MAP2K2 (P36507) variants and mutations
MAP2K2 (also known as P36507) is a human protein-coding gene encoding a dual specificity mitogen-activated protein kinase kinase 2 protein. It works with MEK1 to activate ERK signaling downstream of RAS and RAF. Germline activating variants can cause cardio-facio-cutaneous syndrome, while acquired activation can support oncogenic MAPK signaling and drug resistance. This analysis covers 1,648 MAP2K2 variants and mutations. Of these, 51% have computational variant effect predictions. Disease context includes cardiofaciocutaneous syndrome, melanoma, and cancer. Example MAP2K2 variants include A3S, A3T, and A3V.
Variant analysis overview
- Gene: MAP2K2
- Protein: P36507
- UniProt accession: P36507
- Organism: Homo sapiens
- Variants analyzed: 1648
- Variant scope: all variants
- Completed: 2026-08-18
Variant and mutation evidence
- Variant composition: 1,466 unspecified-consequence records; 9 frameshift variants; 1 stop lost; 108 missense variants; 48 synonymous variants; 1 in-frame deletions; 4 stop-gained variants; 5 splice-region variants; 4 substitution
- Prediction scores: 838 variants have prediction scores (51% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: cardiofaciocutaneous syndrome, melanoma, cancer, Noonan syndrome, RASopathy, neurofibromatosis type 1, neoplasm, metastatic melanoma, hypertrophic cardiomyopathy, plexiform neurofibroma, Costello syndrome, low grade glioma.
Protein structure and variant hotspots
- Protein features: 1 domains; 2 binding sites; 11 post-translational modification sites.
- Structural context: 1,236 variants have structural context.
- PTM context: 36 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 MAP2K2 variants
Examples include A3S, A3T, A3V, R4P, R4Q, R4W, R5G, R5S. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- A3S (p.Ala3Ser), rs1399102007, ClinGen CA403396078, ClinVar RCV000788439, ClinVar RCV005029451, REVEL 0.27, CADD 21.60, Uncertain significance, Cardiofaciocutaneous syndrome 4; not provided
- A3T (p.Ala3Thr), TOPMed rs1399102007, gnomAD rs1399102007, REVEL 0.29, CADD 22.90, Uncertain significance, RASopathy
- A3V (p.Ala3Val), Ensembl rs587781030, REVEL 0.31, CADD 23.00, Uncertain significance, RASopathy
- R4P (p.Arg4Pro), Ensembl rs2145090044, REVEL 0.30, CADD 24.20
- R4Q (p.Arg4Gln), Ensembl rs2145090044, REVEL 0.19, CADD 24.00
- R4W (p.Arg4Trp), rs730880524, ClinGen CA296188, ClinVar RCV000158049, Ensembl rs730880524, REVEL 0.51, CADD 26.10, Uncertain significance, not provided
- R5G (p.Arg5Gly), Ensembl rs2145090037, REVEL 0.29, CADD 24.60
- R5S (p.Arg5Ser), Ensembl rs2145090029, REVEL 0.16, CADD 23.00
- K6* (p.Lys6Ter), Ensembl rs2145090022
- K6E (p.Lys6Glu), Ensembl rs2145090022, REVEL 0.45, AlphaMissense 0.42
- K6N (p.Lys6Asn), Ensembl rs2145090011, REVEL 0.25, AlphaMissense 0.79
- K6R (p.Lys6Arg), rs2145090019, ClinGen CA403396060, ClinVar RCV002851265, Ensembl rs2145090019, REVEL 0.21, CADD 22.80, Uncertain significance, RASopathy
- P7S (p.Pro7Ser), Ensembl rs587781031, REVEL 0.27, CADD 23.80
- V8G (p.Val8Gly), Ensembl rs2145089986
- V8M (p.Val8Met), ExAC rs779834046, gnomAD rs779834046, REVEL 0.26, CADD 21.30
- L9P (p.Leu9Pro), rs758307267, ClinGen CA9091114, ClinVar RCV000704590, ClinVar RCV000824941, REVEL 0.36, AlphaMissense 0.11, Uncertain significance, not specified; RASopathy; Cardiovascular phenotype
- P10L (p.Pro10Leu), TOPMed rs2041336109, REVEL 0.33, CADD 23.30
- P10R (p.Pro10Arg), TOPMed rs2041336109, Uncertain significance, RASopathy
- P10S (p.Pro10Ser), Ensembl rs2145089963, REVEL 0.34, CADD 22.20
- A11G (p.Ala11Gly), rs1555699410, ClinGen CA403396034, ClinVar RCV000597450, Ensembl rs1555699410, REVEL 0.32, AlphaMissense 0.29, Uncertain significance, not specified
- A11P (p.Ala11Pro), ExAC rs750214699, gnomAD rs750214699, REVEL 0.39, CADD 21.40
- A11V (p.Ala11Val), Ensembl rs1555699410, REVEL 0.33, AlphaMissense 0.41, Uncertain significance
- L12F (p.Leu12Phe), Ensembl rs2041335933, REVEL 0.32, CADD 24.90, Uncertain significance
- L12H (p.Leu12His), Ensembl rs2145089922, REVEL 0.45, CADD 30.00
- L12I (p.Leu12Ile), rs2041335933, ClinGen CA403396031, ClinVar RCV001307458, Ensembl rs2041335933, REVEL 0.19, CADD 23.10, Uncertain significance, RASopathy
- L12P (p.Leu12Pro), Ensembl rs2145089922, REVEL 0.31, CADD 25.40
- L12R (p.Leu12Arg), Ensembl rs2145089922
- T13I (p.Thr13Ile), rs756416031, ExAC rs756416031, TOPMed rs756416031, gnomAD rs756416031, REVEL 0.14, CADD 23.10, Variant assessed as somatic; moderate impact.
