SPPL2C

protein-coding

signal peptide peptidase like 2C, the group of Peptidase family A22

Gene summary

Enables protein homodimerization activity. Predicted to be involved in several processes, including acrosome assembly; fusion of sperm to egg plasma membrane involved in single fertilization; and membrane protein intracellular domain proteolysis. Located in cytoplasmic side of endoplasmic reticulum membrane and lumenal side of endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2025]

MANE transcript

NM_175882.3

Inheritance

—

ClinVar variants

U:145B:25

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.57

Max pathogenic AF

—

Genomic locus

chr17:45,844,881-45,847,067

External References & Databases

Ensembl (ENSG00000185294)

Transcript & Mutation Effects

hg38 • Region Span ~2.2 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 SPPL2C variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 155

not providedTotal: 15

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_175882.3. 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				3 clinvar	3 clinvar	6
missense			145 clinvar	12 clinvar	7 clinvar	164
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	145	15	10	170

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_175882.3	RefSeq	NP_787078.2	1	MANE Select
ENST00000329196.7	Ensembl	ENSP00000332488.5	1	MANE Select

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

membrane protein ectodomain proteolysis
membrane protein intracellular domain proteolysis
membrane protein proteolysis

Molecular Function

aspartic endopeptidase activity, intramembrane cleaving
protein homodimerization activity

Cellular Component

lysosomal membrane
endoplasmic reticulum membrane
Golgi-associated vesicle membrane
integral component of cytoplasmic side of endoplasmic reticulum membrane
integral component of lumenal side of endoplasmic reticulum membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000329196
Coding exons: 1
Length: 2183
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	0.193	411	422	0.974	0.0000263	4368
Missense (PolyPhen)		125	134.61	0.92863		1560
Synonymous	0.415	180	187	0.961	0.0000123	1502
Loss of Function	1.50	8	14.1	0.568	7.79e-7	138

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: dbNSFP

Function: FUNCTION: Intramembrane-cleaving aspartic protease (I-CLiP) that may be able to cleave type II membrane signal peptides in the hydrophobic plane of the membrane. {ECO:0000250}.;

Intolerance Scores

RVIS EVS: 2.19
RVIS percentile EVS: 98.1

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

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