PTCH1

protein-coding

patched 1

Gene summary

This gene encodes a member of the patched family of proteins and a component of the hedgehog signaling pathway. Hedgehog signaling is important in embryonic development and tumorigenesis. The encoded protein is the receptor for the secreted hedgehog ligands, which include sonic hedgehog, indian hedgehog and desert hedgehog. Following binding by one of the hedgehog ligands, the encoded protein is trafficked away from the primary cilium, relieving inhibition of the G-protein-coupled receptor smoothened, which results in activation of downstream signaling. Mutations of this gene have been associated with basal cell nevus syndrome and holoprosencephaly. [provided by RefSeq, Aug 2017]

Previous symbols:

NBCCS
PTCH

MANE transcript

NM_000264.5

Inheritance

ClinVar variants

P:768U:2526B:2043

Top phenotype

Basal cell nevus syndrome 1

gnomAD constraint

pLI —, LoF o/e 0.02

Max pathogenic AF

—

Genomic locus

chr9:95,442,980-95,517,057

External References & Databases

Ensembl (ENSG00000185920)

Transcript & Mutation Effects

hg38 • Region Span ~74.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

holoprosencephaly 7LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0012562

Submitter: Ambry Genetics

holoprosencephalyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0016296

Submitter: Illumina

holoprosencephalyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0016296

Submitter: ClinGen

*PTCH1* was first reported in relation to autosomal dominant holoprosencephaly in 2002 (Ming et al., PMID: 11941477). Disease-causing variants in the *PTCH1* gene have been found to cause a disorder characterized by holoprosencephaly, developmental delay, neurodevelopmental delay, seizures, and craniofacial anomalies. Most of the disease-causing variants are missense variants. Four variants (missense) that have been reported in five probands across two publications (PMIDs: 17001668, 37880672) are included in this curation. This gene-disease relationship is also supported by a mouse model (PMID: 10395791). In this study, overexpression of Ptch in the mouse neural tube resulted in suppression of Gli1 and Ptch1 expression, indicating impaired Sonic hedgehog (SHH) signaling. A subset of mice with increased Ptch activity exhibited fusion of the lateral ventricles, consistent with holoprosencephaly. This phenotype parallels that observed in Shh null mice, which develop holoprosencephaly and cyclopia, supporting the conclusion that elevated PTCH activity functionally inhibits SHH pathway signaling during forebrain development. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Intellectual Disability and Autism GCEP on July 9th, 2025 (SOP Version 10).

holoprosencephaly 7LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0012562

Submitter: Labcorp Genetics (formerly Invitae)

nevoid basal cell carcinoma syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007187

Submitter: Labcorp Genetics (formerly Invitae)

nevoid basal cell carcinoma syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007187

Submitter: Genomics England PanelApp

exstrophy-epispadias complexSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0017919

Submitter: PanelApp Australia

holoprosencephaly 7DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012562

Submitter: G2P

basal cell nevus syndrome 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0958174

Submitter: G2P

nevoid basal cell carcinoma syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007187

Submitter: Orphanet

nevoid basal cell carcinoma syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007187

Submitter: ClinGen

There has been sufficient amount of evidence published associating the PTCH1 gene with nevoid basal cell carcinoma syndrome (Gorlin syndrome) since the gene-disease relationship was first proposed by Johnson et al. (1996). Plenty of case level studies have been performed with BCC patients that have variants in the PTCH1 gene. Multiple PTCH1 deficient mouse models have been established to show consistent phenotypes with NBCCS patients. Untreated Ptch+/– mice have microscopic skin tumors. UV and ionizing radiation enhances BCC tumorigenesis in Ptch+/– mouse. All of these types of evidence suggest a definitive relationship between the PTCH1 gene and nevoid basal cell carcinoma syndrome (Gorlin syndrome).

holoprosencephaly 7STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012562

Submitter: PanelApp Australia

basal cell nevus syndrome 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0958174

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Basal cell nevus syndrome 1AD

Manifestation: Craniofacial; Dermatologic; Endocrine; Musculoskeletal; Neurologic; Oncologic

Intervention: Oncologic

Rationale: Individuals are at risk for a number of types of malignancies, including basal cell carcinomas and medulloblastoma , as well as (rare) malignant rare keratocyst transformation, and awareness and surveillance may allow early diagnosis and treatment (including with molecular therapies that target the Hedgehog signaling pathway), potentially reducing morbidity and mortality; Avoidance of agents such as radiation therapy is indicated

Refs: 13851319; 8326488; 9096761; 9096762; 8981943; 11382639; 11941477; 16906569; 19439922; 19557015; 21368767; 22007994; 22565648; 22670903; 22670904; 22844361; 23677114

