complement factor I deficiency

Summary

complement factor I deficiency (MONDO:0012594) is a disease caused by CFI (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CFI (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 162

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		35	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	complement factor I deficiency
Mondo ID	MONDO:0012594
MeSH	C572568
OMIM	610984
Orphanet	200418
DOID	DOID:0050419
UMLS	C3463916
MedGen	483045
GARD	0017098
Is cancer (heuristic)	no

Also known as: C3 inactivator deficiency · CFID · complement component 3 inactivator deficiency · complement factor I deficiency

Data availability: 162 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › complement deficiency › complement factor I deficiency

Related subtypes (7): classic complement early component deficiency, recurrent Neisseria infections due to factor D deficiency, immunodeficiency due to a classical component pathway complement deficiency, immunodeficiency due to a late component of complement deficiency, atypical hemolytic-uremic syndrome, complement receptor deficiency, disorder of lectin complement activation pathway

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

162 retrieved; paginated sample, class counts are floors:

74 uncertain significance, 35 conflicting classifications of pathogenicity, 11 likely pathogenic, 11 likely benign, 10 benign/likely benign, 7 pathogenic/likely pathogenic, 5 benign, 4 pathogenic, 2 likely pathogenic/pathogenic, low penetrance, 1 pathogenic/likely pathogenic, low penetrance, 1 pathogenic/pathogenic, low penetrance, 1 likely pathogenic, low penetrance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1066334	NM_000204.5(CFI):c.1429+1G>C	CFI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1179031	NM_000204.5(CFI):c.763_772+9delinsGTATCCAC	CFI	Pathogenic	criteria provided, single submitter
12121	NM_000204.5(CFI):c.1420C>T (p.Arg474Ter)	CFI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12124	NM_000204.5(CFI):c.728G>A (p.Gly243Asp)	CFI	Pathogenic	no assertion criteria provided
1451295	NM_000204.5(CFI):c.772G>A (p.Ala258Thr)	CFI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455473	NM_000204.5(CFI):c.265_266del (p.Lys89fs)	CFI	Pathogenic	criteria provided, multiple submitters, no conflicts
1458867	NM_000204.5(CFI):c.1450_1454del (p.Leu484fs)	CFI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1802728	NM_000204.5(CFI):c.563G>T (p.Gly188Val)	CFI	Pathogenic/Likely pathogenic, low penetrance	criteria provided, multiple submitters, no conflicts
1923366	NM_000204.5(CFI):c.1300del (p.Glu434fs)	CFI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
280145	NM_000204.5(CFI):c.1176_1177dup (p.Trp393fs)	CFI	Pathogenic	criteria provided, multiple submitters, no conflicts
286534	NM_000204.5(CFI):c.80_81del (p.Asp27fs)	CFI	Pathogenic/Pathogenic, low penetrance	criteria provided, multiple submitters, no conflicts
3589772	NM_000204.5(CFI):c.413del (p.Met138fs)	CFI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
631934	NM_000204.5(CFI):c.559C>T (p.Arg187Ter)	CFI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1179053	NM_000204.5(CFI):c.1638G>A (p.Trp546Ter)	CFI	Likely pathogenic	criteria provided, single submitter
1343352	NM_000204.5(CFI):c.57+1G>C	CFI	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2627275	NM_000204.5(CFI):c.658+1G>A	CFI	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3589744	NM_000204.5(CFI):c.1326dup (p.Asp443fs)	CFI	Likely pathogenic	criteria provided, single submitter
3589750	NM_000204.5(CFI):c.1122_1123insT (p.Ile375fs)	CFI	Likely pathogenic	criteria provided, single submitter
3589758	NM_000204.5(CFI):c.905-1G>C	CFI	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3589760	NM_000204.5(CFI):c.773-1G>A	CFI	Likely pathogenic	criteria provided, single submitter
3589761	NM_000204.5(CFI):c.772+1G>T	CFI	Likely pathogenic	criteria provided, single submitter
3589762	NM_000204.5(CFI):c.764G>A (p.Cys255Tyr)	CFI	Likely pathogenic/Pathogenic, low penetrance	criteria provided, multiple submitters, no conflicts
3589763	NM_000204.5(CFI):c.748C>T (p.Gln250Ter)	CFI	Likely pathogenic	criteria provided, single submitter
3589781	NM_000204.5(CFI):c.57+1G>A	CFI	Likely pathogenic	criteria provided, single submitter
4280433	NM_000204.5(CFI):c.587G>C (p.Cys196Ser)	CFI	Likely pathogenic, low penetrance	criteria provided, single submitter
4280491	NM_000204.5(CFI):c.212G>T (p.Gly71Val)	CFI	Likely pathogenic	criteria provided, single submitter
452535	NM_000204.5(CFI):c.1233C>A (p.Tyr411Ter)	CFI	Likely pathogenic/Pathogenic, low penetrance	criteria provided, multiple submitters, no conflicts
12118	NM_000204.5(CFI):c.1253A>T (p.His418Leu)	CFI	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1319494	NM_000204.5(CFI):c.1015C>T (p.Arg339Ter)	CFI	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1337881	NM_000204.5(CFI):c.616T>A (p.Tyr206Asn)	CFI	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 7 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
CFI	Strong	Autosomal recessive	complement factor I deficiency	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CFI	Orphanet:200418	Immunodeficiency with factor I anomaly
CFI	Orphanet:244242	HELLP syndrome
CFI	Orphanet:244275	De novo thrombotic microangiopathy after kidney transplantation
CFI	Orphanet:544472	Atypical hemolytic uremic syndrome with complement gene abnormality
CFI	Orphanet:75376	Familial drusen
C3	Orphanet:280133	Complement component 3 deficiency
C3	Orphanet:544472	Atypical hemolytic uremic syndrome with complement gene abnormality

