C1R

Chr 12AD

complement C1r

Also known as: EDS8, EDSPD1

NCBI Gene: 715 ENSG00000159403 UniProt: P00736 OMIM: 613785

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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the peptidase S1 protein family. The encoded protein is a proteolytic subunit in the complement system C1 complex. The complement system acts as a mediator in the innate immune response by ultimately triggering phagocytosis, inflammation, and rupturing the bacterial cell wall. Mutations in this gene are associated with Ehlers-Danlos Syndrome. [provided by RefSeq, Dec 2018]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Ehlers-Danlos syndrome, periodontal type, 1MIM #130080

Clinical highlights

Gene–disease validity

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

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.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.39

LOEUF

GOF

Mechanism· predicted

📖

GeneReview available — C1R

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.39LOEUF

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 OE?0.19 (0.10–0.39)

0≤0.351.4

Missense OE?0.71 (0.64–0.78)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 5 / 27.0Missense obs/exp: 271 / 382.7Syn Z: -0.05

Background carrier burden — how many people carry a rare variant somewhere in C1R?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 71

651 rare PASS variants

Rare truncating (LoF)

1 in 1,800

76 rare PASS variants

Rare synonymous (reference)

1 in 110

294 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for C1R. 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 88	1 in 2,000
South Asian	~43k	1 in 54	1 in 3,000
Remaining (unassigned)	~30k	1 in 63	1 in 2,000
European (Finnish)	~27k	1 in 440	1 in 710
Admixed American	~22k	1 in 66	1 in 910
African / African American	~21k	1 in 55	1 in 920
East Asian	~20k	1 in 70	1 in 2,200
Ashkenazi Jewish	~13k	1 in 510	≈ 1 in 5,800
Middle Eastern	~2,884	1 in 73	≈ 1 in 1,000

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): 1 of 11 coding exons well covered in gnomAD exomes; exons 1, 2, 3, 4, 5 and 4 more poorly covered; exon 10 marginal. Genomes: all 11.? see exons ↓