SPPL2C

Chr 17

signal peptide peptidase like 2C

Also known as: IMP5

NCBI Gene: 162540 ENSG00000185294 UniProt: Q8IUH8 OMIM: 608284

SPPL2C encodes a sperm-specific intramembrane-cleaving aspartic protease that cleaves tail-anchored proteins and SNARE proteins, modulating intracellular calcium homeostasis and supporting vesicular trafficking during spermatogenesis and acrosome formation. The gene is not well-constrained against loss-of-function variants and no established human disease associations have been reported in the pediatric neurogenetics literature. Given its sperm-specific expression and function, mutations would most likely manifest as male infertility rather than pediatric neurological phenotypes.

OMIM ResearchSummary from RefSeq, UniProt

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]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.03

Clinical Summary— SPPL2C

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

145 VUS of 171 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

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?

0.19Z-score

OE missense 0.97 (0.90–1.06)

411 obs / 422.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.57 (0.33–1.03)

0≤0.351.4

Missense OE?0.97 (0.90–1.06)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 8 / 14.1Missense obs/exp: 411 / 422.2Syn Z: 0.41

This gene — mechanism propensity

0.7228th %ile

GOF

0.77top 25%

LOF

0.2484th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

171 submitted variants in ClinVar

ClinVar

Classification Summary

VUS145

Likely Benign15

Benign11

145

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	145	0	145
Likely Benign	12	3	15
Benign	8	3	11
Total	165	6	171

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

View in ClinVar →

59 pathogenic / likely-pathogenic (of 64) ClinVar copy-number / structural variants overlap SPPL2C — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →