SMO (Protein smoothened) variants and mutations
SMO (also known as Protein smoothened) is a human protein-coding gene encoding a protein smoothened protein. It transmits Hedgehog signals across the membrane after inhibition by PTCH1 is relieved, activating GLI-dependent developmental transcription. Activating variants or upstream pathway loss can drive basal-cell carcinoma, medulloblastoma, and other Hedgehog-dependent tumors. This analysis covers 3,706 SMO variants and mutations. Of these, 39% have computational variant effect predictions. Disease context includes Curry-Jones syndrome, basal cell carcinoma, and congenital hypothalamic hamartoma syndrome. Example SMO variants include A2D, A2G, and A2P.
Variant analysis overview
- Gene: SMO
- Protein: Protein smoothened
- UniProt accession: Q99835
- Organism: Homo sapiens
- Variants analyzed: 3706
- Variant scope: all variants
- Completed: 2026-08-19
Variant and mutation evidence
- Variant composition: 3,461 unspecified-consequence records; 102 synonymous variants; 103 missense variants; 18 frameshift variants; 7 in-frame deletions; 5 in-frame insertions; 2 stop-gained variants; 1 splice-region variants; 7 substitution
- Prediction scores: 1,449 variants have prediction scores (39% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: Curry-Jones syndrome, basal cell carcinoma, congenital hypothalamic hamartoma syndrome, acute myeloid leukemia, medulloblastoma, neoplasm, Hirschsprung disease, osteoarthritis, hip, microcephaly, meningioma, skin basal cell carcinoma, ameloblastoma.
Protein structure and variant hotspots
- Protein features: 7 transmembrane segments; 1 domains; 3 binding sites; 13 post-translational modification sites.
- Structural context: 1,234 variants have structural context.
- PTM context: 55 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 SMO variants
Examples include A2D, A2G, A2P, A2S, A2T, A2V, A2A, A3G. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- A2D (p.Ala2Asp), gnomAD rs1563144479, REVEL 0.40, MetaLR 0.42
- A2G (p.Ala2Gly), gnomAD rs1563144479, REVEL 0.36, MetaLR 0.38
- A2P (p.Ala2Pro), Ensembl rs2150637710
- A2S (p.Ala2Ser), Ensembl rs2150637710, REVEL 0.35, MetaLR 0.33
- A2T (p.Ala2Thr), Ensembl rs2150637710, REVEL 0.39, MetaLR 0.35
- A2V (p.Ala2Val), gnomAD rs1563144479, REVEL 0.41, MetaLR 0.33
- A2A (p.Ala2Ala), rs1793442217, gnomAD 7-129189157-C-T, CADD 13.50
- A3G (p.Ala3Gly), Ensembl rs2150637719
- A3P (p.Ala3Pro), 1000Genomes rs562868539, TOPMed rs562868539
- A3S (p.Ala3Ser), 1000Genomes rs562868539, TOPMed rs562868539, REVEL 0.23, MetaLR 0.21
- A3T (p.Ala3Thr), 1000Genomes rs562868539, TOPMed rs562868539, REVEL 0.18, MetaLR 0.21
- A3V (p.Ala3Val), Ensembl rs2150637719, REVEL 0.34, MetaLR 0.23
- A3D (p.Ala3Asp), gnomAD 7-129189159-C-A, REVEL 0.40, CADD 22.60
- A3A (p.Ala3Ala), gnomAD 7-129189160-T-C, CADD 13.50
