HRAS (GTPase HRas) variants and mutations
HRAS (also known as GTPase HRas) is a human protein-coding gene encoding a GTPase protein. Its GTP-bound state activates RAF-MEK-ERK and other pathways downstream of growth-factor receptors. Somatic activating variants drive several cancers, while germline activating variants cause Costello syndrome. This analysis covers 949 HRAS variants and mutations. Of these, 60% have computational variant effect predictions. Disease context includes Costello syndrome, linear nevus sebaceous syndrome, and Linear nevus sebaceus syndrome. Example HRAS variants include T2A, T2K, and T2M.
Variant analysis overview
- Gene: HRAS
- Protein: GTPase HRas
- UniProt accession: P01112
- Organism: Homo sapiens
- Variants analyzed: 949
- Variant scope: all variants
- Completed: 2026-08-18
Variant and mutation evidence
- Variant composition: 808 unspecified-consequence records; 3 stop lost; 70 synonymous variants; 43 missense variants; 2 stop-gained variants; 14 frameshift variants; 4 in-frame deletions; 2 splice-region variants; 3 substitution
- Prediction scores: 571 variants have prediction scores (60% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: Costello syndrome, linear nevus sebaceous syndrome, Linear nevus sebaceus syndrome, urinary bladder cancer, nevus, epidermal, urinary bladder carcinoma, Noonan syndrome, thyroid cancer, nonmedullary, 2, cancer, large congenital melanocytic nevus, myopathy, congenital, with excess of muscle spindles, RASopathy.
Protein structure and variant hotspots
- Protein features: 5 binding sites; 5 post-translational modification sites.
- PTM context: 13 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 HRAS variants
Examples include T2A, T2K, T2M, T2R, T2S, E3*, E3G, E3K. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- T2A (p.Thr2Ala), rs878854761, ClinGen CA10582926, ClinVar RCV000232309, Ensembl rs878854761, AlphaMissense 0.19, MetaLR 0.15, Uncertain significance, Costello syndrome
- T2K (p.Thr2Lys), cosmic curated COSV54246
- T2M (p.Thr2Met), rs1447218022, ClinGen CA378926303, cosmic curated COSV10504, ClinVar RCV000816525, REVEL 0.44, AlphaMissense 0.31, Likely benign, Costello syndrome
- T2R (p.Thr2Arg), rs1447218022, ClinGen CA378926314, ClinVar RCV001917995, gnomAD rs1447218022, AlphaMissense 0.31, MetaLR 0.10, Uncertain significance, Costello syndrome
- T2S (p.Thr2Ser), Ensembl rs878854761, SIFT 0.00, Uncertain significance
- E3* (p.Glu3Ter), Ensembl rs2133995214
- E3G (p.Glu3Gly), Ensembl rs2133995205, REVEL 0.51, AlphaMissense 0.86
- E3K (p.Glu3Lys), cosmic curated COSV54241, Ensembl rs2133995214
- E3Q (p.Glu3Gln), Ensembl rs2133995214, SIFT 0.00
- Y4* (p.Tyr4Ter), Ensembl rs2133995153, Likely benign
- Y4C (p.Tyr4Cys), rs764622691, ClinGen CA5779438, ClinVar RCV000598510, ClinVar RCV001322927, REVEL 0.50, AlphaMissense 0.85, Uncertain significance, Thyroid cancer, nonmedullary, 2; Linear nevus sebaceous syndrome; Malignant tumo
- Y4D (p.Tyr4Asp), Ensembl rs1554885164, Uncertain significance
- Y4H (p.Tyr4His), rs1554885164, ClinGen CA378926252, cosmic curated COSV54239, ClinVar RCV000590817, REVEL 0.61, AlphaMissense 0.94, Uncertain significance, not provided
- Y4N (p.Tyr4Asn), Ensembl rs1554885164, Uncertain significance
- Y4S (p.Tyr4Ser), rs764622691, ClinGen CA378926248, ClinVar RCV001912723, ExAC rs764622691, REVEL 0.62, AlphaMissense 0.96, Uncertain significance, Costello syndrome
- K5E (p.Lys5Glu), Ensembl rs2133995142
- L6P (p.Leu6Pro), NCI-TCGA TCGA novel, REVEL 0.84, AlphaMissense 1.00, Variant assessed as somatic; moderate impact.
- L6Q (p.Leu6Gln), Ensembl rs2133995114
- L6V (p.Leu6Val), ExAC rs763376142, TOPMed rs763376142, gnomAD rs763376142, Likely benign
- V7A (p.Val7Ala), cosmic curated COSV10638
- V7E (p.Val7Glu), Ensembl rs2133995083
- V7G (p.Val7Gly), Ensembl rs2133995083, SIFT 0.00
- V7L (p.Val7Leu), rs2133995093, cosmic curated COSV54242, Ensembl rs2133995093, ClinGen CA378926169, REVEL 0.74, AlphaMissense 0.99, Uncertain significance, Costello syndrome
- V8L (p.Val8Leu), Ensembl rs2133995063
- V8M (p.Val8Met), Ensembl rs2133995063
- V9L (p.Val9Leu), Ensembl rs1851320945
- V9M (p.Val9Met), Ensembl rs1851320945, cosmic curated COSV54241
- G10A (p.Gly10Ala), cosmic curated COSV54243
- G10C (p.Gly10Cys), Ensembl rs2133995008
- G10D (p.Gly10Asp), cosmic curated COSV99062
- G10R (p.Gly10Arg), Ensembl rs2133995008
- G10S (p.Gly10Ser), Ensembl rs2133995008
- A11D (p.Ala11Asp), cosmic curated COSV99530
- A11G (p.Ala11Gly), Ensembl rs2133994968, cosmic curated COSV10638
- A11P (p.Ala11Pro), ExAC rs727504496, TOPMed rs727504496, gnomAD rs727504496, REVEL 0.48, AlphaMissense 0.88, Uncertain significance
- A11S (p.Ala11Ser), cosmic curated COSV54247
- A11T (p.Ala11Thr), rs727504496, ClinGen CA183175, cosmic curated COSV54237, ClinVar RCV000155632, REVEL 0.36, AlphaMissense 0.61, Uncertain significance, Cardiovascular phenotype; not specified; Costello syndrome
- A11V (p.Ala11Val), Ensembl rs2133994968, SIFT 0.00
- G12A (p.Gly12Ala), rs727503094, ClinGen CA296077, ClinVar RCV000157929, Pathogenic, Epidermal nevus; Linear nevus sebaceous syndrome; Large congenital melanocytic n
- G12C (p.Gly12Cys), rs104894229, ClinGen CA129948, NCI-TCGA Cosmic COSV5423, AlphaMissense 1.00, MetaLR 0.51, Pathogenic, Thyroid cancer, nonmedullary, 2; Malignant tumor of urinary bladder; Large conge
- G12D (p.Gly12Asp), rs727503094, ClinGen CA296072, ClinVar RCV001678586, Pathogenic, Noonan syndrome and Noonan-related syndrome; not provided; RASopathy
- G12E (p.Gly12Glu), rs727503094, ClinGen CA273158, ClinVar RCV000150836, ClinVar RCV000255809, Pathogenic/Likely pathogenic, not provided; Costello syndrome
- G12N (p.Gly12Asn), cosmic curated COSV54245
- G12R (p.Gly12Arg), rs104894229, ClinGen CA16602439, NCI-TCGA Cosmic COSV5423, cosmic curated COSV54236, AlphaMissense 1.00, MetaLR 0.51, Likely pathogenic, Costello syndrome
- G12S (p.Gly12Ser), rs104894229, ClinGen CA122549, NCI-TCGA Cosmic COSV5423, AlphaMissense 1.00, MetaLR 0.51, Pathogenic, Costello syndrome
- G12V (p.Gly12Val), rs727503094, ClinGen CA10603217, ClinVar RCV000322736, ClinGen CA658795203, Pathogenic, Costello syndrome; not provided
- G13A (p.Gly13Ala), Ensembl rs104894226, REVEL 0.56, AlphaMissense 0.99, Pathogenic, in SFM
