SHH
protein-codingsonic hedgehog signaling molecule, the group of Hedgehog signaling molecule family
Gene summary
This gene encodes a protein that is instrumental in patterning the early embryo. It has been implicated as the key inductive signal in patterning of the ventral neural tube, the anterior-posterior limb axis, and the ventral somites. Of three human proteins showing sequence and functional similarity to the sonic hedgehog protein of Drosophila, this protein is the most similar. The protein is made as a precursor that is autocatalytically cleaved; the N-terminal portion is soluble and contains the signalling activity while the C-terminal portion is involved in precursor processing. More importantly, the C-terminal product covalently attaches a cholesterol moiety to the N-terminal product, restricting the N-terminal product to the cell surface and preventing it from freely diffusing throughout the developing embryo. Defects in this protein or in its signalling pathway are a cause of holoprosencephaly (HPE), a disorder in which the developing forebrain fails to correctly separate into right and left hemispheres. HPE is manifested by facial deformities. It is also thought that mutations in this gene or in its signalling pathway may be responsible for VACTERL syndrome, which is characterized by vertebral defects, anal atresia, tracheoesophageal fistula with esophageal atresia, radial and renal dysplasia, cardiac anomalies, and limb abnormalities. Additionally, mutations in a long range enhancer located approximately 1 megabase upstream of this gene disrupt limb patterning and can result in preaxial polydactyly. [provided by RefSeq, Jul 2008]
- HPE3
- HLP3
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~12.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0007733
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007819
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0007733
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0008270
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008515
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0005172
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007733
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007819
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007733
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0008270
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0018777
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007733
Submitter: ClinGen
SHH Evidence Summary: The Brain Malformations GCEP concludes that there is definitive evidence to support the relationship between SHH and autosomal dominant holoprosencephaly 3 (HPE3) as of June 23, 2026. Variants in sonic hedgehog (SHH; OMIM: 600725) were first reported in relation to autosomal dominant HPE3 (OMIM: 142945) in 1996 (Roessler et al., PMID: 8896572). Holoprosencephaly is a severe congenital brain malformation defined by failure of the embryonic forebrain to cleave into two distinct hemispheres. The clinical spectrum ranges from alobar HPE (complete non-cleavage with a single fused ventricle and absent interhemispheric fissure) to semilobar and lobar forms. It extends to microforms including single median maxillary central incisor (SMMCI) and hypotelorism. Facial features including cleft lip and palate and ocular hypotelorism are common and typically correlate with the severity of the brain malformation. SHH encodes a secreted morphogen critical for spatial patterning of the central nervous system and facial midline. The active N-terminal signaling domain (SHH-N) binds the PTCH1 receptor complex, assisted by co-receptors GAS1, CDO, and BOC, to drive downstream GLI-mediated transcription essential for forebrain midline induction. Cases of HPE3 have been reported as de novo, maternally inherited, or paternally inherited, consistent with autosomal dominant transmission. Reduced penetrance and variable expressivity are documented features of this gene-disease relationship. Obligate carriers of SHH variants may present with microforms such as SMMCI or hypotelorism rather than overt HPE, and some carriers remain clinically unaffected, as demonstrated by a paternally inherited variant (p.Leu382Pro) in a family with fetal HPE reported in Paulussen et al. 2010. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or inheritance pattern. Therefore, the following disease entities have been lumped into one disease entity: holoprosencephaly 3 (OMIM:142945), microphthalmia/coloboma 5 (OMIM:611638), and single median maxillary central incisor (OMIM:147250). At least 15 unique variants, including nonsense, frameshift, in-frame deletion, and missense variants distributed throughout the SHH-N signaling domain, have been reported in scored probands across four publications (Nanni et al. 1999, PMID: 10556296; Paulussen et al. 2010, PMID: 20531442; Gekas et al. 2012, PMID: 23181171; Savastano et al. 2014, PMID: 24764759). Additional family segregation evidence was contributed by candidate-gene sequencing across four kindreds. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The mechanism of pathogenicity is haploinsufficiency: heterozygous loss-of-function variants reduce the effective dose of SHH signaling in the developing forebrain, thereby failing midline induction and leading to HPE (PMIDs: 15888442, 19060208, 31685615). This gene-disease relationship is also supported by experimental evidence across five independent categories, including biochemical function, protein interaction, expression, functional alteration, and model systems, achieving a maximum experimental score of 6.0 points (PMIDs: 15888442, 19060208, 19478089, 31685615). In summary, there is definitive evidence to support the relationship between SHH and autosomal dominant holoprosencephaly 3 (HPE3). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Brain Malformations Gene Curation Expert Panel on June 23, 2026 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0012709
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Endocrine; Neurologic; Ophthalmologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
Comments: Variants in SHH have also been implicated in schizencephaly, but the data are unclear, and this may have co-occurred with typical holoprosencephaly-type malformations; Individuals with holoprosencephaly may demonstrate endocrine anomalies, including diabetes insipidus
