C1S

Chr 12AD

complement C1s

Also known as: EDSPD2

NCBI Gene: 716 ENSG00000182326 UniProt: P09871 OMIM: 120580

This serine protease is activated by C1R within the complement C1 complex and subsequently cleaves C2 and C4 to initiate the classical complement pathway following antigen-antibody complex formation. Mutations cause C1s deficiency and Ehlers-Danlos syndrome periodontal type 2, both following autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (LOEUF 0.596), indicating intolerance to protein-truncating mutations.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a serine protease, which is a major constituent of the human complement subcomponent C1. C1s associates with two other complement components C1r and C1q in order to yield the first component of the serum complement system. Defects in this gene are the cause of selective C1s deficiency. [provided by RefSeq, Mar 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

C1s deficiencyMIM #613783

Ehlers-Danlos syndrome, periodontal type, 2MIM #617174

UniProtComplement component C1s deficiency

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists C1s deficiency; Ehlers-Danlos syndrome, periodontal type; no ClinGen or GenCC tier

Active trials

123

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.60

LOEUF

Multiple*

Mechanism· predicted

📖

GeneReview available — C1S

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.60LOEUF

pLI 0.001

Z-score 3.28

OE 0.36 (0.23–0.60)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.56Z-score

OE missense 0.92 (0.84–1.00)

342 obs / 372.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.36 (0.23–0.60)

0≤0.351.4

Missense OE?0.92 (0.84–1.00)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 11 / 30.5Missense obs/exp: 342 / 372.4Syn Z: -0.39

Background carrier burden — how many people carry a rare variant somewhere in C1S?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 66

776 rare PASS variants

Rare truncating (LoF)

1 in 2,200

92 rare PASS variants

Rare synonymous (reference)

1 in 100

304 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for C1S. 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 98	1 in 2,400
South Asian	~43k	1 in 73	1 in 1,500
Remaining (unassigned)	~30k	1 in 73	1 in 760
European (Finnish)	~27k	1 in 190	≈ 1 in 8,900
Admixed American	~22k	1 in 61	≈ 1 in 11,000
African / African American	~21k	1 in 71	1 in 1,600
East Asian	~20k	1 in 80	1 in 1,000
Ashkenazi Jewish	~13k	1 in 220	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 74	none seen

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): 10 of 11 coding exons well covered in gnomAD exomes; exon 9 marginal. Genomes: all 11.? see exons ↓