C1R

Chr 12AD

complement C1r

Also known as: EDS8, EDSPD1

NCBI Gene: 715ENSG00000159403UniProt: P00736

The C1R protein is a serine protease component of the complement C1 complex that catalyzes the first enzymatic step in the classical complement pathway, cleaving and activating C1S to initiate the cascade leading to pathogen destruction and immune signaling. Mutations cause Ehlers-Danlos syndrome, periodontal type, 1, which follows autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (LOEUF 0.39), indicating intolerance to protein-disrupting mutations.

Summary from RefSeq, OMIM, UniProt
Research Assistant →

Primary Disease Associations & Inheritance

Ehlers-Danlos syndrome, periodontal type, 1MIM #130080
AD
0
Active trials
47
Pubs (1 yr)
89
P/LP submissions
26%
P/LP missense
0.39
LOEUF
GOF
Mechanism· predicted
Clinical Summary— C1R
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.78) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
65 unique Pathogenic / Likely Pathogenic· 49 VUS of 199 total submissions
Explore recent and relevant literature in Research Assistant →
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GeneReview available — C1R
Authoritative clinical overview · Recommended first read
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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
0.39LOEUF
pLI 0.779
Z-score 3.92
OE 0.19 (0.10–0.39)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
2.03Z-score
OE missense 0.71 (0.64–0.78)
271 obs / 382.7 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.19 (0.10–0.39)
0≤0.351.4
Missense OE0.71 (0.64–0.78)
0≤0.61.4
Synonymous OE1.00
0≤1.21.6
LoF obs/exp: 5 / 27.0Missense obs/exp: 271 / 382.7Syn Z: -0.05
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveC1R-related Ehlers-Danlos syndrome, periodontal typeOTHERAD
DN
0.5181th %ile
GOF
0.6345th %ile
LOF
0.4627th %ile

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction above median · 1 literature citation

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

GOFThe diagnosis of pEDS is established in a proband with suggestive clinical findings and a heterozygous pathogenic gain-of-function variant in either C1R or C1S identified by molecular genetic testing.PMID:34324282

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

ClinVar Variant Classifications

199 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic57
Likely Pathogenic8
VUS49
Likely Benign55
Benign23
Conflicting6
57
Pathogenic
8
Likely Pathogenic
49
VUS
55
Likely Benign
23
Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
11
45
0
57
Likely Pathogenic
0
6
2
0
8
VUS
3
31
15
0
49
Likely Benign
0
18
11
26
55
Benign
0
2
15
6
23
Conflicting
—6
Total4688832198

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

View in ClinVar →

Protein Context — Lollipop Plot

C1R · 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 →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Tumor Electric Field Therapy Inhibits TGF-β/C1R Signaling Axis-Driven Epithelial-Mesenchymal Transition in Glioblastoma.
Chen J et al.·CNS Neurosci Ther
2026Open Access
Increased Serum Signal Peptide-Complement C1r/C1s, Uegf, Bmp1 (CUB)-Epithelial Growth Factor Domain-Containing Protein-1 May Have a Role in the Pathophysiology of Late-Onset Fetal Growth Restriction.
Dinc G et al.·Diagnostics (Basel)
2025Open Access
Complement components C1r and C1s promote oral squamous cell carcinoma cell proliferation.
Truong TTK et al.·J Oral Biosci
2025
Impact of a Heterozygous C1RR301P/WT Mutation on Collagen Metabolism and Inflammatory Response in Human Gingival Fibroblasts.
Qu C et al.·Cells
2025Open Access
Blocking activation of the C1r zymogen defines a novel mode of complement inhibition.
Duan H et al.·J Biol Chem
2025Open Access
Top 5 resultsSearch Europe PMC ↗

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