- G13C (p.Gly13Cys), rs104894228, Ensembl rs104894228, ClinGen CA295247, NCI-TCGA Cosmic COSV5423, AlphaMissense 0.98, MetaLR 0.48, Pathogenic, Noonan syndrome
- G13D (p.Gly13Asp), rs104894226, Ensembl rs104894226, ClinGen CA256488, NCI-TCGA Cosmic COSV5423, AlphaMissense 0.99, MetaLR 0.65, Pathogenic, Noonan syndrome and Noonan-related syndrome; HRAS-related disorder; Thyroid canc
- G13K (p.Gly13Lys), cosmic curated COSV10453
- G13N (p.Gly13Asn), cosmic curated COSV54241
- G13R (p.Gly13Arg), rs104894228, Ensembl rs104894228, ClinGen CA129950, NCI-TCGA Cosmic COSV5423, AlphaMissense 0.98, MetaLR 0.48, Pathogenic/Likely pathogenic, Noonan syndrome and Noonan-related syndrome; Non-immune hydrops fetalis; Epiderm
- G13S (p.Gly13Ser), rs104894228, Ensembl rs104894228, ClinGen CA16602769, NCI-TCGA Cosmic COSV5423, AlphaMissense 0.98, MetaLR 0.48, Likely pathogenic, Costello syndrome
- G13V (p.Gly13Val), rs104894226, Ensembl rs104894226, ClinGen CA296055, NCI-TCGA Cosmic COSV5423, AlphaMissense 0.99, MetaLR 0.65, Pathogenic/Likely pathogenic, Large congenital melanocytic nevus; not provided; Costello syndrome
- V14E (p.Val14Glu), Ensembl rs1589793707, Uncertain significance
- V14G (p.Val14Gly), rs1589793707, ClinGen CA378925982, cosmic curated COSV54244, ClinVar RCV000810329, REVEL 0.87, AlphaMissense 0.84, Uncertain significance, Costello syndrome
- V14L (p.Val14Leu), Ensembl rs2133994832
- V14M (p.Val14Met), Ensembl rs2133994832
- G15A (p.Gly15Ala), rs1554885139, ClinGen CA378925961, ClinVar RCV001922109, Ensembl rs1554885139, AlphaMissense 1.00, MetaLR 0.98, Uncertain significance, Costello syndrome
- G15C (p.Gly15Cys), Ensembl rs2133994803
- G15D (p.Gly15Asp), rs1554885139, ClinGen CA378925957, cosmic curated COSV54246, ClinVar RCV000662271, AlphaMissense 1.00, MetaLR 0.98, Uncertain significance, Vascular Tumors Including Pyogenic Granuloma
- G15R (p.Gly15Arg), Ensembl rs2133994803
- G15S (p.Gly15Ser), cosmic curated COSV54244, Ensembl rs2133994803
- G15V (p.Gly15Val), rs1554885139, ClinGen CA378925964, ClinVar RCV003057955, Ensembl rs1554885139, AlphaMissense 1.00, MetaLR 0.98, Uncertain significance, Costello syndrome
- K16E (p.Lys16Glu), Ensembl rs2133994767
- K16M (p.Lys16Met), Ensembl rs2133994758
- K16N (p.Lys16Asn), Ensembl rs2133994746, Uncertain significance, not provided
- K16R (p.Lys16Arg), Ensembl rs2133994758, cosmic curated COSV54249
- K16T (p.Lys16Thr), cosmic curated COSV54240, SIFT 0.03
- S17C (p.Ser17Cys), Ensembl rs2133994736
- S17G (p.Ser17Gly), cosmic curated COSV54240
- S17I (p.Ser17Ile), Ensembl rs2133994723
- S17N (p.Ser17Asn), Ensembl rs2133994723, cosmic curated COSV99530
- S17R (p.Ser17Arg), Ensembl rs2133994714