- I14L (p.Ile14Leu), Ensembl rs2145089901
- I14S (p.Ile14Ser), Ensembl rs2145089896
- N15H (p.Asn15His), gnomAD rs1217991816, REVEL 0.19, AlphaMissense 0.09
- N15S (p.Asn15Ser), TOPMed rs1408360787, REVEL 0.12, CADD 20.40, Uncertain significance
- N15T (p.Asn15Thr), rs1408360787, ClinGen CA403396010, ClinVar RCV003177074, ClinVar RCV005101073, REVEL 0.15, CADD 21.30, Uncertain significance, Cardiovascular phenotype; RASopathy
- N15Y (p.Asn15Tyr), gnomAD rs1217991816
- P16A (p.Pro16Ala), TOPMed rs904859028, Uncertain significance
- P16L (p.Pro16Leu), TOPMed rs2041335513, REVEL 0.17, CADD 22.30
- P16S (p.Pro16Ser), TOPMed rs904859028, REVEL 0.15, CADD 18.00, Uncertain significance
- P16T (p.Pro16Thr), rs904859028, ClinGen CA304449330, ClinVar RCV000761005, ClinVar RCV002533858, REVEL 0.16, CADD 18.10, Uncertain significance, RASopathy; Cardiofaciocutaneous syndrome 4; Noonan syndrome
- T17A (p.Thr17Ala), rs397517415, ClinGen CA137949, ClinVar RCV000039486, ClinVar RCV001564919, REVEL 0.13, CADD 11.10, Conflicting interpretations, not specified; not provided
- T17I (p.Thr17Ile), gnomAD rs1380162746, REVEL 0.10, AlphaMissense 0.27
- T17P (p.Thr17Pro), ExAC rs397517415, gnomAD rs397517415, REVEL 0.16, CADD 15.30, Likely benign
- I18F (p.Ile18Phe), rs774968670, ClinGen CA403395995, ClinVar RCV001357033, ExAC rs774968670, REVEL 0.25, AlphaMissense 0.07, Uncertain significance, not provided
- I18L (p.Ile18Leu), ExAC rs774968670, gnomAD rs774968670, Uncertain significance
- I18S (p.Ile18Ser), Ensembl rs2145089846
- I18T (p.Ile18Thr), Ensembl rs2145089846
- I18V (p.Ile18Val), ExAC rs774968670, gnomAD rs774968670, REVEL 0.12, AlphaMissense 0.05, Uncertain significance
- A19P (p.Ala19Pro), Ensembl rs2145089839
- A19S (p.Ala19Ser), rs2145089839, ClinGen CA403395988, ClinVar RCV003539541, REVEL 0.16, CADD 17.30, Uncertain significance, RASopathy
- A19T (p.Ala19Thr), Ensembl rs2145089839, REVEL 0.17, CADD 19.60
- E20D (p.Glu20Asp), NCI-TCGA TCGA novel, Ensembl rs2145089821, REVEL 0.25, CADD 21.50, Variant assessed as somatic; moderate impact.
