SCP2

protein-coding

sterol carrier protein 2, the group of MicroRNA protein coding host genes

Gene summary

This gene encodes two proteins: sterol carrier protein X (SCPx) and sterol carrier protein 2 (SCP2), as a result of transcription initiation from 2 independently regulated promoters. The transcript initiated from the proximal promoter encodes the longer SCPx protein, and the transcript initiated from the distal promoter encodes the shorter SCP2 protein, with the 2 proteins sharing a common C-terminus. Evidence suggests that the SCPx protein is a peroxisome-associated thiolase that is involved in the oxidation of branched chain fatty acids, while the SCP2 protein is thought to be an intracellular lipid transfer protein. This gene is highly expressed in organs involved in lipid metabolism, and may play a role in Zellweger syndrome, in which cells are deficient in peroxisomes and have impaired bile acid synthesis. Alternative splicing of this gene produces multiple transcript variants, some encoding different isoforms.[provided by RefSeq, Aug 2010]

MANE transcript

NM_002979.5

Inheritance

ClinVar variants

P:29U:196B:112

Top phenotype

Leukoencephalopathy with dystonia and motor neuropathy

gnomAD constraint

pLI —, LoF o/e 0.49

Max pathogenic AF

—

Genomic locus

chr1:52,927,276-53,051,698

External References & Databases

Ensembl (ENSG00000116171)

Transcript & Mutation Effects

hg38 • Region Span ~124.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

sterol carrier protein 2 deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013391

Submitter: Orphanet

sterol carrier protein 2 deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013391

Submitter: ClinGen

The relationship between *SCP2* and sterol carrier protein 2 deficiency (Leukoencephalopathy with dystonia and motor neuropathy included), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of January, 2020 and reviewed in March 2022 and update to SOP v9 in October 2022. SCP2 encodes two proteins, SCPx and SCP2 due to transcription initiation from two different promoters. SCPx is a peroxisome-associated thiolase involved in oxidation of branched-chain fatty acids while SCP2 is an intracellular lipid transfer protein. SCP2 was first reported in relation to autosomal recessive sterol carrier protein 2 deficiency in 2006 (Ferdinandusse et al, PMID: 16685654). Only three loss of function variants have been reported in this gene in relation to this disease. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data (9 points): At least 3 patients from unrelated families in 4 publications have been reported with the null variants (PMID: 16685654, 26497993, 28033445, 37905191). The mechanism of disease is expected to be biallelic loss of function. Summary of experimental data (4.5 points): This gene-disease association is supported by mouse models that recapitulate human disease (PMID: 9553048, 15574183, 17068117). The protein is localized to the peroxisomes in hepatocytes (PMID: 2925789 ) and it interacts with PEX5 and has a role in peroxisomal fatty acid metabolism (PMID: 21375735). This gene-disease pair was originally evaluated by the Peroxisomal GCEP on Nov 4, 2022. It was re-evaluated on February 7, 2025. As a result of this reevaluation, the classification increased from Moderate to Definitive with the addition of a new case and protein interaction evidence (PMIDs: 37905191, 36407094).

sterol carrier protein 2 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013391

Submitter: Labcorp Genetics (formerly Invitae)

sterol carrier protein 2 deficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013391

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Leukoencephalopathy with dystonia and motor neuropathyAR

Manifestation: Biochemical; Endocrine; Genitourinary; Neurologic

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

Refs: 16685654

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SCP2 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 446

not specifiedTotal: 69

SCP2-related disorderTotal: 56

Sterol carrier protein 2 deficiencyTotal: 12

LeukodystrophyTotal: 1

Sensorineural hearing loss disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002979.5. 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			4 clinvar	108 clinvar		112
missense			185 clinvar	4 clinvar		189
nonsense	6 clinvar		1 clinvar			7
start loss			1 clinvar			1
frameshift	10 clinvar	2 clinvar	2 clinvar			14
splice donor/acceptor (+/-2bp)		11 clinvar	3 clinvar			14
Total	16	13	196	112	0	337

Highest pathogenic variant AF is 0.00007142378

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 64 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002979.5	RefSeq	NP_002970.2	16	MANE Select
ENST00000371514.8	Ensembl	ENSP00000360569.3	16	MANE Select
NM_001007098.3	RefSeq	NP_001007099.1	11	Standard
NM_001007099.3	RefSeq	NP_001007100.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Peroxisome - Homo sapiens (human)
Primary bile acid biosynthesis - Homo sapiens (human)
PPAR signaling pathway - Homo sapiens (human)
27-Hydroxylase Deficiency
Bile Acid Biosynthesis

Biological Process

protein targeting to peroxisome
steroid biosynthetic process
bile acid biosynthetic process
phospholipid transport
positive regulation of intracellular cholesterol transport

Molecular Function

fatty-acyl-CoA binding
signaling receptor binding
protein binding
cholesterol binding
propanoyl-CoA C-acyltransferase activity

Cellular Component

nucleoplasm
mitochondrion
peroxisome
peroxisomal matrix
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000371514
Coding exons: 16
Length: 124475
Individuals with no LoFs: 125683
Homozygous LoFs: 0
Heterozygous LoFs: 65
Defined: 125748
p: 0.000258

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.26	226	286	0.790	0.0000135	3598
Missense (PolyPhen)		89	123.04	0.72334		1534
Synonymous	0.235	96	99.0	0.970	0.00000512	1017
Loss of Function	2.59	15	30.4	0.493	0.00000139	388

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00014	0.00012	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00054	0.00054	rare
Finnish	0.00019	0.00018	rare
European (Non-Finnish)	0.00036	0.00035	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Mediates in vitro the transfer of all common phospholipids, cholesterol and gangliosides between membranes. May play a role in regulating steroidogenesis. {ECO:0000269|PubMed:17157249, ECO:0000269|PubMed:8300590}.;
Disease: DISEASE: Leukoencephalopathy with dystonia and motor neuropathy (LKDMN) [MIM:613724]: A syndrome characterized by leukoencephalopathy, dystonic head tremor, spasmodic torticollis and reduced tendon reflexes in lower extremities. Additional features include hyposmia, pathologic saccadic eye movements, a slight hypoacusis, accumulation of branched-chain pristanic acid in plasma, and the presence of abnormal bile alcohol glucuronides in urine. {ECO:0000269|PubMed:16685654}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.401

Intolerance Scores

LoFtool: 0.180
RVIS EVS: -0.8
RVIS percentile EVS: 12.24

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.990

Gene Damage Prediction

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