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PTCH1 variants in ClinVar

53 Conditions Cataloged

Gorlin syndromeTotal: 4391

Hereditary cancer-predisposing syndromeTotal: 3821

not providedTotal: 920

not specifiedTotal: 312

Basal cell carcinoma, susceptibility to, 1Total: 272

Holoprosencephaly 7Total: 214

PTCH1-related disorderTotal: 195

Basal cell nevus syndrome 1Total: 173

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000264.5. 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	1 clinvar	3 clinvar	18 clinvar	1418 clinvar	16 clinvar	1456
missense	17 clinvar	57 clinvar	2427 clinvar	575 clinvar	34 clinvar	3110
nonsense	165 clinvar	13 clinvar	16 clinvar			194
start loss	1 clinvar		2 clinvar			3
frameshift	349 clinvar	48 clinvar	47 clinvar			444
splice donor/acceptor (+/-2bp)	65 clinvar	49 clinvar	16 clinvar			130
Total	598	170	2526	1993	50	5337

Highest pathogenic variant AF is 0.0000065717704

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 29 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000264.5	RefSeq	NP_000255.2	23	MANE Select
ENST00000331920.11	Ensembl	ENSP00000332353.6	23	MANE Select
NM_001083602.3	RefSeq	NP_001077071.1	23	Standard
NM_001083603.3	RefSeq	NP_001077072.1	23	MANE Plus Clinical

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
ptch1	Danio rerio	Structure: Muller cell Quality: physical object quality abnormal

Gene / Model

Organism

Observed Phenotype

ptch1

Danio rerio

Structure: Muller cell

Quality: physical object quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Axon guidance - Homo sapiens (human)
Basal cell carcinoma - Homo sapiens (human)
cAMP signaling pathway - 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 ureteric bud morphogenesis
in utero embryonic development
cell fate determination
neural tube closure

Molecular Function

patched binding
smoothened binding
protein binding
hedgehog receptor activity
heparin binding

Cellular Component

nucleus
Golgi apparatus
plasma membrane
caveola
postsynaptic density

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000331920
Coding exons: 23
Length: 74078
Individuals with no LoFs: 125741
Homozygous LoFs: 0
Heterozygous LoFs: 7
Defined: 125748
p: 0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.68	708	845	0.838	0.0000560	9381
Missense (PolyPhen)		137	244.15	0.56113		2695
Synonymous	-3.76	453	362	1.25	0.0000278	2943
Loss of Function	7.25	1	63.3	0.0158	0.00000322	739

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000044	0.000044	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acts as a receptor for sonic hedgehog (SHH), indian hedgehog (IHH) and desert hedgehog (DHH). Associates with the smoothened protein (SMO) to transduce the hedgehog's proteins signal. Seems to have a tumor suppressor function, as inactivation of this protein is probably a necessary, if not sufficient step for tumorigenesis. {ECO:0000269|PubMed:21537345}.;
Disease: DISEASE: Basal cell nevus syndrome (BCNS) [MIM:109400]: An autosomal dominant disease characterized by nevoid basal cell carcinomas and developmental abnormalities such as rib and craniofacial alterations, polydactyly, syndactyly, and spina bifida. In addition, the patients suffer from a multitude of tumors like basal cell carcinomas, fibromas of the ovaries and heart, cysts of the skin, jaws and mesentery, as well as medulloblastomas and meningiomas. {ECO:0000269|PubMed:11231326, ECO:0000269|PubMed:15459969, ECO:0000269|PubMed:8840969, ECO:0000269|PubMed:8981943, ECO:0000269|PubMed:9620294}. Note=The disease may be caused by mutations affecting the gene represented in this entry.; DISEASE: Basal cell carcinoma (BCC) [MIM:605462]: A common malignant skin neoplasm that typically appears on hair-bearing skin, most commonly on sun-exposed areas. BCC is slow growing and rarely metastasizes, but has potentialities for local invasion and destruction. It usually develops as a flat, firm, pale area that is small, raised, pink or red, translucent, shiny, and waxy, and the area may bleed following minor injury. Tumor size can vary from a few millimeters to several centimeters in diameter. {ECO:0000269|PubMed:8658145, ECO:0000269|PubMed:9620294}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Holoprosencephaly 7 (HPE7) [MIM:610828]: 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. {ECO:0000269|PubMed:11941477, ECO:0000269|PubMed:17001668, ECO:0000269|PubMed:17096318}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.787

Intolerance Scores

LoFtool: 0.000344
RVIS EVS: -2.73
RVIS percentile EVS: 0.71

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.972

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High