- A4D (p.Ala4Asp), Ensembl rs1214436136, REVEL 0.32, MetaLR 0.20
- A4V (p.Ala4Val), Ensembl rs1214436136, REVEL 0.30, MetaLR 0.20
- A4T (p.Ala4Thr), gnomAD 7-129189161-G-A, REVEL 0.33, CADD 22.80
- A4P (p.Ala4Pro), gnomAD 7-129189161-G-C, REVEL 0.27, CADD 21.40
- A4S (p.Ala4Ser), gnomAD 7-129189161-G-T, REVEL 0.26, CADD 19.30
- A4A (p.Ala4Ala), rs1793442299, gnomAD 7-129189163-C-T, CADD 14.80
- R5C (p.Arg5Cys), rs1793442337, ClinGen CA369234506, ClinVar RCV004461984, Ensembl rs1793442337, REVEL 0.45, MetaLR 0.41, Uncertain significance, Inborn genetic diseases
- R5L (p.Arg5Leu), TOPMed rs1406355067, gnomAD rs1406355067, REVEL 0.45, MetaLR 0.37, Uncertain significance
- R5P (p.Arg5Pro), rs1406355067, ClinGen CA369234511, ClinVar RCV002920074, TOPMed rs1406355067, REVEL 0.47, MetaLR 0.41, Uncertain significance, Inborn genetic diseases
- R5S (p.Arg5Ser), Ensembl rs1793442337, REVEL 0.39, MetaLR 0.37, Uncertain significance
- R5H (p.Arg5His), gnomAD 7-129189165-G-A, REVEL 0.39, CADD 26.10
- R5R (p.Arg5Arg), gnomAD 7-129189166-C-A, CADD 13.30
- P6L (p.Pro6Leu), gnomAD rs1793442461, REVEL 0.14, MetaLR 0.18
- P6R (p.Pro6Arg), gnomAD rs1793442461
- P6S (p.Pro6Ser), Ensembl rs2150637729, REVEL 0.18, MetaLR 0.21
- P6Q (p.Pro6Gln), gnomAD 7-129189165-GC-G, CADD 23.40
- P6T (p.Pro6Thr), gnomAD 7-129189167-C-A, REVEL 0.20, CADD 16.00
- P6P (p.Pro6Pro), gnomAD 7-129189169-A-G, CADD 13.30
- A7E (p.Ala7Glu), TOPMed rs1317452947, REVEL 0.35, MetaLR 0.20
- A7G (p.Ala7Gly), TOPMed rs1317452947
- A7T (p.Ala7Thr), Ensembl rs2150637735, REVEL 0.24, MetaLR 0.20
- A7V (p.Ala7Val), TOPMed rs1317452947, REVEL 0.25, MetaLR 0.16
- A7P (p.Ala7Pro), gnomAD 7-129189170-G-C, REVEL 0.37, CADD 20.90
- A7S (p.Ala7Ser), gnomAD 7-129189170-G-T, REVEL 0.29, CADD 18.50
- A7A (p.Ala7Ala), rs1793442534, gnomAD 7-129189172-G-A, CADD 12.60
- R8P (p.Arg8Pro), TOPMed rs981209235
- R8Q (p.Arg8Gln), TOPMed rs981209235, REVEL 0.34, MetaLR 0.18
- R8A (p.Arg8Ala), gnomAD 7-129189171-C-CG, CADD 23.80
- R8W (p.Arg8Trp), gnomAD 7-129189173-C-T, REVEL 0.45, CADD 24.00
- R8G (p.Arg8Gly), gnomAD 7-129189173-C-G, REVEL 0.44, CADD 23.30
- R8R (p.Arg8Arg), gnomAD 7-129189173-C-A, CADD 14.70
- R8L (p.Arg8Leu), gnomAD 7-129189174-G-T, REVEL 0.47, CADD 22.60
- G9R (p.Gly9Arg), TOPMed rs1563144493, REVEL 0.30, MetaLR 0.24
- p.Gly9 Pro10del, gnomAD 7-129189174-GGGGG, CADD 21.30
- G9V (p.Gly9Val), gnomAD 7-129189177-G-T, REVEL 0.18, CADD 22.90
- G9E (p.Gly9Glu), gnomAD 7-129189177-G-A, REVEL 0.22, CADD 23.00
- G9G (p.Gly9Gly), gnomAD 7-129189178-G-A, CADD 15.00
- P10A (p.Pro10Ala), gnomAD rs1793442706, REVEL 0.27, MetaLR 0.23
- P10L (p.Pro10Leu), Ensembl rs1793442744, REVEL 0.20, MetaLR 0.29
- P10Q (p.Pro10Gln), Ensembl rs1793442744, REVEL 0.23, MetaLR 0.27
- P10R (p.Pro10Arg), Ensembl rs1793442744
- P10S (p.Pro10Ser), gnomAD rs1793442706, REVEL 0.29, MetaLR 0.27
- P10T (p.Pro10Thr), gnomAD rs1793442706, REVEL 0.21, MetaLR 0.27
