SMO

Chr 7AR

smoothened, frizzled class receptor

Also known as: CRJS, FZD11, Gx, PHLS, SMOH

The protein encoded by this gene is a G protein-coupled receptor that interacts with the patched protein, a receptor for hedgehog proteins. The encoded protein tranduces signals to other proteins after activation by a hedgehog protein/patched protein complex. [provided by RefSeq, Jul 2010]

GeneReviewsOMIMResearchGenerating clinical summary…
MultiplemechanismARLOEUF 0.683 OMIM phenotypes
Clinical SummarySMO
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Gene-Disease Validity (ClinGen)
congenital hypothalamic hamartoma syndrome · ARModerate

Moderate evidence — consider for supplementary testing

2 total gene-disease associations curated

Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
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Clinical Trials
12 active or recruiting trials — potential therapeutic options may be available
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GeneReview available — SMO
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Tolerant — LoF & missense variants common in population
LoF Constraint?
0.68LOEUF
pLI 0.000
Z-score 3.08
OE 0.46 (0.310.68)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?
1.90Z-score
OE missense 0.75 (0.690.82)
345 obs / 459.4 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?
LoF OE?0.46 (0.310.68)
00.351.4
Missense OE?0.75 (0.690.82)
00.61.4
Synonymous OE?0.99
01.21.6
LoF obs/exp: 17 / 37.3Missense obs/exp: 345 / 459.4Syn Z: 0.10
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveSMO-related Curry-Jones syndromeGOFAD
strongSMO-related developmental disorderLOFAR

This gene — mechanism propensity

DN
0.6646th %ile
GOF
0.77top 25%
LOF
0.3260th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation
DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFThe identification of a gain-of-function mutation in SMO causing a type 1 mosaic form of BCNS further expands our understanding of the pathogenesis of BCC, with implications for the treatment of these tumours, whether sporadic or inherited.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

  1. 1.PMID 26822128

ClinVar Variant Classifications

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

SMO · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

Carcinoma, Non-Small-Cell LungNeoplasm Metastasis

A Study of First-Line Olomorasib (LY3537982) and Pembrolizumab With or Without Chemotherapy in Patients With Advanced KRAS G12C-Mutant Non-small Cell Lung Cancer

RECRUITING
NCT06119581Phase PHASE3Eli Lilly and CompanyStarted 2023-12-21
LY3537982PembrolizumabPlacebo
Hereditary Angioedema

HAELO: A Phase 3 Study to Evaluate NTLA-2002 in Participants With Hereditary Angioedema (HAE)

ACTIVE NOT RECRUITING
NCT06634420Phase PHASE3Intellia TherapeuticsStarted 2025-01-15
NTLA-2002Normal Saline IV Administration
Anatomic Stage I Breast Cancer AJCC v8Anatomic Stage II Breast Cancer AJCC v8Anatomic Stage III Breast Cancer AJCC v8

Additional Support Program Via Text Messaging and Telephone-Based Counseling for Breast Cancer Patients Receiving Hormonal Therapy

ACTIVE NOT RECRUITING
NCT04379570Phase PHASE3Alliance for Clinical Trials in OncologyStarted 2021-02-15
Educational InterventionText Message-based Navigation InterventionMotivational Interviewing
Degenerative SpondylolisthesisLumbar Spinal Stenosis

LimiFlex Clinical Trial for the Treatment of Degenerative Spondylolisthesis With Spinal Stenosis

ACTIVE NOT RECRUITING
NCT03115983Phase NAEmpirical Spine, Inc.Started 2017-07-17
LimiFlexFusion InstrumentationDecompression
Unresectable or Metastatic Melanoma or Advanced Solid TumorsMelanomaUveal Melanoma

A Study of APG-115 in as a Monotherapy or Combination With Pembrolizumab in Patients With Metastatic Melanomas or Advanced Solid Tumors

ACTIVE NOT RECRUITING
NCT03611868Phase PHASE1, PHASE2Ascentage Pharma Group Inc.Started 2018-08-29
Phase 1b: APG-115+pembrolizumab
Breast CancerCholangiocarcinomaColorectal Cancer

Basket Study of Entrectinib (RXDX-101) for the Treatment of Patients With Solid Tumors Harboring NTRK 1/2/3 (Trk A/B/C), ROS1, or ALK Gene Rearrangements (Fusions)

ACTIVE NOT RECRUITING
NCT02568267Phase PHASE2Hoffmann-La RocheStarted 2015-11-19
Entrectinib
Advanced LymphomaAdvanced Malignant Solid NeoplasmBladder Carcinoma

Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma (The MATCH Screening Trial)

ACTIVE NOT RECRUITING
NCT02465060Phase PHASE2National Cancer Institute (NCI)Started 2015-08-17
AdavosertibAfatinibAfatinib Dimaleate
Intermediate Risk Non-Muscle Invasive Bladder Cancer

Trial of Nadofaragene Firadenovec vs. Observation in Participants With Intermediate Risk Non-Muscle Invasive Bladder Cancer

RECRUITING
NCT06510374Phase PHASE3Ferring PharmaceuticalsStarted 2024-10-01
Nadofaragene Firadenovec
Platinum-Resistant Fallopian Tube CarcinomaPlatinum-Resistant Primary Peritoneal CarcinomaPARP Inhibitor

Vismodegib Combined With Atezolizumab in Platinum Resistant Ovarian, Fallopian Tube, and Primary Peritoneal Cancer

RECRUITING
NCT05538091Phase PHASE2Ronald BuckanovichStarted 2023-05-15
VismodegibAtezolizumab
Melanoma

A Trial to See if the Combination of Fianlimab With Cemiplimab Works Better Than Pembrolizumab for Preventing or Delaying Melanoma From Coming Back After it Has Been Removed With Surgery

ACTIVE NOT RECRUITING
NCT05608291Phase PHASE3Regeneron PharmaceuticalsStarted 2023-01-16
FianlimabCemiplimabPembrolizumab
Breast CancerMetastatic Breast CancerBreast Neoplasm

Study of the Bria-IMT Regimen and CPI vs Physicians' Choice in Advanced Metastatic Breast Cancer.

RECRUITING
NCT06072612Phase PHASE3BriaCell Therapeutics CorporationStarted 2023-12-05
SV-BR-1-GMCyclophosphamideInterferon infiltration of the inoculation site
Advanced Solid Tumor

Study of CX-5461 in Patients With Solid Tumours and BRCA1/2, PALB2 or Homologous Recombination Deficiency (HRD) Mutation

RECRUITING
NCT04890613Phase PHASE1Senhwa Biosciences, Inc.Started 2021-09-08
CX-5461