- S17T (p.Ser17Thr), Ensembl rs2133994723, cosmic curated COSV99529, SIFT 0.03
- A18E (p.Ala18Glu), Ensembl rs2133994692
- A18G (p.Ala18Gly), Ensembl rs2133994692
- A18P (p.Ala18Pro), Ensembl rs2133994706
- A18T (p.Ala18Thr), cosmic curated COSV54237
- A18V (p.Ala18Val), cosmic curated COSV54236, Ensembl rs2133994692, SIFT 0.02
- L19M (p.Leu19Met), rs2133994674, ClinGen CA378925856, ClinVar RCV003111807, AlphaMissense 0.57, MetaLR 0.58, Uncertain significance, Costello syndrome
- L19Q (p.Leu19Gln), Ensembl rs2133994664
- L19V (p.Leu19Val), Ensembl rs2133994674, Likely benign
- T20A (p.Thr20Ala), Ensembl rs2133994636
- T20I (p.Thr20Ile), rs1851317850, ClinGen CA378925822, cosmic curated COSV54248, ClinVar RCV003514667, AlphaMissense 0.94, MetaLR 0.62, Uncertain significance, Costello syndrome
- T20P (p.Thr20Pro), Ensembl rs2133994636
- T20S (p.Thr20Ser), Ensembl rs2133994636, SIFT 0.00, Uncertain significance
- I21F (p.Ile21Phe), Ensembl rs2133994602
- I21M (p.Ile21Met), TOPMed rs1851317598
- I21N (p.Ile21Asn), Ensembl rs2133994591
- I21S (p.Ile21Ser), Ensembl rs2133994591
- I21T (p.Ile21Thr), Ensembl rs2133994591, SIFT 0.01
- Q22* (p.Gln22Ter), rs121917757, ClinGen CA5779431, cosmic curated COSV54249, ClinVar RCV000269895, AlphaMissense 0.97, MetaLR 0.48, Pathogenic, in CMEMS
- Q22H (p.Gln22His), ExAC rs749193206, gnomAD rs749193206
- Q22K (p.Gln22Lys), rs121917757, ClinGen CA122553, cosmic curated COSV54249, ClinVar RCV000013443, AlphaMissense 0.97, MetaLR 0.48, Likely pathogenic, HRAS-related disorder; not provided; Costello syndrome
- Q22R (p.Gln22Arg), TOPMed rs1445047175, gnomAD rs1445047175, REVEL 0.41, AlphaMissense 0.85
- L23P (p.Leu23Pro), Ensembl rs2133994532
- L23Q (p.Leu23Gln), Ensembl rs2133994532
- L23V (p.Leu23Val), Ensembl rs2133994539, Likely benign
- I24M (p.Ile24Met), gnomAD rs1227307993
- I24N (p.Ile24Asn), Ensembl rs2133994492
- I24S (p.Ile24Ser), Ensembl rs2133994492
- I24V (p.Ile24Val), Ensembl rs2133994508, SIFT 0.00
- Q25* (p.Gln25Ter), Ensembl rs2133994479
- Q25H (p.Gln25His), ExAC rs779600254, TOPMed rs779600254, gnomAD rs779600254, cosmic curated COSV54248
- Q25R (p.Gln25Arg), rs2539802400, ClinGen CA378925198, ClinVar RCV003828868, Uncertain significance, Costello syndrome
- N26D (p.Asn26Asp), cosmic curated COSV54243
- N26H (p.Asn26His), Ensembl rs2133994454
- N26I (p.Asn26Ile), Ensembl rs2133994440
- N26K (p.Asn26Lys), Ensembl rs2133994430
- N26S (p.Asn26Ser), Ensembl rs2133994440
- N26T (p.Asn26Thr), Ensembl rs2133994440
- N26Y (p.Asn26Tyr), Ensembl rs2133994454
- H27D (p.His27Asp), Ensembl rs2133994418
- H27L (p.His27Leu), Ensembl rs2133994409
- H27N (p.His27Asn), Ensembl rs2133994418, SIFT 0.00
- H27Y (p.His27Tyr), Ensembl rs2133994418, REVEL 0.45, AlphaMissense 0.46
- V29E (p.Val29Glu), Ensembl rs2133994386
- D30A (p.Asp30Ala), cosmic curated COSV10720
- D30E (p.Asp30Glu), ExAC rs745489020, TOPMed rs745489020, gnomAD rs745489020, REVEL 0.35, AlphaMissense 0.35, Likely benign
- D30G (p.Asp30Gly), Ensembl rs2133994355, REVEL 0.64, AlphaMissense 0.74
- D30H (p.Asp30His), gnomAD rs1226305644, Uncertain significance
- D30N (p.Asp30Asn), rs1226305644, ClinGen CA378925062, ClinVar RCV001996287, gnomAD rs1226305644, REVEL 0.36, AlphaMissense 0.68, Uncertain significance, Costello syndrome
- D30Y (p.Asp30Tyr), gnomAD rs1226305644, Uncertain significance
- E31* (p.Glu31Ter), Ensembl rs2133994335, cosmic curated COSV99529, Uncertain significance
- E31D (p.Glu31Asp), cosmic curated COSV10960
- E31K (p.Glu31Lys), Ensembl rs2133994335, cosmic curated COSV54245, Uncertain significance
- E31Q (p.Glu31Gln), rs2133994335, Ensembl rs2133994335, ClinGen CA378925029, ClinVar RCV003628135, AlphaMissense 0.78, MetaLR 0.30, Uncertain significance, Costello syndrome
- E31V (p.Glu31Val), Ensembl rs2133994324, SIFT 0.01
- Y32* (p.Tyr32Ter), cosmic curated COSV54236, ESP rs369039481, ExAC rs369039481, gnomAD rs369039481, CADD 31.00, Likely benign
- Y32C (p.Tyr32Cys), Ensembl rs2133994304, cosmic curated COSV54240
- Y32D (p.Tyr32Asp), Ensembl rs2133994310
- Y32F (p.Tyr32Phe), Ensembl rs2133994304
- Y32H (p.Tyr32His), Ensembl rs2133994310
- Y32N (p.Tyr32Asn), Ensembl rs2133994310
- Y32S (p.Tyr32Ser), Ensembl rs2133994304, SIFT 0.03
- D33A (p.Asp33Ala), Ensembl rs2133994258
- D33E (p.Asp33Glu), rs756934316, ExAC rs756934316, gnomAD rs756934316, ClinGen CA378924972, REVEL 0.42, AlphaMissense 0.99, Uncertain significance, Costello syndrome
- D33G (p.Asp33Gly), Ensembl rs2133994258
- D33H (p.Asp33His), NCI-TCGA Cosmic COSV5423, NCI-TCGA Cosmic COSV5424, Ensembl rs1851315835, Uncertain significance
- D33N (p.Asp33Asn), rs1851315835, ClinGen CA378924982, NCI-TCGA Cosmic COSV5423, NCI-TCGA Cosmic COSV5424, AlphaMissense 0.99, MetaLR 0.51, Uncertain significance, Costello syndrome
- D33V (p.Asp33Val), Ensembl rs2133994258
- D33Y (p.Asp33Tyr), cosmic curated COSV54238, Ensembl rs1851315835, Uncertain significance, Costello syndrome
- P34H (p.Pro34His), Ensembl rs2133994210, SIFT 0.00, Uncertain significance
- P34L (p.Pro34Leu), rs2133994210, ClinGen CA378924959, cosmic curated COSV10720, ClinVar RCV001360851, REVEL 0.81, AlphaMissense 1.00, Likely benign, not specified; Costello syndrome
- P34R (p.Pro34Arg), Ensembl rs2133994210, REVEL 0.85, AlphaMissense 0.99, Uncertain significance
- P34S (p.Pro34Ser), rs1348427922, ClinGen CA378924962, cosmic curated COSV54246, ClinVar RCV000662272, REVEL 0.77, AlphaMissense 1.00, Uncertain significance, Cardiovascular phenotype; Costello syndrome
