HMGCR (P04035) variants and mutations
HMGCR (also known as P04035) is a human protein-coding gene encoding a 3-hydroxy-3-methylglutaryl-coenzyme A reductase protein. It controls the rate-limiting step of the mevalonate pathway and therefore strongly regulates endogenous cholesterol production. Statins lower LDL cholesterol by inhibiting this activity, causing the liver to increase LDL-receptor-mediated clearance from blood. This analysis covers 981 HMGCR variants and mutations. Of these, 73% have computational variant effect predictions. Disease context includes Hypercholesterolemia, hyperlipidemia, and coronary artery disorder. Example HMGCR variants include L2L, S3L, and S3*.
Variant analysis overview
- Gene: HMGCR
- Protein: P04035
- UniProt accession: P04035
- Organism: Homo sapiens
- Variants analyzed: 981
- Variant scope: all variants
- Completed: 2026-08-18
Variant and mutation evidence
- Variant composition: 763 unspecified-consequence records; 74 synonymous variants; 120 missense variants; 8 stop-gained variants; 11 frameshift variants; 3 splice-region variants; 2 substitution
- Prediction scores: 714 variants have prediction scores (73% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: Hypercholesterolemia, hyperlipidemia, coronary artery disorder, familial hypercholesterolemia, stroke disorder, cardiovascular disorder, muscular dystrophy, limb-girdle, autosomal recessive 28, type 2 diabetes mellitus, myocardial infarction, angina pectoris, congestive heart failure, Abnormal circulating lipid concentration.
Protein structure and variant hotspots
- Protein features: 8 transmembrane segments; 1 domains; 6 binding sites; 4 post-translational modification sites.
- Structural context: 394 variants have structural context.
- PTM context: 2 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 HMGCR variants
Examples include L2L, S3L, S3*, R4T, R4G, L5L, F6S, R7*. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- L2L (p.Leu2Leu), gnomAD 5-75342609-T-C, CADD 8.86
- S3L (p.Ser3Leu), gnomAD 5-75342613-C-T, REVEL 0.28, CADD 23.90
- S3* (p.Ser3Ter), gnomAD 5-75342613-C-G, CADD 36.00
- R4T (p.Arg4Thr), cosmic curated COSV10460
- R4G (p.Arg4Gly), gnomAD 5-75342615-A-G, REVEL 0.39, CADD 22.30
- L5L (p.Leu5Leu), rs1457215934, gnomAD 5-75342620-T-A, CADD 8.25
- F6S (p.Phe6Ser), rs1338918395, gnomAD 5-75342618-CTT-C, CADD 29.40
- R7* (p.Arg7Ter), cosmic curated COSV10515, CADD 36.00
- R7G (p.Arg7Gly), cosmic curated COSV55316
- R7L (p.Arg7Leu), ExAC rs751171582, TOPMed rs751171582, gnomAD rs751171582
- R7P (p.Arg7Pro), ExAC rs751171582, TOPMed rs751171582, gnomAD rs751171582, REVEL 0.51, CADD 31.00
- R7Q (p.Arg7Gln), cosmic curated COSV99843, ExAC rs751171582, TOPMed rs751171582, gnomAD rs751171582, REVEL 0.16, CADD 24.10
- M8T (p.Met8Thr), TOPMed rs1051046202, REVEL 0.13, CADD 22.00
- M8V (p.Met8Val), gnomAD rs1267761914, REVEL 0.14, CADD 18.70
- H9R (p.His9Arg), gnomAD rs1399840363, REVEL 0.67, CADD 26.20
- G10D (p.Gly10Asp), NCI-TCGA TCGA novel, Ensembl rs2150352999, Variant assessed as somatic; moderate impact.
