser22Ter), gnomAD 14-61697915-C-A, CADD 25.40
- S22S (p.Ser22Ser), gnomAD 14-61697916-A-G, CADD 12.60
- R23* (p.Arg23Ter), cosmic curated COSV60190, Ensembl rs2044413097, CADD 35.00
- R23L (p.Arg23Leu), gnomAD 14-61720414-G-T, REVEL 0.53, MetaLR 0.51
- R23Q (p.Arg23Gln), gnomAD 14-61720414-G-A, REVEL 0.46, MetaLR 0.51
- D24N (p.Asp24Asn), gnomAD rs1323460722, REVEL 0.27, CADD 25.10
- D24Y (p.Asp24Tyr), cosmic curated COSV10004, REVEL 0.42, CADD 29.80
- D24V (p.Asp24Val), gnomAD 14-61720417-A-T, REVEL 0.50, MetaLR 0.42
- A25G (p.Ala25Gly), rs2044413174, gnomAD 14-61720418-T-TG, CADD 33.00
- A25A (p.Ala25Ala), rs771986517, gnomAD 14-61720421-A-T, CADD 11.70
- A26G (p.Ala26Gly), gnomAD 14-61720423-C-G, REVEL 0.39, MetaLR 0.34
- R27G (p.Arg27Gly), Ensembl rs754062510, MetaLR 0.55, MetaSVM 0.20
- R27R (p.Arg27Arg), gnomAD 14-61720427-A-G, CADD 13.90
- S28Y (p.Ser28Tyr), cosmic curated COSV60188, ExAC rs779897997, TOPMed rs779897997, gnomAD rs779897997, REVEL 0.06, CADD 25.30
- R29Q (p.Arg29Gln), Ensembl rs1566567018, MetaLR 0.74, MetaSVM 0.65
- R29W (p.Arg29Trp), cosmic curated COSV10004, ExAC rs746540920, gnomAD rs746540920, REVEL 0.70, CADD 29.60
- R29R (p.Arg29Arg), gnomAD 14-61720433-G-A, CADD 8.87
- R30Q (p.Arg30Gln), NCI-TCGA Cosmic COSV6018, cosmic curated COSV60188, REVEL 0.58, CADD 32.00, Variant assessed as somatic; moderate impact.
- R30E (p.Arg30Glu), gnomAD 14-61697939-TC-T, CADD 25.00
- R30K (p.Arg30Lys), gnomAD 14-61697941-AG-A, CADD 27.90
- K32K (p.Lys32Lys), gnomAD 14-61720442-A-G, CADD 13.40
- E33* (p.Glu33Ter), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- E33K (p.Glu33Lys), gnomAD 14-61697935-G-A, CADD 21.70, SIFT 0.13
- E33A (p.Glu33Ala), gnomAD 14-61697948-A-C, CADD 23.00, SIFT 0.01
- S34C (p.Ser34Cys), gnomAD rs1249408665, REVEL 0.28, CADD 26.80
- S34Y (p.Ser34Tyr), gnomAD rs1249408665, REVEL 0.56, CADD 26.30
- S34S (p.Ser34Ser), rs1471380569, gnomAD 14-61720448-T-G, CADD 11.80
- E35E (p.Glu35Glu), rs768001409, gnomAD 14-61720451-A-G, CADD 13.40
- V36I (p.Val36Ile), TOPMed rs1167775993, gnomAD rs1167775993, REVEL 0.36, CADD 24.60
- V36F (p.Val36Phe), gnomAD 14-61697887-G-T, CADD 15.70
- V36D (p.Val36Asp), gnomAD 14-61697888-T-A, CADD 16.90
- V36A (p.Val36Ala), gnomAD 14-61697888-T-C, CADD 15.80
- V36V (p.Val36Val), gnomAD 14-61697889-C-A, CADD 6.65
- F37L (p.Phe37Leu), gnomAD 14-61697884-T-C, CADD 19.60
- F37I (p.Phe37Ile), gnomAD 14-61697884-T-A, CADD 19.30
- F37S (p.Phe37Ser), rs2044134455, gnomAD 14-61697885-T-C, CADD 22.80
- Y38H (p.Tyr38His), gnomAD rs1174275971, REVEL 0.54, CADD 29.30
- Y38S (p.Tyr38Ser), TOPMed rs2044413699, MetaLR 0.31, MetaSVM -0.36
- Y38* (p.Tyr38Ter), gnomAD 14-61720459-ATGAG, CADD 32.00
- E39D (p.Glu39Asp), gnomAD 14-61720463-G-C, REVEL 0.31, MetaLR 0.27
- L40W (p.Leu40Trp), gnomAD 14-61697873-T-G, CADD 9.76
- L40F (p.Leu40Phe), gnomAD 14-61697874-G-T, CADD 10.40
- L40L (p.Leu40Leu), gnomAD 14-61697874-G-A, CADD 6.72
- L40* (p.Leu40Ter), rs140402206, gnomAD 14-61697889-CT-C, CADD 20.20
- L40K (p.Leu40Lys), gnomAD 14-61697889-CTT-C, CADD 24.40
- L40G (p.Leu40Gly), gnomAD 14-61697928-ATT-A, CADD 23.10
- L40V (p.Leu40Val), gnomAD 14-61697929-T-G, CADD 10.90, SIFT 0.03
- L40S (p.Leu40Ser), gnomAD 14-61697930-T-C, CADD 21.50, SIFT 0.00
- A41S (p.Ala41Ser), rs2503118753, ClinGen CA389923984, ClinVar RCV004148661, Uncertain significance, not specified
- A41V (p.Ala41Val), TOPMed rs1008529581, REVEL 0.43, CADD 26.30, Uncertain significance, not specified
- A41G (p.Ala41Gly), gnomAD 14-61720468-C-G, REVEL 0.37, MetaLR 0.42
- H42Y (p.His42Tyr), rs776377120, NCI-TCGA Cosmic COSV6018, cosmic curated COSV60189, ExAC rs776377120, AlphaMissense 0.30, MetaLR 0.19, Variant assessed as somatic; moderate impact.
