MAPK1 (P28482) variants and mutations
MAPK1 (also known as P28482) is a human protein-coding gene encoding a mitogen-activated protein kinase 1 protein. It converts upstream RAS-RAF-MEK signaling into phosphorylation of cytoplasmic and nuclear targets controlling proliferation, differentiation, and development. Germline dysregulating variants can cause neurodevelopmental RASopathy phenotypes, while pathway hyperactivation is common in cancer. This analysis covers 624 MAPK1 variants and mutations. Of these, 49% have computational variant effect predictions. Disease context includes Noonan syndrome, Noonan syndrome 13, and cancer. Example MAPK1 variants include A2G, A2V, and A3E.
Variant analysis overview
- Gene: MAPK1
- Protein: P28482
- UniProt accession: P28482
- Organism: Homo sapiens
- Variants analyzed: 624
- Variant scope: all variants
- Completed: 2026-08-19
Variant and mutation evidence
- Variant composition: 475 unspecified-consequence records; 1 stop retained variant; 1 stop lost; 53 missense variants; 4 stop-gained variants; 79 synonymous variants; 4 frameshift variants; 6 splice-region variants; 1 substitution
- Prediction scores: 307 variants have prediction scores (49% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: Noonan syndrome, Noonan syndrome 13, cancer, Abnormal facial shape, Atypical behavior, Specific learning disability, cervical squamous cell carcinoma, Intellectual disability, hypertrophic cardiomyopathy, Costello syndrome, Abnormal heart morphology, Short stature.
Protein structure and variant hotspots
- Protein features: 1 domains; 2 binding sites; 8 post-translational modification sites.
- Structural context: 456 variants have structural context.
- PTM context: 12 variants overlap post-translational modification sites.
- Experimental data: 359 protein positions have experimental scores. Source: MAPK1 DOX, MAP1K ETP, MAPK1 SCH772984.
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 MAPK1 variants
Examples include A2G, A2V, A3E, A3G, A3V, A4G, A4T, A4V. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- A2G (p.Ala2Gly), Ensembl rs2145760505
- A2V (p.Ala2Val), cosmic curated COSV53187, Ensembl rs2145760505, REVEL 0.21, CADD 23.40
- A3E (p.Ala3Glu), Ensembl rs1378179068, REVEL 0.24, CADD 23.80
- A3G (p.Ala3Gly), Ensembl rs1378179068
- A3V (p.Ala3Val), Ensembl rs1378179068, REVEL 0.26, CADD 24.10
- A4G (p.Ala4Gly), Ensembl rs2145760493, REVEL 0.07, CADD 22.60
- A4T (p.Ala4Thr), TOPMed rs2070000610, REVEL 0.09, CADD 21.80
- A4V (p.Ala4Val), Ensembl rs2145760493, REVEL 0.14, CADD 21.70
- A5G (p.Ala5Gly), 1000Genomes rs1282708145, TOPMed rs1282708145, gnomAD rs1282708145, REVEL 0.12, CADD 22.90
- A5V (p.Ala5Val), 1000Genomes rs1282708145, TOPMed rs1282708145, gnomAD rs1282708145, REVEL 0.17, CADD 22.50
- A6G (p.Ala6Gly), 1000Genomes rs2070000468, TOPMed rs2070000468, REVEL 0.12, CADD 23.00
- A6V (p.Ala6Val), 1000Genomes rs2070000468, TOPMed rs2070000468, REVEL 0.13, CADD 22.40
- A7G (p.Ala7Gly), Ensembl rs2145760476, REVEL 0.18, CADD 22.40
- A9P (p.Ala9Pro), cosmic curated COSV99307
- A9T (p.Ala9Thr), cosmic curated COSV53186, REVEL 0.14, CADD 21.70
- A9V (p.Ala9Val), gnomAD rs2070000055, REVEL 0.13, CADD 22.10
- G10S (p.Gly10Ser), cosmic curated COSV53189, REVEL 0.20, CADD 22.20
- P11A (p.Pro11Ala), TOPMed rs977423767, REVEL 0.13, CADD 20.70
- P11L (p.Pro11Leu), TOPMed rs1165567498, gnomAD rs1165567498, REVEL 0.18, CADD 23.20, Uncertain significance, not provided