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CFI	HGNC:5394	ENSG00000205403	P05156	Complement factor I	gencc,clinvar
C3	HGNC:1318	ENSG00000125730	P01024	Complement C3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CFI	Complement factor I	Trypsin-like serine protease that plays an essential role in regulating the immune response by controlling all complement pathways.
C3	Complement C3	Precursor of non-enzymatic components of the classical, alternative, lectin and GZMK complement pathways, which consist in a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adapt…

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Complement	1	134.0×	0.015
Protease	1	18.3×	0.054

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CFI	Protease	yes	3.4.21.45	SRCR, Trypsin_dom, Peptidase_S1A
C3	Complement	yes	3.4.21.47	Anaphylatoxin/fibulin, Netrin_domain, Macroglobln_a2

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
parietal pleura	2
right lobe of liver	2
germinal epithelium of ovary	1
palpebral conjunctiva	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CFI	240	broad	marker	germinal epithelium of ovary, parietal pleura, right lobe of liver
C3	289	ubiquitous	marker	parietal pleura, right lobe of liver, palpebral conjunctiva

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
C3	3,199
CFI	1,120

Intra-cohort edges

A	B	Sources
C3	CFI	biogrid_interaction, intact, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
C3	P01024	75
CFI	P05156	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of Complement cascade	2	233.1×	2e-04	CFI, C3
Alternative complement activation	1	1142.0×	0.004	C3
Activation of C3 and C5	1	634.4×	0.005	C3
Purinergic signaling in leishmaniasis infection	1	211.5×	0.012	C3
Post-translational protein phosphorylation	1	50.1×	0.033	C3
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	1	43.6×	0.033	C3
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	43.3×	0.033	C3
Peptide ligand-binding receptors	1	37.1×	0.033	C3
G alpha (i) signalling events	1	19.5×	0.056	C3
Neutrophil degranulation	1	11.5×	0.085	C3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
complement activation, classical pathway	2	543.6×	1e-04	CFI, C3
regulation of triglyceride biosynthetic process	1	4213.0×	0.002	C3
complement-dependent cytotoxicity	1	4213.0×	0.002	C3
positive regulation of type IIa hypersensitivity	1	2808.7×	0.002	C3
positive regulation of activation of membrane attack complex	1	2808.7×	0.002	C3
oviduct epithelium development	1	2808.7×	0.002	C3
vertebrate eye-specific patterning	1	2808.7×	0.002	C3
complement-mediated synapse pruning	1	2106.5×	0.002	C3
positive regulation of apoptotic cell clearance	1	1203.7×	0.003	C3
positive regulation of D-glucose transmembrane transport	1	1053.2×	0.003	C3
positive regulation of lipid storage	1	702.2×	0.004	C3
positive regulation of phagocytosis, engulfment	1	648.1×	0.004	C3
complement activation, GZMK pathway	1	648.1×	0.004	C3
neuron remodeling	1	601.9×	0.004	C3
complement receptor mediated signaling pathway	1	561.7×	0.004	C3
positive regulation of G protein-coupled receptor signaling pathway	1	526.6×	0.004	C3
complement activation, alternative pathway	1	495.6×	0.004	C3
amyloid-beta clearance	1	468.1×	0.004	C3
positive regulation of receptor-mediated endocytosis	1	401.2×	0.004	C3
complement activation	1	312.1×	0.005	C3
positive regulation of vascular endothelial growth factor production	1	247.8×	0.006	C3
B cell activation	1	227.7×	0.006	C3
positive regulation of protein phosphorylation	1	138.1×	0.010	C3
fatty acid metabolic process	1	96.8×	0.013	C3
response to bacterium	1	96.8×	0.013	C3
positive regulation of angiogenesis	1	57.7×	0.021	C3
immune response	1	23.5×	0.050	C3
inflammatory response	1	18.9×	0.060	C3
G protein-coupled receptor signaling pathway	1	18.1×	0.060	C3
proteolysis	1	17.1×	0.061	CFI

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CFI	0	0
C3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
C3	15	Binding:15

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CFI	3.4.21.45	complement factor I
C3	3.4.21.47	alternative-complement-pathway C3/C5 convertase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	CFI, C3
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
CFI	0	—
C3	15	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.