- H42H (p.His42His), rs1038759891, gnomAD 14-61720472-T-C, CADD 11.80
- Q43S (p.Gln43Ser), NCI-TCGA TCGA novel, MetaLR 0.16, MetaSVM -0.77, Variant assessed as somatic; high impact.
- Q43K (p.Gln43Lys), gnomAD 14-61697860-C-A, CADD 2.52
- Q43R (p.Gln43Arg), rs1210485987, gnomAD 14-61697861-A-G, CADD 6.05
- Q43H (p.Gln43His), gnomAD 14-61697862-A-T, CADD 6.53
- Q43Q (p.Gln43Gln), rs976913804, gnomAD 14-61697862-A-G, CADD 4.04
- P45H (p.Pro45His), NCI-TCGA TCGA novel, MetaLR 0.73, MetaSVM 0.68, Variant assessed as somatic; high impact.
- P45T (p.Pro45Thr), gnomAD 14-61697920-C-A, CADD 9.94, SIFT 0.35
- P45A (p.Pro45Ala), gnomAD 14-61697920-C-G, CADD 6.57, SIFT 0.65
- P45R (p.Pro45Arg), rs774960388, gnomAD 14-61697921-C-G, CADD 13.00, SIFT 0.07
- P45L (p.Pro45Leu), rs774960388, gnomAD 14-61697921-C-T, CADD 12.40, SIFT 0.38
- P45P (p.Pro45Pro), gnomAD 14-61697922-T-C, CADD 9.04
- L46L (p.Leu46Leu), gnomAD 14-61720484-T-C, CADD 10.50
- P47S (p.Pro47Ser), ExAC rs761337243, gnomAD rs761337243
- P47T (p.Pro47Thr), ExAC rs761337243, gnomAD rs761337243, REVEL 0.39, CADD 23.40
- P47P (p.Pro47Pro), gnomAD 14-61720487-A-T, CADD 10.50
- H48P (p.His48Pro), gnomAD 14-61720489-A-C, REVEL 0.36, MetaLR 0.11
- H48H (p.His48His), rs2044413984, gnomAD 14-61720490-T-C, CADD 10.90
- N49I (p.Asn49Ile), TOPMed rs1244683277, MetaLR 0.06, MetaSVM -1.11
- N49M (p.Asn49Met), gnomAD 14-61697947-GA-G, CADD 25.60
- N49K (p.Asn49Lys), gnomAD 14-61697947-G-GA, CADD 26.60
- N49N (p.Asn49Asn), gnomAD 14-61697952-T-C, CADD 6.80
- N49del (p.Asn49del), gnomAD 14-61720488-CATA-, CADD 20.30
- N49H (p.Asn49His), gnomAD 14-61720491-A-C, REVEL 0.08, MetaLR 0.06
- N49T (p.Asn49Thr), gnomAD 14-61720492-A-C, REVEL 0.04, MetaLR 0.05
- V50L (p.Val50Leu), rs61755705, ClinGen CA7215638, ClinVar RCV002468421, ClinVar RCV005232988, REVEL 0.14, CADD 23.40, Conflicting interpretations, Maffucci syndrome; not provided
- V50M (p.Val50Met), gnomAD 14-61720494-G-A, REVEL 0.28, MetaLR 0.20
Public HIF1A analysis runs
- HIF1A analysis run — HIF1A (1,105 variants) — completed 2026-07-30