- G10G (p.Gly10Gly), rs1284474140, gnomAD 5-75342635-C-A, CADD 12.80
- L11L (p.Leu11Leu), rs1760048477, gnomAD 5-75342638-C-T, CADD 11.90
- V13V (p.Val13Val), gnomAD 5-75342644-G-C, CADD 11.70
- A14G (p.Ala14Gly), ExAC rs763611929, TOPMed rs763611929, gnomAD rs763611929, REVEL 0.42, CADD 27.30
- A14V (p.Ala14Val), ExAC rs763611929, TOPMed rs763611929, gnomAD rs763611929, REVEL 0.43, CADD 24.40
- A14A (p.Ala14Ala), rs1760048909, gnomAD 5-75342647-C-T, CADD 12.60
- S15P (p.Ser15Pro), TOPMed rs1760049073, REVEL 0.42, CADD 31.00
- S15F (p.Ser15Phe), gnomAD 5-75342649-C-T, REVEL 0.47, CADD 27.40
- S15S (p.Ser15Ser), gnomAD 5-75342650-C-T, CADD 13.10
- H16P (p.His16Pro), gnomAD rs1201009521, REVEL 0.74, CADD 27.80
- P17A (p.Pro17Ala), gnomAD rs1416769598
- P17S (p.Pro17Ser), cosmic curated COSV10515
- P17H (p.Pro17His), gnomAD 5-75342655-C-A, REVEL 0.56, CADD 26.40
- P17P (p.Pro17Pro), gnomAD 5-75342656-C-T, CADD 10.70
- W18* (p.Trp18Ter), cosmic curated COSV55317
- W18L (p.Trp18Leu), cosmic curated COSV99073
- W18C (p.Trp18Cys), gnomAD 5-75342659-G-C, REVEL 0.65, CADD 32.00
- V20F (p.Val20Phe), ExAC rs780893840, gnomAD rs780893840, REVEL 0.64, CADD 28.70
- V20V (p.Val20Val), rs892502039, gnomAD 5-75342665-C-T, CADD 9.82
- I21T (p.Ile21Thr), ExAC rs745371345, TOPMed rs745371345, gnomAD rs745371345, REVEL 0.66, CADD 27.80
- V22A (p.Val22Ala), TOPMed rs1273881990, REVEL 0.60, CADD 28.20
- V22L (p.Val22Leu), NCI-TCGA Cosmic COSV9984, cosmic curated COSV99843, Variant assessed as somatic; moderate impact.
- G23A (p.Gly23Ala), gnomAD 5-75342673-G-C, REVEL 0.27, CADD 20.00
- T24S (p.Thr24Ser), gnomAD 5-75342675-A-T, REVEL 0.27, CADD 26.50
- T24R (p.Thr24Arg), gnomAD 5-75342676-C-G, REVEL 0.57, CADD 25.40
- T24T (p.Thr24Thr), gnomAD 5-75342677-A-C, CADD 3.29
- V25M (p.Val25Met), TOPMed rs1218851648, gnomAD rs1218851648, REVEL 0.16, CADD 23.90
- V25L (p.Val25Leu), gnomAD 5-75342678-G-C, REVEL 0.16, CADD 18.20
- T26S (p.Thr26Ser), gnomAD 5-75342681-A-T, REVEL 0.26, CADD 25.10
- T26T (p.Thr26Thr), gnomAD 5-75342683-A-G, CADD 12.80
- L27V (p.Leu27Val), ESP rs367706109, ExAC rs367706109, TOPMed rs367706109, gnomAD rs367706109, REVEL 0.12, CADD 18.10
- L27L (p.Leu27Leu), rs367706109, gnomAD 5-75342684-C-T, CADD 12.00
- T28S (p.Thr28Ser), gnomAD 5-75342686-G-GTCC, CADD 29.90
- T28P (p.Thr28Pro), gnomAD 5-75342687-A-C, REVEL 0.69, CADD 28.40
- T28T (p.Thr28Thr), rs1162669029, gnomAD 5-75342689-C-T, CADD 11.60
- I29T (p.Ile29Thr), Ensembl rs1760050981
- I29S (p.Ile29Ser), gnomAD 5-75342687-AC-A, CADD 28.40
- I29I (p.Ile29Ile), rs1365225685, gnomAD 5-75342692-C-T, CADD 13.30
- C30G (p.Cys30Gly), Ensembl rs1561194850
- M31I (p.Met31Ile), NCI-TCGA Cosmic COSV9984, cosmic curated COSV99843, Variant assessed as somatic; moderate impact.