- P11T (p.Pro11Thr), TOPMed rs977423767, REVEL 0.17, CADD 21.50
- E12G (p.Glu12Gly), cosmic curated COSV10956, Ensembl rs2145760432, REVEL 0.40, CADD 28.80
- E12Q (p.Glu12Gln), cosmic curated COSV10605, REVEL 0.35, CADD 23.60
- M13I (p.Met13Ile), NCI-TCGA TCGA novel, REVEL 0.17, CADD 22.60, Uncertain significance, Inborn genetic diseases
- M13R (p.Met13Arg), Ensembl rs2145760421
- M13T (p.Met13Thr), Ensembl rs2145760421, REVEL 0.20, CADD 21.20
- M13V (p.Met13Val), Ensembl rs2145760426, REVEL 0.15, CADD 21.00
- V14F (p.Val14Phe), TOPMed rs1349430059, gnomAD rs1349430059, REVEL 0.53, CADD 25.20
- V14G (p.Val14Gly), cosmic curated COSV10875, Ensembl rs2145760416
- V14I (p.Val14Ile), TOPMed rs1349430059, gnomAD rs1349430059, REVEL 0.17, CADD 20.30
- R15G (p.Arg15Gly), TOPMed rs2069999510, REVEL 0.31, CADD 23.50, Uncertain significance, Noonan syndrome 13
- R15P (p.Arg15Pro), Ensembl rs2145760408
- G16W (p.Gly16Trp), gnomAD rs1213398032, REVEL 0.73, CADD 28.60
- Q17K (p.Gln17Lys), TOPMed rs1333567613, REVEL 0.25, CADD 22.50
- V18G (p.Val18Gly), Ensembl rs2145760387, REVEL 0.27, CADD 23.10
- V18L (p.Val18Leu), ExAC rs768479151, TOPMed rs768479151, gnomAD rs768479151, REVEL 0.14, CADD 19.10
- F19L (p.Phe19Leu), 1000Genomes rs749142638, ExAC rs749142638, gnomAD rs749142638, REVEL 0.23, CADD 25.70
- D20E (p.Asp20Glu), Ensembl rs867115970, REVEL 0.10, CADD 17.10
- D20G (p.Asp20Gly), Ensembl rs2145760377, REVEL 0.12, CADD 23.70
- D20V (p.Asp20Val), Ensembl rs2145760377, REVEL 0.35, CADD 24.60
- V21G (p.Val21Gly), Ensembl rs2145760369
- G22V (p.Gly22Val), cosmic curated COSV10586, REVEL 0.19, CADD 25.70
- P23Q (p.Pro23Gln), Ensembl rs868522804, REVEL 0.20, CADD 24.80
- P23S (p.Pro23Ser), cosmic curated COSV53189, REVEL 0.13, CADD 22.00
- T26A (p.Thr26Ala), gnomAD rs1293681277, REVEL 0.06, CADD 22.50
- N27D (p.Asn27Asp), rs2517546999, ClinGen CA410865484, ClinVar RCV002308956, REVEL 0.06, CADD 22.80, Uncertain significance, not provided
- L28H (p.Leu28His), cosmic curated COSV10586, REVEL 0.38, CADD 27.70
- I31F (p.Ile31Phe), TOPMed rs2069998375, REVEL 0.27, CADD 24.30
- I31M (p.Ile31Met), cosmic curated COSV53187, REVEL 0.22, CADD 23.90
- E33* (p.Glu33Ter), Ensembl rs865964391, CADD 38.00
- E33Q (p.Glu33Gln), cosmic curated COSV53185, REVEL 0.27, CADD 23.60
- G34C (p.Gly34Cys), NCI-TCGA Cosmic COSV5319, cosmic curated COSV53190, REVEL 0.95, CADD 28.70, Variant assessed as somatic; moderate impact.
- G34D (p.Gly34Asp), cosmic curated COSV53188, REVEL 0.94, CADD 26.70
- A35T (p.Ala35Thr), rs868472778, ClinGen CA322146468, ClinVar RCV003442640, Ensembl rs868472778, REVEL 0.30, CADD 23.90, Uncertain significance, not provided
- Y36S (p.Tyr36Ser), Ensembl rs2145760305
- M38I (p.Met38Ile), TOPMed rs2069997848, gnomAD rs2069997848, REVEL 0.21, CADD 20.40
- M38L (p.Met38Leu), Ensembl rs2145760296, REVEL 0.25, CADD 22.80
- A42V (p.Ala42Val), Ensembl rs2145705758
- Y43N (p.Tyr43Asn), ExAC rs758481470
- D44N (p.Asp44Asn), ExAC rs779189994, TOPMed rs779189994, gnomAD rs779189994, REVEL 0.32, CADD 24.30
- D44Y (p.Asp44Tyr), ExAC rs779189994, TOPMed rs779189994, gnomAD rs779189994, REVEL 0.62, CADD 28.00
- N45S (p.Asn45Ser), TOPMed rs1008537544, gnomAD rs1008537544, REVEL 0.07, CADD 20.50
- V46F (p.Val46Phe), NCI-TCGA Cosmic COSV9930, cosmic curated COSV99308, Variant assessed as somatic; moderate impact.
