SCUBE2

protein-coding

signal peptide, CUB domain and EGF like domain containing 2, the group of MicroRNA protein coding host genes

Gene summary

Predicted to enable hedgehog family protein binding activity. Predicted to be involved in signal transduction. Predicted to act upstream of or within several processes, including positive regulation of chondrocyte proliferation; positive regulation of osteoblast differentiation; and positive regulation of smoothened signaling pathway. Predicted to be located in extracellular region. Predicted to be active in cell surface and obsolete extracellular space. [provided by Alliance of Genome Resources, Jun 2026]

MANE transcript

NM_001367977.2

Inheritance

—

ClinVar variants

P:1U:153B:8

Top phenotype

Cerebral arteriovenous malformation

gnomAD constraint

pLI —, LoF o/e 0.73

Max pathogenic AF

—

Genomic locus

chr11:9,019,476-9,138,114

External References & Databases

Ensembl (ENSG00000175356)

Transcript & Mutation Effects

hg38 • Region Span ~118.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SCUBE2 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 150

not providedTotal: 6

Cerebral arteriovenous malformationTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001367977.2. 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 clinvar	3 clinvar	1 clinvar	6
missense		1 clinvar	150 clinvar	3 clinvar		154
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			1 clinvar	1 clinvar		2
Total	0	1	153	7	1	162

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 79 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001367977.2	RefSeq	NP_001354906.1	23	MANE Select
ENST00000649792.2	Ensembl	ENSP00000497523.1	23	MANE Select
NM_001170690.3	RefSeq	NP_001164161.1	18	Standard
NM_001330199.3	RefSeq	NP_001317128.1	22	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
scube2	Danio rerio	Structure: melanocyte Quality: irregular spatial pattern abnormal

Gene / Model

Organism

Observed Phenotype

scube2

Danio rerio

Structure: melanocyte

Quality: irregular spatial pattern

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Signal Transduction
Release of Hh-Np from the secreting cell
Hedgehog ligand biogenesis
Signaling by Hedgehog

Biological Process

multicellular organism development

Molecular Function

calcium ion binding
lipid binding

Cellular Component

extracellular region
extracellular space
cell surface

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000520467
Coding exons: 22
Length: 118591
Individuals with no LoFs: 125432
Homozygous LoFs: 2
Heterozygous LoFs: 314
Defined: 125748
p: 0.00126

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.977	482	546	0.882	0.0000306	6377
Missense (PolyPhen)		246	264.36	0.93055		2965
Synonymous	0.839	198	214	0.927	0.0000129	1851
Loss of Function	1.85	40	54.8	0.730	0.00000314	618

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0014	0.0014	notable
Latino/Admixed American	0.0016	0.0016	notable
Ashkenazi Jewish	0.00079	0.00079	rare
East Asian	0.00049	0.00049	rare
Finnish	0.00037	0.00037	rare
European (Non-Finnish)	0.00083	0.00083	rare
South Asian	0.0038	0.0037	notable
Other	0.00082	0.00081	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Lipid-binding protein required for SHH long-range signaling by binding to the dually lipid-modified SHH (ShhNp) and by promoting ShhNp mobilization, solubilization and release from the cell membrane (PubMed:22902404, PubMed:22677548). Acts by enhancing the proteolytic processing (shedding) of the lipid- modified N- and C- terminal of ShhNp at the cell surface (PubMed:24522195). Synergizes with DISP1 to increase SHH secretion (PubMed:22902404). Probable cell surface coreceptor for VEGFR2 involved in VEGFR2-mediated angiogenesis (PubMed:27834687). {ECO:0000269|PubMed:22677548, ECO:0000269|PubMed:22902404, ECO:0000269|PubMed:24522195, ECO:0000269|PubMed:27834687, ECO:0000303|PubMed:26875496}.;

Recessive Scores

pRec: 0.101

Intolerance Scores

LoFtool: 0.156
RVIS EVS: -0.7
RVIS percentile EVS: 14.81

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.213

Gene Damage Prediction

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