- E20K (p.Glu20Lys), rs2145089829, ClinGen CA403395984, ClinVar RCV003877338, ClinVar RCV006270616, REVEL 0.36, AlphaMissense 0.06, Uncertain significance, not provided; RASopathy
- E20Q (p.Glu20Gln), Ensembl rs2145089829, Uncertain significance
- G21R (p.Gly21Arg), rs2512327845, ClinGen CA403395975, ClinVar RCV003655889, REVEL 0.39, AlphaMissense 0.13, Uncertain significance, RASopathy
- P22L (p.Pro22Leu), gnomAD rs1325938060, REVEL 0.35, CADD 22.90
- P22S (p.Pro22Ser), ExAC rs766829845, gnomAD rs766829845, REVEL 0.34, CADD 20.80
- P22T (p.Pro22Thr), ExAC rs766829845, gnomAD rs766829845, REVEL 0.27, CADD 21.40
- S23F (p.Ser23Phe), TOPMed rs2041335185, REVEL 0.24, AlphaMissense 0.08, Uncertain significance, RASopathy
- S23P (p.Ser23Pro), Ensembl rs2145089801, REVEL 0.25, CADD 24.40
- P24A (p.Pro24Ala), rs2512327821, ClinGen CA403395958, ClinVar RCV003423210, Uncertain significance, not provided
- P24H (p.Pro24His), gnomAD rs1420256288, REVEL 0.21, AlphaMissense 0.14
- P24L (p.Pro24Leu), gnomAD rs1420256288, REVEL 0.16, AlphaMissense 0.11
- P24T (p.Pro24Thr), NCI-TCGA Cosmic COSV9950, REVEL 0.17, CADD 22.40, Variant assessed as somatic; moderate impact.
- T25A (p.Thr25Ala), rs1161407396, ClinGen CA403395952, ClinVar RCV002571923, gnomAD rs1161407396, REVEL 0.14, CADD 21.50, Uncertain significance, RASopathy
- T25I (p.Thr25Ile), Ensembl rs2145089782, REVEL 0.15, AlphaMissense 0.07, Uncertain significance
- T25N (p.Thr25Asn), rs2145089782, ClinGen CA403395950, ClinVar RCV001757075, Ensembl rs2145089782, REVEL 0.17, AlphaMissense 0.10, Uncertain significance, not provided
- T25P (p.Thr25Pro), gnomAD rs1161407396, REVEL 0.22, CADD 23.20, Uncertain significance
- T25S (p.Thr25Ser), gnomAD rs1161407396, REVEL 0.11, AlphaMissense 0.11, Uncertain significance
- S26G (p.Ser26Gly), Ensembl rs2041334984, REVEL 0.29, AlphaMissense 0.05
- S26I (p.Ser26Ile), TOPMed rs1207931346, gnomAD rs1207931346, REVEL 0.43, CADD 22.80
- S26R (p.Ser26Arg), gnomAD rs1404619027, REVEL 0.31, CADD 23.00
- E27D (p.Glu27Asp), Ensembl rs2145089756, REVEL 0.22, CADD 16.70, Uncertain significance, RASopathy
- E27K (p.Glu27Lys), rs1414051360, ClinGen CA403395939, ClinVar RCV002904875, gnomAD rs1414051360, REVEL 0.20, CADD 22.50, Uncertain significance, RASopathy
- E27Q (p.Glu27Gln), gnomAD rs1414051360, Uncertain significance
- G28D (p.Gly28Asp), rs763455417, ClinGen CA9091104, ClinVar RCV002711397, ExAC rs763455417, REVEL 0.33, CADD 22.50, Uncertain significance, RASopathy
- G28E (p.Gly28Glu), rs730880520, ClinGen CA296176, ClinVar RCV000158045, ClinVar RCV001852681, Uncertain significance, not provided; RASopathy
- G28R (p.Gly28Arg), Ensembl rs2145089750
- G28S (p.Gly28Ser), Ensembl rs2145089750, REVEL 0.27, AlphaMissense 0.11
- A29D (p.Ala29Asp), ExAC rs747864035, gnomAD rs747864035, REVEL 0.40, CADD 21.80
- A29S (p.Ala29Ser), rs770134564, ClinGen CA9091102, ClinVar RCV001813679, ClinVar RCV005095229, REVEL 0.26, AlphaMissense 0.13, Uncertain significance, RASopathy; Noonan syndrome and Noonan-related syndrome
- A29T (p.Ala29Thr), ExAC rs770134564, gnomAD rs770134564, REVEL 0.28, AlphaMissense 0.08, Uncertain significance, RASopathy
- S30C (p.Ser30Cys), Ensembl rs2145089711
- S30A (p.Ser30Ala), rs866862003, []
- E31D (p.Glu31Asp), Ensembl rs2145080963
- E31K (p.Glu31Lys), rs2145089707, ClinGen CA403395916, ClinVar RCV004517802, Ensembl rs2145089707, REVEL 0.37, CADD 21.10, Uncertain significance, Cardiovascular phenotype
- A32E (p.Ala32Glu), NCI-TCGA TCGA novel, REVEL 0.34, CADD 24.00, Variant assessed as somatic; moderate impact.