- N47D (p.Asn47Asp), ExAC rs755253671, gnomAD rs755253671, REVEL 0.14, CADD 24.40
- N47S (p.Asn47Ser), Ensembl rs2145705735, REVEL 0.08, CADD 21.60
- K48R (p.Lys48Arg), Ensembl rs2069154866
- V49D (p.Val49Asp), TOPMed rs2069154803, REVEL 0.30, CADD 22.90
- V49G (p.Val49Gly), TOPMed rs2069154803
- R50* (p.Arg50Ter), cosmic curated COSV53189
- R50Q (p.Arg50Gln), ExAC rs754193785, gnomAD rs754193785, REVEL 0.32, CADD 25.10, Uncertain significance, not provided
- A52D (p.Ala52Asp), rs2145705712, ClinGen CA410867649, cosmic curated COSV10803, ClinVar RCV002273208, AlphaMissense 1.00, MetaLR 0.75, Uncertain significance, Noonan syndrome 13
- A52S (p.Ala52Ser), NCI-TCGA Cosmic COSV5318, cosmic curated COSV53188, Variant assessed as somatic; moderate impact.
- I53M (p.Ile53Met), Ensembl rs2145705701
- I53N (p.Ile53Asn), Ensembl rs2145705705
- K54R (p.Lys54Arg), Ensembl rs2145705696
- P58L (p.Pro58Leu), cosmic curated COSV53185
- E60V (p.Glu60Val), Ensembl rs2145705688
- H61P (p.His61Pro), Ensembl rs1459279170
- H61Y (p.His61Tyr), Ensembl rs2145705676
- T63I (p.Thr63Ile), cosmic curated COSV53186, Ensembl rs147916567, REVEL 0.39, CADD 23.80
- C65* (p.Cys65Ter), Ensembl rs1601701152
- C65S (p.Cys65Ser), ExAC rs756644901, REVEL 0.56, CADD 23.30
- Q66E (p.Gln66Glu), Ensembl rs2145705654
- R67I (p.Arg67Ile), cosmic curated COSV53189
- T68I (p.Thr68Ile), Ensembl rs2145705653
- T68S (p.Thr68Ser), Ensembl rs2145705653
- R70S (p.Arg70Ser), TOPMed rs1432764704, gnomAD rs1432764704
- E71* (p.Glu71Ter), Ensembl rs2145705638
- I72V (p.Ile72Val), TOPMed rs1035981670
- I74N (p.Ile74Asn), rs2069154121, ClinGen CA410867490, ClinVar RCV001261413, ClinVar RCV001264762, AlphaMissense 0.99, MetaLR 0.47, Pathogenic, Intellectual disability; Short stature; Atypical behavior
- L76V (p.Leu76Val), ExAC rs761386086, TOPMed rs761386086, gnomAD rs761386086, REVEL 0.16, CADD 22.70
- R77C (p.Arg77Cys), NCI-TCGA Cosmic COSV5318, cosmic curated COSV53185, gnomAD rs1330050442, REVEL 0.61, CADD 26.20, Variant assessed as somatic; moderate impact.
- R77G (p.Arg77Gly), gnomAD rs1330050442, REVEL 0.56, CADD 24.90
- R77H (p.Arg77His), Ensembl rs2145705620, REVEL 0.33, CADD 21.70
- R79S (p.Arg79Ser), NCI-TCGA Cosmic COSV9930, cosmic curated COSV99307, Variant assessed as somatic; moderate impact.