- M31V (p.Met31Val), ExAC rs769016687, gnomAD rs769016687, REVEL 0.10, CADD 19.70
- M32T (p.Met32Thr), ESP rs371769368, ExAC rs371769368, gnomAD rs371769368, REVEL 0.15, CADD 22.90
- M32I (p.Met32Ile), gnomAD 5-75342701-G-T, REVEL 0.06, CADD 22.60
- S33P (p.Ser33Pro), gnomAD 5-75342702-T-C, REVEL 0.39, CADD 28.70
- S33S (p.Ser33Ser), gnomAD 5-75342704-C-A, CADD 11.40
- M34V (p.Met34Val), cosmic curated COSV99843
- N35S (p.Asn35Ser), TOPMed rs1009595037
- M36V (p.Met36Val), ESP rs201541062, ExAC rs201541062, TOPMed rs201541062, gnomAD rs201541062, REVEL 0.23, CADD 20.30
- F37L (p.Phe37Leu), NCI-TCGA Cosmic COSV5531, cosmic curated COSV55317, Variant assessed as somatic; moderate impact.
- G39W (p.Gly39Trp), gnomAD 5-75342718-C-CT, CADD 28.50
- N40S (p.Asn40Ser), TOPMed rs1381654025, gnomAD rs1381654025, REVEL 0.11, CADD 18.10
- N41S (p.Asn41Ser), ExAC rs772179314, gnomAD rs772179314, REVEL 0.06, CADD 7.89
- K42T (p.Lys42Thr), NCI-TCGA Cosmic COSV5531, cosmic curated COSV55314, Variant assessed as somatic; moderate impact.
- K42N (p.Lys42Asn), gnomAD 5-75342731-G-C, REVEL 0.08, CADD 22.60
- K42K (p.Lys42Lys), rs1760052673, gnomAD 5-75342731-G-A, CADD 13.60
- I43S (p.Ile43Ser), cosmic curated COSV55316
- I43V (p.Ile43Val), ExAC rs773624826, gnomAD rs773624826, REVEL 0.03, CADD 21.10
- I43I (p.Ile43Ile), rs1760052965, gnomAD 5-75342734-C-A, CADD 13.00
- C44L (p.Cys44Leu), gnomAD 5-75342734-C-CT, CADD 32.00
- C44C (p.Cys44Cys), rs760814083, gnomAD 5-75342737-T-C, CADD 11.90
- G45G (p.Gly45Gly), rs766602846, gnomAD 5-75342740-T-C, CADD 10.00
- N47K (p.Asn47Lys), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- N47N (p.Asn47Asn), gnomAD 5-75342746-T-C, CADD 12.50
- Y48Y (p.Tyr48Tyr), rs1359795975, gnomAD 5-75342749-T-C, CADD 5.17
- E49* (p.Glu49Ter), cosmic curated COSV55317
- E49Q (p.Glu49Gln), gnomAD 5-75342750-G-C, REVEL 0.38, CADD 22.10
- E49G (p.Glu49Gly), gnomAD 5-75342751-A-G, REVEL 0.45, CADD 23.20
- C50F (p.Cys50Phe), NCI-TCGA Cosmic COSV9984, cosmic curated COSV99842, Variant assessed as somatic; moderate impact.