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SHH variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000193.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 2 | 91 | 6 | 99 | ||
| missense | 11 | 57 | 217 | 14 | 299 | |
| nonsense | 24 | 8 | 1 | 33 | ||
| start loss | 1 | 1 | ||||
| frameshift | 20 | 9 | 2 | 31 | ||
| splice donor/acceptor (+/-2bp) | 1 | 2 | 2 | 5 | ||
| Total | 56 | 77 | 224 | 105 | 6 | 468 |
Highest pathogenic variant AF is 0.00009659523
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000184.1 | 3 | MANE Select | |
| Ensembl | ENSP00000297261.2 | 3 | MANE Select | |
| RefSeq | NP_001297391.1 | 3 | Standard | |
| Ensembl | ENSP00000396621.1 | 3 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| shhb | Danio rerio | Structure: somite Quality: morphology abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Gastric cancer - Homo sapiens (human)
- Axon guidance - Homo sapiens (human)
- Basal cell carcinoma - Homo sapiens (human)
- Proteoglycans in cancer - Homo sapiens (human)
- Pathways in cancer - Homo sapiens (human)
Biological Process
- negative regulation of transcription by RNA polymerase II
- branching involved in blood vessel morphogenesis
- vasculogenesis
- metanephros development
- branching involved in ureteric bud morphogenesis
Molecular Function
- endopeptidase activity
- patched binding
- calcium ion binding
- protein binding
- glycosaminoglycan binding
Cellular Component
- extracellular region
- extracellular space
- endoplasmic reticulum lumen
- cytosol
- plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000297261
- Coding exons
- 3
- Length
- 12288
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.95 | 106 | 232 | 0.456 | 0.0000119 | 2873 |
| Missense (PolyPhen) | 29 | 110.06 | 0.26349 | 1320 | ||
| Synonymous | -1.15 | 128 | 113 | 1.14 | 0.00000628 | 1027 |
| Loss of Function | 3.25 | 0 | 12.3 | 0.00 | 5.36e-7 | 147 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Sonic hedgehog protein: The C-terminal part of the sonic hedgehog protein precursor displays an autoproteolysis and a cholesterol transferase activity (By similarity). Both activities result in the cleavage of the full-length protein into two parts (ShhN and ShhC) followed by the covalent attachment of a cholesterol moiety to the C-terminal of the newly generated ShhN (By similarity). Both activities occur in the reticulum endoplasmic (By similarity). Once cleaved, ShhC is degraded in the endoplasmic reticulum (By similarity). {ECO:0000250|UniProtKB:Q62226}.;
- Disease
- DISEASE: Microphthalmia, isolated, with coloboma, 5 (MCOPCB5) [MIM:611638]: A disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues. Ocular abnormalities like opacities of the cornea and lens, scaring of the retina and choroid, and other abnormalities may also be present. Ocular colobomas are a set of malformations resulting from abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure). {ECO:0000269|PubMed:12503095}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Holoprosencephaly 3 (HPE3) [MIM:142945]: A structural anomaly of the brain, in which the developing forebrain fails to correctly separate into right and left hemispheres. Holoprosencephaly is genetically heterogeneous and associated with several distinct facies and phenotypic variability. The majority of holoprosencephaly type 3 cases are apparently sporadic, although clear examples of autosomal dominant inheritance have been described. {ECO:0000269|PubMed:10441331, ECO:0000269|PubMed:10556296, ECO:0000269|PubMed:11479728, ECO:0000269|PubMed:15107988, ECO:0000269|PubMed:15221788, ECO:0000269|PubMed:15942952, ECO:0000269|PubMed:15942953, ECO:0000269|PubMed:16282375, ECO:0000269|PubMed:17001669, ECO:0000269|PubMed:19603532, ECO:0000269|PubMed:8896572, ECO:0000269|PubMed:9302262}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Solitary median maxillary central incisor (SMMCI) [MIM:147250]: Rare dental anomaly characterized by the congenital absence of one maxillary central incisor. {ECO:0000269|PubMed:11471164, ECO:0000269|PubMed:15103725}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Triphalangeal thumb-polysyndactyly syndrome (TPTPS) [MIM:174500]: Autosomal dominant syndrome. It is characterized by a wide spectrum of pre- and post-axial abnormalities due to altered SHH expression pattern during limb development. {ECO:0000269|PubMed:12837695, ECO:0000269|PubMed:18417549}. Note=The gene represented in this entry is involved in disease pathogenesis. Mutations located in intron 5 of LMBR1 disrupt a long-range, cis-regulatory element of SHH expression.; DISEASE: Preaxial polydactyly 2 (PPD2) [MIM:174500]: Polydactyly consists of duplication of the distal phalanx. The thumb in PPD2 is usually opposable and possesses a normal metacarpal. {ECO:0000269|PubMed:12837695}. Note=The gene represented in this entry is involved in disease pathogenesis. Mutations located in intron 5 of LMBR1 disrupt a long-range, cis-regulatory element of SHH and result in abnormal, ectopic SHH expression with pathological consequences (PubMed:12837695). {ECO:0000269|PubMed:12837695}.; DISEASE: Hypoplasia or aplasia of tibia with polydactyly (THYP) [MIM:188740]: An autosomal dominant disease characterized by hypoplastic or absent tibia, and polydactyly. {ECO:0000269|PubMed:19847792, ECO:0000269|PubMed:24965254}. Note=The gene represented in this entry is involved in disease pathogenesis. Mutations located in intron 5 of LMBR1 disrupt a long-range, cis-regulatory element of SHH and result in abnormal, ectopic SHH expression with pathological consequences. {ECO:0000303|PubMed:19847792, ECO:0000303|PubMed:24965254}.; DISEASE: Laurin-Sandrow syndrome (LSS) [MIM:135750]: A rare autosomal dominant disorder characterized by polysyndactyly of hands and/or feet, mirror image duplication of the feet, nasal defects, and loss of identity between fibula and tibia. Some patients do not have nasal abnormalities (segmental Laurin-Sandrow syndrome). {ECO:0000269|PubMed:24456159}. Note=The gene represented in this entry is involved in disease pathogenesis. Abnormal SHH limb expression with pathological consequences is caused by duplications (16-75 kb) involving the ZPA regulatory sequence (ZRS), a SHH long-range cis-regulatory element, located in LMBR1 intron 5 (PubMed:24456159).;
Recessive Scores
- pRec
- 0.891
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- H
- Indispensability pred.
- E
- Indispensability score
- 0.750
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |