SPPL2C

Chr 17

signal peptide peptidase like 2C

Also known as: IMP5

NCBI Gene: 162540UniProt: Q8IUH8

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]

0
Active trials
232
ClinVar variants
57
Pathogenic / LP
0.2
Missense Z
1.03
LOEUF
3
Pubs (2 yr)
Clinical Summary— SPPL2C
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
57 Pathogenic / Likely Pathogenic· 148 VUS of 232 total submissions
Some data sources returned errors (1)

ensembl: Error: Ensembl fetch failed: 500 for https://rest.ensembl.org/lookup/symbol/homo_sapiens/SPPL2C?content-type=application/json&expand=1

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.03LOEUF
pLI 0.000
Z-score 1.50
OE 0.57 (0.33–1.03)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.19Z-score
OE missense 0.97 (0.90–1.06)
411 obs / 422.2 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.57 (0.33–1.03)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.97 (0.90–1.06)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.96
0≤1.21.6
LoF obs/exp: 8 / 14.1Missense obs/exp: 411 / 422.2Syn Z: 0.41

ClinVar Variant Classifications

232 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic54
Likely Pathogenic3
VUS148
Likely Benign15
Benign11
Conflicting1
54
Pathogenic
3
Likely Pathogenic
148
VUS
15
Likely Benign
11
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
54
0
54
Likely Pathogenic
0
0
3
0
3
VUS
0
144
4
0
148
Likely Benign
0
12
0
3
15
Benign
0
8
0
3
11
Conflicting
—1
Total0164616232

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

SPPL2C · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
INTRAMEMBRANE PROTEASE 5
MIM #608284 · *
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Genome-wide and phenome-wide studies provided insights into brain glymphatic system function and its clinical associations.
Ran L et al.·Sci Adv
2025
MAPT Locus in Parkinson's Disease Patients of Ashkenazi Origin: A Stratified Analysis.
Shani S et al.·Genes (Basel)
2023Cohort
Exome-wide age-of-onset analysis reveals exonic variants in ERN1 and SPPL2C associated with Alzheimer's disease.
He L et al.·Transl Psychiatry
2021
Screening non-MAPT genes of the Chr17q21 H1 haplotype in Parkinson's disease.
Soto-Beasley AI et al.·Parkinsonism Relat Disord
2020
Genetic variants associated with idiopathic pulmonary fibrosis susceptibility and mortality: a genome-wide association study.
Noth I et al.·Lancet Respir Med
2013
Regulated intramembrane proteolysis of Bri2 (Itm2b) by ADAM10 and SPPL2a/SPPL2b.
Martin L et al.·J Biol Chem
2008
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Selective regulation of aspartyl intramembrane protease activity by calnexin
Contreras W et al.·Cell Mol Life Sci
2024
Exome sequencing reveals variants in known and novel candidate genes for severe sperm motility disorders
Oud MS et al.·Hum Reprod
2021
The transmembrane domain of Frey1 harbors a transplantable inhibitory motif for intramembrane proteases
Contreras W et al.·Cell Mol Life Sci
2023
On the track of intramembrane clippers: the SPPL2a/b proteases caught in the act in animal models.
Trávníčková K et al.·FEBS J
2022Functional
The role of SPP/SPPL intramembrane proteases in membrane protein homeostasis.
Mentrup T et al.·FEBS J
2023
The N-terminal PA domains of signal-peptide-peptidase-like 2 (SPPL2) proteases impact on TNFalpha cleavage
Schlosser C et al.·Commun Biol
2025
Signal peptide peptidase-like 2 proteases: Regulatory switches or proteasome of the membrane?
Mentrup T et al.·Biochim Biophys Acta Mol Cell Res
2022
Identification of Breast Cancer Metastasis Markers from Gene Expression Profiles Using Machine Learning Approaches
Jung J et al.·Genes (Basel)
2023
Top 8 full-text resultsSearch PubTator3 ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients