SPCS3

Chr 4

signal peptidase complex subunit 3

Also known as: PRO3567, SPC22, SPC22/23, SPC23, SPC3, YLR066W

NCBI Gene: 60559ENSG00000129128UniProt: P61009

SPCS3 encodes an essential component of the signal peptidase complex that cleaves N-terminal signal sequences from nascent proteins as they enter the endoplasmic reticulum lumen. The gene is highly constrained against loss-of-function variants (pLI 0.82, LOEUF 0.53), suggesting mutations would cause severe disease, though specific associated disorders have not yet been established in the literature. Given its essential role in protein processing and high constraint scores, pathogenic variants would likely affect multiple organ systems.

Summary from RefSeq, UniProt
Research Assistant →
0
Active trials
1
Pubs (1 yr)
75
P/LP submissions
0%
P/LP missense
0.53
LOEUF
—
Mechanism
Clinical Summary— SPCS3
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.82) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
75 unique Pathogenic / Likely Pathogenic· 19 VUS of 107 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
0.53LOEUF
pLI 0.820
Z-score 2.20
OE 0.00 (0.00–0.53)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
2.04Z-score
OE missense 0.39 (0.30–0.52)
35 obs / 89.2 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.00 (0.00–0.53)
0≤0.351.4
Missense OE0.39 (0.30–0.52)
0≤0.61.4
Synonymous OE0.93
0≤1.21.6
LoF obs/exp: 0 / 5.7Missense obs/exp: 35 / 89.2Syn Z: 0.36

ClinVar Variant Classifications

107 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic73
Likely Pathogenic2
VUS19
73
Pathogenic
2
Likely Pathogenic
19
VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
73
0
73
Likely Pathogenic
0
0
2
0
2
VUS
0
12
7
0
19
Likely Benign
0
0
0
0
0
Benign
0
0
0
0
0
Total01282094

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

View in ClinVar →

Protein Context — Lollipop Plot

SPCS3 · protein map & ClinVar variants

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

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