- A32G (p.Ala32Gly), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- A32P (p.Ala32Pro), gnomAD rs866862003
- A32S (p.Ala32Ser), gnomAD rs866862003, REVEL 0.26, CADD 16.50, Uncertain significance, RASopathy
- A32T (p.Ala32Thr), gnomAD rs866862003
- N33D (p.Asn33Asp), Ensembl rs2145080951
- N33H (p.Asn33His), rs2145080951, ClinGen CA403393003, NCI-TCGA Cosmic COSV5356, ClinVar RCV003852400, AlphaMissense 0.15, MetaLR 0.73, Uncertain significance, RASopathy
- N33I (p.Asn33Ile), Ensembl rs1599307469
- N33K (p.Asn33Lys), TOPMed rs940667388, gnomAD rs940667388, REVEL 0.35, CADD 17.10, Uncertain significance, RASopathy
- N33S (p.Asn33Ser), Ensembl rs1599307469
- N33T (p.Asn33Thr), Ensembl rs1599307469
- N33Y (p.Asn33Tyr), Ensembl rs2145080951, REVEL 0.34, AlphaMissense 0.15
- L34M (p.Leu34Met), ExAC rs766428454, TOPMed rs766428454, gnomAD rs766428454
- L34P (p.Leu34Pro), Ensembl rs2145080921
- L34Q (p.Leu34Gln), Ensembl rs2145080921, Uncertain significance, Cardiovascular phenotype
- L34R (p.Leu34Arg), Ensembl rs2145080921
- L34V (p.Leu34Val), ExAC rs766428454, TOPMed rs766428454, gnomAD rs766428454, REVEL 0.36, CADD 18.10
- V35E (p.Val35Glu), TOPMed rs1049115576
- V35G (p.Val35Gly), TOPMed rs1049115576
- V35L (p.Val35Leu), gnomAD rs1057519810, REVEL 0.27, CADD 21.20
- V35M (p.Val35Met), gnomAD rs1057519810, REVEL 0.33, CADD 23.70
- D36E (p.Asp36Glu), Ensembl rs2041240226
- D36H (p.Asp36His), Ensembl rs2041240255
- D36N (p.Asp36Asn), Ensembl rs2041240255
- D36Y (p.Asp36Tyr), Ensembl rs2041240255
- L37P (p.Leu37Pro), Ensembl rs2145080869, Uncertain significance
- L37Q (p.Leu37Gln), rs2145080869, ClinGen CA403392958, ClinVar RCV003540370, ClinVar RCV004369442, AlphaMissense 0.96, MetaLR 0.82, Uncertain significance, Cardiovascular phenotype; RASopathy
- L37V (p.Leu37Val), Ensembl rs2145080874
- Q38* (p.Gln38Ter), Ensembl rs2145080857
- Q38E (p.Gln38Glu), Ensembl rs2145080857
- Q38H (p.Gln38His), Ensembl rs2041240188
- Q38K (p.Gln38Lys), Ensembl rs2145080857
- Q38L (p.Gln38Leu), Ensembl rs2145080850
- Q38R (p.Gln38Arg), Ensembl rs2145080850
- K39* (p.Lys39Ter), Ensembl rs2145080837
- K39M (p.Lys39Met), Ensembl rs2145080831
- K39R (p.Lys39Arg), Ensembl rs2145080831
- K40* (p.Lys40Ter), TOPMed rs1321520649, gnomAD rs1321520649, Uncertain significance
- K40M (p.Lys40Met), Ensembl rs2145080812
- K40N (p.Lys40Asn), Ensembl rs2145080800
- K40Q (p.Lys40Gln), rs1321520649, ClinGen CA403392927, ClinVar RCV002351333, ClinVar RCV006262438, REVEL 0.68, AlphaMissense 0.27, Uncertain significance, Cardiovascular phenotype; not provided
- K40R (p.Lys40Arg), Ensembl rs2145080812
- L41M (p.Leu41Met), Ensembl rs2145080789
- L41P (p.Leu41Pro), Ensembl rs2145080779
- L41Q (p.Leu41Gln), Ensembl rs2145080779
- L41V (p.Leu41Val), Ensembl rs2145080789
- E42* (p.Glu42Ter), Ensembl rs2145080766
- E42D (p.Glu42Asp), Ensembl rs2145080757
- E42K (p.Glu42Lys), Ensembl rs2145080766
- E42Q (p.Glu42Gln), Ensembl rs2145080766
- E43* (p.Glu43Ter), Ensembl rs2145080744
- E43D (p.Glu43Asp), Ensembl rs375010133
- E43G (p.Glu43Gly), gnomAD rs1281225185, REVEL 0.63, CADD 26.90
- E43K (p.Glu43Lys), Ensembl rs2145080744
- E43Q (p.Glu43Gln), Ensembl rs2145080744
- E43V (p.Glu43Val), gnomAD rs1281225185
- L44P (p.Leu44Pro), Ensembl rs2145080719, Uncertain significance, not provided
- L44Q (p.Leu44Gln), Ensembl rs2145080719
- L44R (p.Leu44Arg), Ensembl rs2145080719
- L44V (p.Leu44Val), Ensembl rs2041239991
- E45K (p.Glu45Lys), Ensembl rs2145080710
- E45Q (p.Glu45Gln), Ensembl rs2145080710, REVEL 0.42, CADD 23.20
- L46F (p.Leu46Phe), TOPMed rs1057519809, gnomAD rs1057519809
- L46H (p.Leu46His), Ensembl rs2145080697
- L46V (p.Leu46Val), TOPMed rs1057519809, gnomAD rs1057519809, REVEL 0.40, CADD 22.80
- D47A (p.Asp47Ala), Ensembl rs2145080677
- D47E (p.Asp47Glu), 1000Genomes rs201526172, ExAC rs201526172, TOPMed rs201526172, gnomAD rs201526172, Benign
- D47G (p.Asp47Gly), Ensembl rs2145080677
- D47H (p.Asp47His), Ensembl rs2145080685
- D47N (p.Asp47Asn), Ensembl rs2145080685
- D47V (p.Asp47Val), Ensembl rs2145080677
- D47Y (p.Asp47Tyr), Ensembl rs2145080685
- E48D (p.Glu48Asp), Ensembl rs2145080656
- E48G (p.Glu48Gly), rs1064793306, ClinGen CA16620852, ClinVar RCV000480980, ClinVar RCV005090926, REVEL 0.75, CADD 29.90, Uncertain significance, not provided; RASopathy
- E48K (p.Glu48Lys), gnomAD rs1295043645, REVEL 0.72, CADD 27.10, Uncertain significance, RASopathy
- E48V (p.Glu48Val), TOPMed rs1064793306, gnomAD rs1064793306, Uncertain significance
- Q49* (p.Gln49Ter), Ensembl rs2145080651
- Q49E (p.Gln49Glu), Ensembl rs2145080651
- Q49H (p.Gln49His), Ensembl rs2145080642
- Q49K (p.Gln49Lys), Ensembl rs2145080651
- Q50* (p.Gln50Ter), Ensembl rs2145080632
- Q50E (p.Gln50Glu), Ensembl rs2145080632, REVEL 0.67, CADD 25.80
- Q50H (p.Gln50His), NCI-TCGA Cosmic COSV5356, Ensembl rs2145080618, Likely benign
- Q50K (p.Gln50Lys), Ensembl rs2145080632
- Q50L (p.Gln50Leu), Ensembl rs1599307416, Likely benign
- Q50R (p.Gln50Arg), rs1599307416, ClinGen CA403392807, ClinVar RCV000824942, Ensembl rs1599307416, AlphaMissense 0.96, MetaLR 0.82, Likely benign, Noonan syndrome
- K51* (p.Lys51Ter), Ensembl rs2145080614
- K51E (p.Lys51Glu), Ensembl rs2145080614
- K51M (p.Lys51Met), Ensembl rs2145080611
- K51N (p.Lys51Asn), Ensembl rs2145080606
- K51R (p.Lys51Arg), Ensembl rs2145080611
- K52* (p.Lys52Ter), ESP rs374336702, ExAC rs374336702, TOPMed rs374336702, gnomAD rs374336702, Likely pathogenic
- K52E (p.Lys52Glu), ESP rs374336702, ExAC rs374336702, TOPMed rs374336702, gnomAD rs374336702, Likely pathogenic
- K52N (p.Lys52Asn), Ensembl rs2145080590
- K52Q (p.Lys52Gln), rs374336702, ClinGen CA9091085, ClinVar RCV001306589, ClinVar RCV004699293, REVEL 0.57, AlphaMissense 0.54, Conflicting interpretations, RASopathy; not specified
- K52R (p.Lys52Arg), Ensembl rs2145080597
Public MAP2K2 analysis runs
- MAP2K2 analysis run — MAP2K2 (1,648 variants) — completed 2026-08-18