- P10P (p.Pro10Pro), rs2150637764, gnomAD 7-129189181-G-A, CADD 12.90
- E11A (p.Glu11Ala), Ensembl rs2150637765
- E11D (p.Glu11Asp), gnomAD rs1390945946, REVEL 0.33, MetaLR 0.27
- E11K (p.Glu11Lys), TOPMed rs1410118911, gnomAD rs1410118911, REVEL 0.25, MetaLR 0.23
- E11Q (p.Glu11Gln), gnomAD 7-129189182-G-C, REVEL 0.30, CADD 16.60
- E11V (p.Glu11Val), gnomAD 7-129189183-A-T, REVEL 0.31, CADD 18.30
- E11G (p.Glu11Gly), gnomAD 7-129189183-A-G, REVEL 0.29, CADD 15.20
- E11E (p.Glu11Glu), rs1390945946, gnomAD 7-129189184-G-A, CADD 12.00
- L12F (p.Leu12Phe), Ensembl rs2150637773, REVEL 0.33, MetaLR 0.24
- L12I (p.Leu12Ile), gnomAD 7-129189185-C-A, REVEL 0.28, CADD 14.10
- L12H (p.Leu12His), gnomAD 7-129189186-T-A, REVEL 0.28, CADD 19.90
- L12P (p.Leu12Pro), gnomAD 7-129189186-T-C, REVEL 0.43, CADD 23.00
- L12L (p.Leu12Leu), gnomAD 7-129189187-C-A, CADD 10.40
- P13L (p.Pro13Leu), TOPMed rs1159103336, gnomAD rs1159103336, REVEL 0.15, MetaLR 0.12
- P13Q (p.Pro13Gln), TOPMed rs1159103336, gnomAD rs1159103336, REVEL 0.29, MetaLR 0.16
- P13R (p.Pro13Arg), TOPMed rs1159103336, gnomAD rs1159103336, REVEL 0.28, MetaLR 0.16
- P13S (p.Pro13Ser), Ensembl rs2150637777, REVEL 0.28, MetaLR 0.19
- P13A (p.Pro13Ala), gnomAD 7-129189188-C-G, REVEL 0.21, CADD 7.18
- P13T (p.Pro13Thr), gnomAD 7-129189188-C-A, REVEL 0.23, CADD 9.60
- P13P (p.Pro13Pro), rs2150637782, gnomAD 7-129189190-G-A, CADD 11.00
- L14F (p.Leu14Phe), TOPMed rs916719717, REVEL 0.12, MetaLR 0.27
- L14I (p.Leu14Ile), TOPMed rs916719717, REVEL 0.12, MetaLR 0.21
- L14P (p.Leu14Pro), gnomAD rs1793442965, REVEL 0.18, MetaLR 0.25
- L14R (p.Leu14Arg), gnomAD rs1793442965, REVEL 0.25, MetaLR 0.26
- L14V (p.Leu14Val), TOPMed rs916719717
- L14H (p.Leu14His), gnomAD 7-129189192-T-A, REVEL 0.19, CADD 20.90
- L14L (p.Leu14Leu), gnomAD 7-129189193-C-G, CADD 11.10
- L15V (p.Leu15Val), rs2150637798, ClinGen CA369234702, ClinVar RCV003152654, Ensembl rs2150637798, AlphaMissense 0.09, MetaLR 0.27, Benign, See cases
- L15L (p.Leu15Leu), rs2150637798, gnomAD 7-129189194-C-T, AlphaMissense 0.09, MetaLR 0.27
- L15M (p.Leu15Met), gnomAD 7-129189194-C-A, REVEL 0.20, CADD 16.40
- L15P (p.Leu15Pro), gnomAD 7-129189195-T-C, REVEL 0.34, CADD 21.90
- G16R (p.Gly16Arg), gnomAD rs1793443037, REVEL 0.29, MetaLR 0.19, Uncertain significance, Inborn genetic diseases
- G16W (p.Gly16Trp), gnomAD rs1793443037, REVEL 0.35, MetaLR 0.19
- G16del (p.Gly16del), gnomAD 7-129189195-TGGG-, CADD 20.60
- p.Gly16 Leu17insArg, gnomAD 7-129189197-G-GGG, CADD 20.70
- G16V (p.Gly16Val), gnomAD 7-129189198-G-T, REVEL 0.30, CADD 21.00
- G16G (p.Gly16Gly), rs1793443070, gnomAD 7-129189199-G-A, CADD 14.90
- L17L (p.Leu17Leu), rs1793443285, gnomAD 7-129189200-C-T, CADD 13.30
- p.Leu17 Leu18insMet, rs1793443371, gnomAD 7-129189200-C-CTG, CADD 16.80
- L17M (p.Leu17Met), gnomAD 7-129189200-C-A, REVEL 0.18, CADD 18.00