- C50G (p.Cys50Gly), ESP rs369987181, ExAC rs369987181, TOPMed rs369987181, gnomAD rs369987181, REVEL 0.93, CADD 29.60
- C50R (p.Cys50Arg), ESP rs369987181, ExAC rs369987181, TOPMed rs369987181, gnomAD rs369987181, REVEL 0.96, CADD 31.00
- C50Y (p.Cys50Tyr), gnomAD 5-75342754-G-A, REVEL 0.86, CADD 29.30
- C50C (p.Cys50Cys), gnomAD 5-75342755-T-C, CADD 13.20
- P51A (p.Pro51Ala), gnomAD 5-75342756-C-G, REVEL 0.62, CADD 23.20
- P51P (p.Pro51Pro), rs1022403092, gnomAD 5-75342758-A-T, CADD 6.92
- F53S (p.Phe53Ser), ExAC rs764673047, TOPMed rs764673047, gnomAD rs764673047, REVEL 0.32, CADD 23.00, Uncertain significance, Inborn genetic diseases
- F53I (p.Phe53Ile), gnomAD 5-75342762-T-A, REVEL 0.19, CADD 22.00
- E54Q (p.Glu54Gln), cosmic curated COSV55314
- D56E (p.Asp56Glu), ExAC rs765808919, gnomAD rs765808919, REVEL 0.24, CADD 17.00
- D56N (p.Asp56Asn), cosmic curated COSV55314, REVEL 0.38, CADD 25.00
- D56Y (p.Asp56Tyr), gnomAD 5-75343853-G-T, REVEL 0.62, CADD 33.00
- D56G (p.Asp56Gly), gnomAD 5-75343854-A-G, REVEL 0.45, CADD 26.60
- D56D (p.Asp56Asp), gnomAD 5-75343855-T-C, CADD 15.20
- V57I (p.Val57Ile), TOPMed rs1760111571, REVEL 0.34, CADD 21.80
- V57A (p.Val57Ala), gnomAD 5-75343857-T-C, REVEL 0.50, CADD 22.50
- V57D (p.Val57Asp), gnomAD 5-75343857-T-A, REVEL 0.61, CADD 23.10
- V57V (p.Val57Val), gnomAD 5-75343858-T-G, CADD 8.44
- L58L (p.Leu58Leu), gnomAD 5-75343859-T-C, CADD 9.48
- L58S (p.Leu58Ser), gnomAD 5-75343860-T-C, REVEL 0.47, CADD 22.00
- L58F (p.Leu58Phe), gnomAD 5-75343861-G-T, REVEL 0.57, CADD 21.80
- S59G (p.Ser59Gly), gnomAD rs1232088692, REVEL 0.58, CADD 23.20
- S59N (p.Ser59Asn), gnomAD 5-75343863-G-A, REVEL 0.47, CADD 23.10
- S59R (p.Ser59Arg), gnomAD 5-75343864-C-A, REVEL 0.72, CADD 22.20
- S59S (p.Ser59Ser), rs1469871771, gnomAD 5-75343864-C-T, CADD 14.10
- S60G (p.Ser60Gly), gnomAD 5-75343865-A-G, REVEL 0.27, CADD 23.10
- S60N (p.Ser60Asn), gnomAD 5-75343866-G-A, REVEL 0.56, CADD 24.40
- S60S (p.Ser60Ser), gnomAD 5-75343867-T-C, CADD 11.70
- D61V (p.Asp61Val), gnomAD 5-75343869-A-T, REVEL 0.93, CADD 29.80
- D61E (p.Asp61Glu), gnomAD 5-75343870-C-A, REVEL 0.72, CADD 24.10
- I62V (p.Ile62Val), gnomAD rs1178012749, REVEL 0.30, CADD 18.40, Uncertain significance, Inborn genetic diseases
- I62T (p.Ile62Thr), gnomAD 5-75343872-T-C, REVEL 0.70, CADD 23.10
- I63V (p.Ile63Val), gnomAD 5-75343874-A-G, REVEL 0.49, CADD 21.30
- I64V (p.Ile64Val), gnomAD 5-75343877-A-G, REVEL 0.30, CADD 19.30
- I64T (p.Ile64Thr), gnomAD 5-75343878-T-C, REVEL 0.67, CADD 23.90
- L65V (p.Leu65Val), NCI-TCGA Cosmic COSV5531, cosmic curated COSV55314, Variant assessed as somatic; moderate impact.