- P34T (p.Pro34Thr), gnomAD rs1348427922, REVEL 0.80, AlphaMissense 1.00, Uncertain significance
- T35A (p.Thr35Ala), rs2133994194, Ensembl rs2133994194, ClinGen CA378924949, ClinVar RCV001997641, AlphaMissense 0.99, MetaLR 0.78, Uncertain significance, Costello syndrome
- T35S (p.Thr35Ser), Ensembl rs2133994186, REVEL 0.75, AlphaMissense 0.99
- I36K (p.Ile36Lys), Ensembl rs775056058, Uncertain significance
- I36L (p.Ile36Leu), Ensembl rs1060502663, Uncertain significance
- I36T (p.Ile36Thr), rs775056058, ClinGen CA216883279, ClinVar RCV001888117, Ensembl rs775056058, REVEL 0.88, AlphaMissense 1.00, Uncertain significance, Costello syndrome
- I36V (p.Ile36Val), rs1060502663, ClinGen CA16613600, cosmic curated COSV54242, ClinVar RCV000475424, AlphaMissense 0.95, MetaLR 0.43, Uncertain significance, Costello syndrome
- E37* (p.Glu37Ter), Ensembl rs2133994136
- E37D (p.Glu37Asp), Ensembl rs1851314734, cosmic curated COSV99531
- E37K (p.Glu37Lys), Ensembl rs2133994136
- E37V (p.Glu37Val), Ensembl rs2133994119
- D38A (p.Asp38Ala), Ensembl rs2133991872
- D38E (p.Asp38Glu), Ensembl rs2133991862, cosmic curated COSV10720
- D38H (p.Asp38His), ExAC rs750680771, gnomAD rs750680771, REVEL 0.85, AlphaMissense 1.00
- D38N (p.Asp38Asn), ExAC rs750680771, gnomAD rs750680771
- D38V (p.Asp38Val), Ensembl rs2133991872
- D38Y (p.Asp38Tyr), ExAC rs750680771, gnomAD rs750680771
- S39C (p.Ser39Cys), Ensembl rs2133991841, REVEL 0.69, AlphaMissense 0.81
- S39F (p.Ser39Phe), Ensembl rs2133991841
- S39T (p.Ser39Thr), rs2133991854, ClinGen CA378924818, ClinVar RCV001948765, Ensembl rs2133991854, AlphaMissense 0.74, MetaLR 0.32, Uncertain significance, Costello syndrome
- S39Y (p.Ser39Tyr), Ensembl rs2133991841, SIFT 0.00
- Y40* (p.Tyr40Ter), ExAC rs763920334, gnomAD rs763920334, Likely benign
- Y40F (p.Tyr40Phe), Ensembl rs2133991806
- Y40H (p.Tyr40His), Ensembl rs2133991816
- Y40N (p.Tyr40Asn), Ensembl rs2133991816
- R41G (p.Arg41Gly), Ensembl rs2133991780
- R41L (p.Arg41Leu), Ensembl rs868439179, Uncertain significance
- R41P (p.Arg41Pro), rs868439179, Ensembl rs868439179, ClinGen CA378924801, ClinVar RCV002790114, AlphaMissense 0.99, MetaLR 0.42, Uncertain significance, Costello syndrome
- R41Q (p.Arg41Gln), rs868439179, Ensembl rs868439179, ClinGen CA378924802, NCI-TCGA Cosmic COSV5424, AlphaMissense 0.99, MetaLR 0.42, Conflicting interpretations, Costello syndrome
- R41W (p.Arg41Trp), Ensembl rs2133991780, SIFT 0.02
- K42* (p.Lys42Ter), Ensembl rs2133991738
- K42E (p.Lys42Glu), Ensembl rs2133991738
- K42M (p.Lys42Met), Ensembl rs2133991728
Public HRAS analysis runs
- HRAS analysis run — HRAS (949 variants) — completed 2026-08-18