- L17P (p.Leu17Pro), gnomAD 7-129189201-T-C, REVEL 0.35, CADD 22.90
- L17Q (p.Leu17Gln), gnomAD 7-129189201-T-A, REVEL 0.30, CADD 22.80
- L17R (p.Leu17Arg), gnomAD 7-129189201-T-G, REVEL 0.30, CADD 22.90
- L18M (p.Leu18Met), Ensembl rs2150637822, REVEL 0.20, MetaLR 0.22
- L18P (p.Leu18Pro), Ensembl rs2150637825, REVEL 0.45, MetaLR 0.39
- L18Q (p.Leu18Gln), Ensembl rs2150637825
- L18R (p.Leu18Arg), Ensembl rs2150637825
- L18V (p.Leu18Val), Ensembl rs2150637822
- L18L (p.Leu18Leu), rs2150637822, gnomAD 7-129189203-C-T, CADD 12.70
- L19M (p.Leu19Met), 1000Genomes rs551830801, TOPMed rs551830801, REVEL 0.16, MetaLR 0.29
- L19Q (p.Leu19Gln), TOPMed rs1793443517, REVEL 0.18, MetaLR 0.22
- L19V (p.Leu19Val), 1000Genomes rs551830801, TOPMed rs551830801, REVEL 0.15, MetaLR 0.25
- L19L (p.Leu19Leu), rs551830801, gnomAD 7-129189206-C-T, CADD 13.80
- L19P (p.Leu19Pro), gnomAD 7-129189207-T-C, REVEL 0.33, CADD 23.40
- L20P (p.Leu20Pro), Ensembl rs2150637842, REVEL 0.42, MetaLR 0.49
- L20Q (p.Leu20Gln), Ensembl rs2150637842
- L20R (p.Leu20Arg), Ensembl rs2150637842, REVEL 0.41, MetaLR 0.49
- L20V (p.Leu20Val), Ensembl rs2150637840
- L20C (p.Leu20Cys), gnomAD 7-129189207-TG-T, CADD 26.00
- L20L (p.Leu20Leu), rs2150637840, gnomAD 7-129189209-C-T, CADD 10.70
- L20M (p.Leu20Met), gnomAD 7-129189209-C-A, REVEL 0.27, CADD 19.00
- L21V (p.Leu21Val), Ensembl rs2150637847, REVEL 0.20, MetaLR 0.33
- p.Leu21 Leu23del, rs570242755, gnomAD 7-129189198-GGCTG, CADD 21.20
- L21G (p.Leu21Gly), gnomAD 7-129189211-GCTGC, CADD 28.20
- L21M (p.Leu21Met), gnomAD 7-129189212-C-A, REVEL 0.25, CADD 23.10
- L21L (p.Leu21Leu), rs2150637847, gnomAD 7-129189212-C-T, CADD 14.10
- p.Leu21 Leu22insVal, gnomAD 7-129189212-C-CTG, CADD 20.20
- L21P (p.Leu21Pro), gnomAD 7-129189212-CTG-C, CADD 28.60
- L21R (p.Leu21Arg), gnomAD 7-129189213-T-G, REVEL 0.36, CADD 24.90
- L22M (p.Leu22Met), gnomAD rs1254310202, REVEL 0.24, MetaLR 0.48
- L22Q (p.Leu22Gln), Ensembl rs2150637852
- L22R (p.Leu22Arg), Ensembl rs2150637852
- p.Leu22 Leu23del, rs570242755, gnomAD 7-129189198-GGCTG, CADD 21.10
- L22C (p.Leu22Cys), gnomAD 7-129189214-GC-G, CADD 24.00
- L22G (p.Leu22Gly), gnomAD 7-129189214-GCTGC, CADD 24.40
- L22L (p.Leu22Leu), rs1254310202, gnomAD 7-129189215-C-T, CADD 13.00
- p.Leu23dup, rs570242755, gnomAD 7-129189198-G-GGC, CADD 21.10
- L23del (p.Leu23del), rs570242755, gnomAD 7-129189198-GGCT-, CADD 20.60
- L23G (p.Leu23Gly), gnomAD 7-129189216-TGC-T, CADD 24.10
- L23W (p.Leu23Trp), gnomAD 7-129189217-GC-G, CADD 23.10
- L23L (p.Leu23Leu), rs2150637863, gnomAD 7-129189218-C-T, CADD 11.50
- L23M (p.Leu23Met), gnomAD 7-129189218-C-A, REVEL 0.17, CADD 19.70
- L23V (p.Leu23Val), gnomAD 7-129189218-C-G, REVEL 0.12, CADD 14.60
- L23R (p.Leu23Arg), gnomAD 7-129189219-T-G, REVEL 0.24, CADD 22.40
- p.Leu23 Gly24insArg, rs2150637875, gnomAD 7-129189219-T-TGC, CADD 15.40