- L65M (p.Leu65Met), gnomAD 5-75343880-C-A, REVEL 0.52, CADD 18.40
- L65P (p.Leu65Pro), gnomAD 5-75343881-T-C, REVEL 0.91, CADD 29.60
- L65L (p.Leu65Leu), gnomAD 5-75343882-G-T, CADD 9.77
- T66A (p.Thr66Ala), gnomAD 5-75343883-A-G, REVEL 0.74, CADD 25.60
- T66I (p.Thr66Ile), gnomAD 5-75343884-C-T, REVEL 0.80, CADD 23.90
- T66K (p.Thr66Lys), gnomAD 5-75343884-C-A, REVEL 0.87, CADD 25.90
- I67V (p.Ile67Val), cosmic curated COSV55317, TOPMed rs1479509540, gnomAD rs1479509540, REVEL 0.24, CADD 19.90
- I67I (p.Ile67Ile), gnomAD 5-75343888-A-T, CADD 13.40
- T68I (p.Thr68Ile), gnomAD 5-75343890-C-T, REVEL 0.60, CADD 20.60
- T68K (p.Thr68Lys), gnomAD 5-75343890-C-A, REVEL 0.89, CADD 26.20
- T68T (p.Thr68Thr), rs1175771124, gnomAD 5-75343891-A-G, CADD 10.60
- R69* (p.Arg69Ter), TOPMed rs1580655061, CADD 36.00
- R69Q (p.Arg69Gln), rs1430662318, NCI-TCGA Cosmic COSV5531, cosmic curated COSV55316, TOPMed rs1430662318, REVEL 0.79, CADD 32.00, Variant assessed as somatic; moderate impact.
- C70F (p.Cys70Phe), gnomAD rs1487837370, REVEL 0.81, CADD 29.80
- C70Y (p.Cys70Tyr), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- C70S (p.Cys70Ser), gnomAD 5-75343896-G-C, REVEL 0.78, CADD 23.40
- C70* (p.Cys70Ter), gnomAD 5-75343897-C-A, CADD 35.00
- C70C (p.Cys70Cys), rs1199932455, gnomAD 5-75343897-C-T, CADD 13.00
- I71V (p.Ile71Val), Ensembl rs1320230215
- I71T (p.Ile71Thr), gnomAD 5-75343899-T-C, REVEL 0.69, CADD 23.00
- A72P (p.Ala72Pro), gnomAD 5-75343901-G-C, REVEL 0.86, CADD 29.20
- A72G (p.Ala72Gly), gnomAD 5-75343902-C-G, REVEL 0.81, CADD 26.20
- A72D (p.Ala72Asp), gnomAD 5-75343902-C-A, REVEL 0.89, CADD 26.50
- I73V (p.Ile73Val), ExAC rs753282492, gnomAD rs753282492, REVEL 0.35, CADD 20.60
- L74M (p.Leu74Met), 1000Genomes rs1760113958, TOPMed rs1760113958, REVEL 0.63, CADD 24.40
- L74V (p.Leu74Val), cosmic curated COSV55317
- L74P (p.Leu74Pro), gnomAD 5-75343908-T-C, REVEL 0.95, CADD 29.40
- L74L (p.Leu74Leu), rs1240788209, gnomAD 5-75343909-G-T, CADD 8.60
- Y75C (p.Tyr75Cys), gnomAD 5-75343911-A-G, REVEL 0.95, CADD 29.30
- I76V (p.Ile76Val), gnomAD 5-75343913-A-G, REVEL 0.63, CADD 22.80
- Y77* (p.Tyr77Ter), NCI-TCGA Cosmic COSV9984, cosmic curated COSV99842, Variant assessed as somatic; high impact.
