C1S
Chr 12ADcomplement C1s
Also known as: EDSPD2
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.
Primary Disease Associations & Inheritance
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
More LoF-intolerant than ~75% of genes
Mild missense constraint
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.
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.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
500 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 13 | 0 | 17 | 0 | 30 |
Likely Pathogenic | 7 | 1 | 1 | 0 | 9 |
VUS | 4 | 257 | 21 | 7 | 289 |
Likely Benign | 0 | 2 | 60 | 88 | 150 |
Benign | 0 | 0 | 1 | 0 | 1 |
Conflicting | — | 2 | |||
| Total | 24 | 260 | 100 | 95 | 481 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
C1S · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
External Resources
Links to major genomics databases and tools