SPCS2

Chr 11

signal peptidase complex subunit 2

NCBI Gene: 9789 ENSG00000118363 UniProt: Q15005 OMIM: 619411

This protein is a component of the signal peptidase complex that cleaves N-terminal signal sequences from nascent proteins as they enter the endoplasmic reticulum lumen. Mutations cause autosomal recessive developmental delays, intellectual disability, and seizures with infantile onset. The gene is highly constrained against loss-of-function variants, indicating that complete loss of protein function is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable peptidase activity. Involved in obsolete signal peptide processing. Located in endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Jun 2026]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.35

LOEUF

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.35LOEUF

pLI 0.929

Z-score 2.69

OE 0.00 (0.00–0.35)

Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.42Z-score

OE missense 0.63 (0.52–0.77)

75 obs / 118.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.35)

0≤0.351.4

Missense OE?0.63 (0.52–0.77)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 0 / 8.4Missense obs/exp: 75 / 118.6Syn Z: 0.39

Background carrier burden — how many people carry a rare variant somewhere in SPCS2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 290

277 rare PASS variants

Rare truncating (LoF)

1 in 2,000

21 rare PASS variants

Rare synonymous (reference)

1 in 440

108 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SPCS2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 460	1 in 2,900
South Asian	~43k	1 in 240	1 in 660
Remaining (unassigned)	~30k	1 in 270	1 in 750
European (Finnish)	~27k	1 in 380	≈ 1 in 9,900
Admixed American	~22k	1 in 470	≈ 1 in 18,000
African / African American	~21k	1 in 200	1 in 2,100
East Asian	~20k	1 in 270	1 in 1,700
Ashkenazi Jewish	~13k	1 in 690	≈ 1 in 3,900
Middle Eastern	~2,883	1 in 560	≈ 1 in 2,000

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 4 of 5 coding exons well covered in gnomAD exomes; exon 5 marginal. Genomes: all 5.? see exons ↓