- H80Y (p.His80Tyr), rs2069154005, ClinGen CA410867453, ClinVar RCV001261414, ClinVar RCV006557089, AlphaMissense 0.99, MetaLR 0.73, Pathogenic, Noonan syndrome 13; not provided; Microcephaly
- E81* (p.Glu81Ter), Ensembl rs2145705605, Likely pathogenic
- E81D (p.Glu81Asp), Ensembl rs2145705597
- E81K (p.Glu81Lys), rs2145705605, ClinGen CA410867446, NCI-TCGA Cosmic COSV5318, cosmic curated COSV53187, AlphaMissense 0.97, MetaLR 0.18, Uncertain significance, Noonan syndrome 13
- E81V (p.Glu81Val), Ensembl rs2145705602
- I84T (p.Ile84Thr), cosmic curated COSV53186
- G85E (p.Gly85Glu), Ensembl rs2145705587
- N87S (p.Asn87Ser), TOPMed rs1163552201, gnomAD rs1163552201, REVEL 0.10, CADD 21.50
- I89V (p.Ile89Val), NCI-TCGA TCGA novel, gnomAD rs2069153808, REVEL 0.22, CADD 22.40, Variant assessed as somatic; moderate impact.
- I90F (p.Ile90Phe), cosmic curated COSV53188
- R91* (p.Arg91Ter), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- R91G (p.Arg91Gly), cosmic curated COSV10507
- R91Q (p.Arg91Gln), TOPMed rs2069153764, REVEL 0.30, CADD 23.50
- A92T (p.Ala92Thr), Ensembl rs2145705568
- A92V (p.Ala92Val), Ensembl rs2145705567, REVEL 0.25, CADD 24.80
- P93L (p.Pro93Leu), Ensembl rs2145705560
- T94A (p.Thr94Ala), rs202041676, ClinGen CA10124771, cosmic curated COSV99308, ClinVar RCV003964635, REVEL 0.08, CADD 22.20, Likely benign, MAPK1-related disorder
- T94I (p.Thr94Ile), 1000Genomes rs141978504, ESP rs141978504, ExAC rs141978504, TOPMed rs141978504, REVEL 0.11, CADD 23.10, Uncertain significance, not provided
- I95F (p.Ile95Phe), gnomAD rs1396992418
- I95V (p.Ile95Val), gnomAD rs1396992418, REVEL 0.10, CADD 21.40
- E96K (p.Glu96Lys), 1000Genomes rs530183395, ExAC rs530183395, TOPMed rs530183395, gnomAD rs530183395, REVEL 0.13, CADD 24.90
- E96Q (p.Glu96Gln), 1000Genomes rs530183395, ExAC rs530183395, TOPMed rs530183395, gnomAD rs530183395, REVEL 0.09, CADD 23.00
- Q97H (p.Gln97His), ESP rs146182599, ExAC rs146182599, TOPMed rs146182599, gnomAD rs146182599, REVEL 0.13, CADD 17.50
- M98I (p.Met98Ile), NCI-TCGA Cosmic COSV9930, cosmic curated COSV99307, Variant assessed as somatic; moderate impact.
- D100=, NCI-TCGA TCGA novel, Variant assessed as somatic; low impact.
- D100N (p.Asp100Asn), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- V101I (p.Val101Ile), Ensembl rs2145705531, REVEL 0.20, CADD 22.60
- Y102C (p.Tyr102Cys), gnomAD rs2069136795, REVEL 0.85, CADD 29.80
- I103R (p.Ile103Arg), cosmic curated COSV53186
- I103V (p.Ile103Val), rs2517495481, ClinGen CA410867278, ClinVar RCV003332885, Uncertain significance, not provided
- V104E (p.Val104Glu), Ensembl rs2148655457
- Q105P (p.Gln105Pro), Ensembl rs2148655456
- D106G (p.Asp106Gly), ESP rs368100872, ExAC rs368100872, gnomAD rs368100872
- D106H (p.Asp106His), NCI-TCGA Cosmic COSV9930, cosmic curated COSV99308, Variant assessed as somatic; moderate impact.
- L107F (p.Leu107Phe), Ensembl rs2148655450, REVEL 0.45, CADD 24.50
- E109K (p.Glu109Lys), Ensembl rs2148655447
- E109Q (p.Glu109Gln), Ensembl rs2148655447
- D111E (p.Asp111Glu), gnomAD rs1315778465
- D111H (p.Asp111His), Ensembl rs2148655439
- D111V (p.Asp111Val), Ensembl rs2148655435
- L112R (p.Leu112Arg), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- L112V (p.Leu112Val), cosmic curated COSV10507, Ensembl rs2069136543
- Y113* (p.Tyr113Ter), TOPMed rs1284302844, gnomAD rs1284302844
- Y113F (p.Tyr113Phe), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- L116S (p.Leu116Ser), cosmic curated COSV53190
- K117N (p.Lys117Asn), Ensembl rs2148655425
- H120N (p.His120Asn), rs2517495405, ClinGen CA410867156, ClinVar RCV002291828, Uncertain significance, not provided
- L121I (p.Leu121Ile), NCI-TCGA Cosmic COSV5318, cosmic curated COSV53189, Variant assessed as somatic; moderate impact.
- S122N (p.Ser122Asn), cosmic curated COSV10956
- N123K (p.Asn123Lys), Ensembl rs957644071
- N123S (p.Asn123Ser), NCI-TCGA TCGA novel, TOPMed rs2069136258, REVEL 0.25, CADD 23.70, Variant assessed as somatic; moderate impact.
- I126F (p.Ile126Phe), NCI-TCGA Cosmic COSV9930, cosmic curated COSV99308, Variant assessed as somatic; moderate impact.
- C127W (p.Cys127Trp), Ensembl rs2069136186
- C127Y (p.Cys127Tyr), Ensembl rs2148655414
- Y128H (p.Tyr128His), TOPMed rs1234816629
- L130F (p.Leu130Phe), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- Y131C (p.Tyr131Cys), NCI-TCGA Cosmic COSV5318, cosmic curated COSV53186, Variant assessed as somatic; moderate impact.
- Q132E (p.Gln132Glu), cosmic curated COSV53187
- I133M (p.Ile133Met), ExAC rs760549021, gnomAD rs760549021
- I133V (p.Ile133Val), gnomAD rs1453621955, REVEL 0.20, CADD 22.90
- L134F (p.Leu134Phe), cosmic curated COSV10633
- L134P (p.Leu134Pro), cosmic curated COSV53190
- R135G (p.Arg135Gly), cosmic curated COSV10608
- R135K (p.Arg135Lys), NCI-TCGA Cosmic COSV5318, cosmic curated COSV53185, Variant assessed as somatic; moderate impact.
- R135T (p.Arg135Thr), rs797044892, ClinGen CA204703, ClinVar RCV000190714, ClinVar RCV003321539, AlphaMissense 0.99, MetaLR 0.37, Likely pathogenic, not provided; Inborn genetic diseases
- G136E (p.Gly136Glu), rs1569090943, NCI-TCGA Cosmic COSV5318, cosmic curated COSV53187, Ensembl rs1569090943, REVEL 0.74, CADD 26.50, Variant assessed as somatic; moderate impact.
- G136W (p.Gly136Trp), Ensembl rs2148655398
- L137I (p.Leu137Ile), Ensembl rs2148655393
- Y139C (p.Tyr139Cys), TOPMed rs2069135754
- H141Y (p.His141Tyr), cosmic curated COSV53187
- S142L (p.Ser142Leu), NCI-TCGA Cosmic COSV5318, cosmic curated COSV53185, Variant assessed as somatic; moderate impact.
- N144K (p.Asn144Lys), cosmic curated COSV53186
- V145I (p.Val145Ile), Ensembl rs2148655374
- H147R (p.His147Arg), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- H147Y (p.His147Tyr), NCI-TCGA Cosmic COSV5318, cosmic curated COSV53187, Variant assessed as somatic; moderate impact.
- R148C (p.Arg148Cys), NCI-TCGA Cosmic COSV5318, NCI-TCGA Cosmic COSV9930, cosmic curated COSV99308, TOPMed rs2069135521, REVEL 0.64, CADD 32.00, Variant assessed as somatic; moderate impact.
- R148G (p.Arg148Gly), cosmic curated COSV10723
- R148H (p.Arg148His), cosmic curated COSV53185, ExAC rs749425404, TOPMed rs749425404, gnomAD rs749425404, REVEL 0.64, CADD 29.10
- R148L (p.Arg148Leu), cosmic curated COSV10940
- R148P (p.Arg148Pro), cosmic curated COSV10875
- R148S (p.Arg148Ser), cosmic curated COSV53184
- D149N (p.Asp149Asn), Ensembl rs2148655353
- L150F (p.Leu150Phe), Ensembl rs2148655349
- K151E (p.Lys151Glu), Ensembl rs2148655344
- P152S (p.Pro152Ser), Ensembl rs2148655342, Uncertain significance, not provided
- L157F (p.Leu157Phe), TOPMed rs1166008722
Public MAPK1 analysis runs
- MAPK1 analysis run — MAPK1 (624 variants) — completed 2026-08-19