- L23P (p.Leu23Pro), gnomAD 7-129189219-T-C, REVEL 0.26, CADD 22.40
- L23Q (p.Leu23Gln), gnomAD 7-129189219-T-A, REVEL 0.25, CADD 22.20
- G24A (p.Gly24Ala), TOPMed rs989530778, gnomAD rs989530778, REVEL 0.21, MetaLR 0.18
- G24E (p.Gly24Glu), TOPMed rs989530778, gnomAD rs989530778, REVEL 0.21, MetaLR 0.21
- G24R (p.Gly24Arg), gnomAD rs1486912211, REVEL 0.20, MetaLR 0.21
- G24V (p.Gly24Val), TOPMed rs989530778, gnomAD rs989530778, REVEL 0.25, MetaLR 0.18
- G24W (p.Gly24Trp), gnomAD rs1486912211, REVEL 0.24, MetaLR 0.30
- G24L (p.Gly24Leu), gnomAD 7-129189220-G-GCT, CADD 28.70
- G24G (p.Gly24Gly), gnomAD 7-129189223-G-T, CADD 13.80
- D25A (p.Asp25Ala), 1000Genomes rs41304185, ExAC rs41304185, gnomAD rs41304185, Benign
- D25G (p.Asp25Gly), rs41304185, ClinGen CA4479060, ClinVar RCV000947070, 1000Genomes rs41304185, REVEL 0.18, MetaLR 0.00, Benign, not provided
- D25H (p.Asp25His), Ensembl rs979704684, REVEL 0.26, MetaLR 0.21, Uncertain significance, Inborn genetic diseases
- D25N (p.Asp25Asn), Ensembl rs979704684, REVEL 0.21, MetaLR 0.20, Uncertain significance, Inborn genetic diseases
- D25V (p.Asp25Val), 1000Genomes rs41304185, ExAC rs41304185, gnomAD rs41304185, Benign
- D25T (p.Asp25Thr), gnomAD 7-129189219-TG-T, CADD 23.20
- D25Y (p.Asp25Tyr), gnomAD 7-129189224-G-T, REVEL 0.22, CADD 20.40
- D25E (p.Asp25Glu), gnomAD 7-129189226-C-A, REVEL 0.28, CADD 17.20
- D25D (p.Asp25Asp), gnomAD 7-129189226-C-T, CADD 13.30
- P26A (p.Pro26Ala), Ensembl rs925643027
- P26L (p.Pro26Leu), TOPMed rs1793444191, REVEL 0.15, MetaLR 0.17
- P26Q (p.Pro26Gln), TOPMed rs1793444191, REVEL 0.08, MetaLR 0.19
- P26S (p.Pro26Ser), Ensembl rs925643027, REVEL 0.11, MetaLR 0.23
- P26T (p.Pro26Thr), gnomAD 7-129189227-C-A, REVEL 0.15, CADD 17.10
- P26R (p.Pro26Arg), gnomAD 7-129189228-C-G, REVEL 0.11, CADD 16.40
- P26P (p.Pro26Pro), rs1793444242, gnomAD 7-129189229-G-A, CADD 13.30
- G27A (p.Gly27Ala), Ensembl rs2150637898
- G27C (p.Gly27Cys), TOPMed rs945565546, gnomAD rs945565546, REVEL 0.26, MetaLR 0.37
- G27D (p.Gly27Asp), Ensembl rs2150637898, REVEL 0.23, MetaLR 0.23
- G27R (p.Gly27Arg), TOPMed rs945565546, gnomAD rs945565546, REVEL 0.23, MetaLR 0.30
- G27S (p.Gly27Ser), TOPMed rs945565546, gnomAD rs945565546, REVEL 0.27, MetaLR 0.21
- G27V (p.Gly27Val), Ensembl rs2150637898, REVEL 0.17, MetaLR 0.33
- G27G (p.Gly27Gly), rs2150637904, gnomAD 7-129189232-C-T, CADD 11.30
- R28L (p.Arg28Leu), Ensembl rs2150637910, REVEL 0.18, MetaLR 0.20
- R28P (p.Arg28Pro), Ensembl rs2150637910, REVEL 0.25, MetaLR 0.22
- R28Q (p.Arg28Gln), Ensembl rs2150637910, REVEL 0.16, MetaLR 0.21
- R28W (p.Arg28Trp), TOPMed rs1041213948, gnomAD rs1041213948, REVEL 0.28, MetaLR 0.22
- R28R (p.Arg28Arg), gnomAD 7-129189233-C-A, CADD 14.50
- R28G (p.Arg28Gly), gnomAD 7-129189233-C-G, REVEL 0.21, CADD 20.10
Public SMO analysis runs
- SMO analysis run — SMO (3,706 variants) — completed 2026-08-19