- F78L (p.Phe78Leu), TOPMed rs1760114290, gnomAD rs1760114290, REVEL 0.50, CADD 22.60
- F78F (p.Phe78Phe), rs1760114290, gnomAD 5-75343921-C-T, CADD 14.40
- Q79K (p.Gln79Lys), gnomAD 5-75343922-C-A, REVEL 0.89, CADD 25.10
- Q79H (p.Gln79His), gnomAD 5-75343924-G-T, REVEL 0.77, CADD 23.80
- Q79Q (p.Gln79Gln), gnomAD 5-75343924-G-A, CADD 10.50
- F80L (p.Phe80Leu), gnomAD 5-75343925-T-C, REVEL 0.84, CADD 23.60
- Q81R (p.Gln81Arg), gnomAD 5-75343929-A-G, REVEL 0.34, CADD 21.00
- Q81Q (p.Gln81Gln), rs1270933778, gnomAD 5-75343930-G-A, CADD 12.00
- L83L (p.Leu83Leu), rs1760114662, gnomAD 5-75343936-A-G, CADD 11.80
- R84C (p.Arg84Cys), rs1354325261, NCI-TCGA Cosmic COSV5531, cosmic curated COSV55315, gnomAD rs1354325261, REVEL 0.78, CADD 28.80, Variant assessed as somatic; moderate impact.
- R84H (p.Arg84His), rs372565038, cosmic curated COSV55315, ESP rs372565038, ExAC rs372565038, REVEL 0.59, CADD 23.30, Variant assessed as somatic; moderate impact.
- Q85K (p.Gln85Lys), gnomAD 5-75343940-C-A, REVEL 0.44, CADD 19.70
- Q85R (p.Gln85Arg), gnomAD 5-75343941-A-G, REVEL 0.41, CADD 22.30
- Q85Q (p.Gln85Gln), rs779264659, gnomAD 5-75343942-A-G, CADD 5.86
- L86I (p.Leu86Ile), gnomAD 5-75343943-C-A, REVEL 0.21, CADD 23.60
- L86P (p.Leu86Pro), gnomAD 5-75343944-T-C, REVEL 0.76, CADD 29.50
- L86L (p.Leu86Leu), gnomAD 5-75343945-T-G, CADD 12.40
- G87* (p.Gly87Ter), cosmic curated COSV55317, CADD 39.00
- G87R (p.Gly87Arg), gnomAD 5-75343946-G-A, REVEL 0.87, CADD 33.00
- S88P (p.Ser88Pro), gnomAD 5-75343949-T-C, REVEL 0.94, CADD 31.00
- S88* (p.Ser88Ter), gnomAD 5-75343950-C-A, CADD 37.00
- S88S (p.Ser88Ser), gnomAD 5-75343951-A-G, CADD 10.30
- K89E (p.Lys89Glu), gnomAD 5-75343952-A-G, REVEL 0.93, CADD 29.40
- Y90C (p.Tyr90Cys), cosmic curated COSV55314
- Y90H (p.Tyr90His), gnomAD 5-75343955-T-C, REVEL 0.92, CADD 29.60
- I91T (p.Ile91Thr), gnomAD 5-75343959-T-C, REVEL 0.88, CADD 27.90
- I91I (p.Ile91Ile), rs748728085, gnomAD 5-75343960-T-C, CADD 14.00
- L92W (p.Leu92Trp), gnomAD 5-75343958-AT-A, CADD 32.00
- L92L (p.Leu92Leu), gnomAD 5-75343963-G-A, CADD 14.60
Public HMGCR analysis runs
- HMGCR analysis run — HMGCR (981 variants) — completed 2026-08-18