atypical hemolytic-uremic syndrome with I factor anomaly

Summary

atypical hemolytic-uremic syndrome with I factor anomaly (MONDO:0013041) is a disease caused by CFI (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: CFI (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 203

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	atypical hemolytic-uremic syndrome with I factor anomaly
Mondo ID	MONDO:0013041
OMIM	612923
Orphanet	93580
UMLS	C2752039
MedGen	414542
GARD	0018553
Is cancer (heuristic)	no

Also known as: aHUS with I factor anomaly · AHUS3 · aHUS3 · atypical HUS with I factor anomaly · D-HUS with I factor anomaly · hemolytic uremic syndrome, atypical, susceptibility to, 3 · hemolytic uremic syndrome, atypical, susceptibility to, type 3 · hemolytic-uremic syndrome without diarrhea with I factor anomaly · hemolytic-uremic syndrome without diarrhoea with I factor anomaly

Data availability: 203 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › atypical hemolytic-uremic syndrome › atypical hemolytic uremic syndrome with complement gene abnormality › atypical hemolytic-uremic syndrome with I factor anomaly

Related subtypes (4): atypical hemolytic-uremic syndrome with MCP/CD46 anomaly, atypical hemolytic-uremic syndrome with B factor anomaly, atypical hemolytic-uremic syndrome with C3 anomaly, atypical hemolytic-uremic syndrome with thrombomodulin anomaly

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

203 retrieved; paginated sample, class counts are floors:

95 uncertain significance, 40 conflicting classifications of pathogenicity, 15 benign/likely benign, 13 likely pathogenic, 13 likely benign, 11 benign, 7 pathogenic, 6 pathogenic/likely pathogenic, 2 likely pathogenic/pathogenic, low penetrance, 1 pathogenic/pathogenic, low penetrance

ClinVar	Variant (HGVS)	Gene	Classification	Review
2500782	NC_000001.11:g.196706898_196873196del	CFH	Pathogenic	criteria provided, single submitter
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
12122	NM_000204.5(CFI):c.1571A>T (p.Asp524Val)	CFI	Pathogenic	criteria provided, single submitter
12123	NM_000204.5(CFI):c.1637G>A (p.Trp546Ter)	CFI	Pathogenic	criteria provided, single submitter
1451295	NM_000204.5(CFI):c.772G>A (p.Ala258Thr)	CFI	Pathogenic/Likely pathogenic	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
2577424	NM_000204.5(CFI):c.1149-1G>A	CFI	Pathogenic	no assertion criteria provided
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
3061879	NM_000204.5(CFI):c.79del (p.Asp27fs)	CFI	Pathogenic	criteria provided, single submitter
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
3236801	NM_000204.5(CFI):c.1487C>T (p.Ser496Phe)	CFI	Likely pathogenic	criteria provided, single submitter
3370349	NM_000204.5(CFI):c.1169dup (p.Tyr390Ter)	CFI	Likely pathogenic	criteria provided, single submitter
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
452535	NM_000204.5(CFI):c.1233C>A (p.Tyr411Ter)	CFI	Likely pathogenic/Pathogenic, low penetrance	criteria provided, multiple submitters, no conflicts
4796780	NM_000204.5(CFI):c.796T>C (p.Cys266Arg)	CFI	Likely pathogenic	criteria provided, single submitter
829988	NM_000204.5(CFI):c.1118G>C (p.Cys373Ser)	CFI	Likely pathogenic	no assertion criteria provided
12126	NM_000204.5(CFI):c.1555G>A (p.Asp519Asn)	CFI	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 12 · 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	Definitive	Autosomal dominant	atypical hemolytic-uremic syndrome	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
CFH	Orphanet:200421	Immunodeficiency with factor H anomaly
CFH	Orphanet:244242	HELLP syndrome
CFH	Orphanet:244275	De novo thrombotic microangiopathy after kidney transplantation
CFH	Orphanet:329903	Immunoglobulin-mediated membranoproliferative glomerulonephritis
CFH	Orphanet:544472	Atypical hemolytic uremic syndrome with complement gene abnormality
CFH	Orphanet:75376	Familial drusen
CFH	Orphanet:93571	Dense deposit disease

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
CFH	HGNC:4883	ENSG00000000971	P08603	Complement factor H	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.
CFH	Complement factor H	Glycoprotein that plays an essential role in maintaining a well-balanced immune response by modulating complement activation.

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
CFH	Complement	yes		Sushi_SCR_CCP_dom, Sushi/SCR/CCP_sf, ComplSys_Reg/VirEntry_Med

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
germinal epithelium of ovary	1
parietal pleura	1
right lobe of liver	1
calcaneal tendon	1
right coronary artery	1
urethra	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
CFH	267	ubiquitous	marker	urethra, calcaneal tendon, right coronary artery

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CFH	1,844
CFI	1,120

Intra-cohort edges

A	B	Sources
CFH	CFI	intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CFH	P08603	51
CFI	P05156	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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-05	CFI, CFH

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
regulation of complement activation, alternative pathway	1	4213.0×	0.002	CFH
regulation of complement-dependent cytotoxicity	1	1685.2×	0.002	CFH
regulation of complement activation	1	1053.2×	0.002	CFH
proteolysis	2	34.2×	0.002	CFI, CFH
complement activation, alternative pathway	1	495.6×	0.003	CFH
central nervous system myelination	1	495.6×	0.003	CFH
complement activation	1	312.1×	0.005	CFH
complement activation, classical pathway	1	271.8×	0.005	CFI
inflammatory response	1	18.9×	0.058	CFH
innate immune response	1	16.8×	0.059	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
CFH	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CFH	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CFI	3.4.21.45	complement factor I

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, CFH
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	—
CFH	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.