atypical hemolytic-uremic syndrome with C3 anomaly

Summary

atypical hemolytic-uremic syndrome with C3 anomaly (MONDO:0013043) is a disease caused by C3 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: C3 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 395

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	atypical hemolytic-uremic syndrome with C3 anomaly
Mondo ID	MONDO:0013043
OMIM	612925
Orphanet	93575
UMLS	C2752037
MedGen	442875
GARD	0018555
Is cancer (heuristic)	no

Also known as: aHUS with C3 anomaly · AHUS5 · atypical HUS with C3 anomaly · D-HUS with C3 anomaly · hemolytic uremic syndrome with DGKE deficiency · hemolytic uremic syndrome, atypical, susceptibility to, 5 · hemolytic uremic syndrome, atypical, susceptibility to, type 5 · hemolytic-uremic syndrome without diarrhea with C3 anomaly · hemolytic-uremic syndrome without diarrhoea with C3 anomaly

Data availability: 395 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 C3 anomaly

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

395 retrieved; paginated sample, class counts are floors:

220 uncertain significance, 76 conflicting classifications of pathogenicity, 36 likely benign, 24 benign, 23 benign/likely benign, 10 likely pathogenic, 5 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1163121	NM_000064.4(C3):c.481C>T (p.Arg161Trp)	C3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455261	NM_000064.4(C3):c.373dup (p.Leu125fs)	C3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17060	NM_000064.4(C3):c.1775G>A (p.Arg592Gln)	C3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2972902	NM_000064.4(C3):c.2290C>T (p.Arg764Ter)	C3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3584123	NM_000064.4(C3):c.2825_2826del (p.Val942fs)	C3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
992385	NM_000064.4(C3):c.3737_3738del (p.Asp1245_Phe1246insTer)	C3	Pathogenic	criteria provided, multiple submitters, no conflicts
17061	NM_000064.4(C3):c.3281C>T (p.Ala1094Val)	C3	Likely pathogenic	criteria provided, single submitter
2575231	NM_000064.4(C3):c.75-1G>A	C3	Likely pathogenic	criteria provided, single submitter
3584072	NM_000064.4(C3):c.4918del (p.Glu1640fs)	C3	Likely pathogenic	criteria provided, single submitter
3584099	NM_000064.4(C3):c.3687del (p.Asn1229fs)	C3	Likely pathogenic	criteria provided, single submitter
3584120	NM_000064.4(C3):c.2863+1G>T	C3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3584127	NM_000064.4(C3):c.2615del (p.Phe872fs)	C3	Likely pathogenic	criteria provided, single submitter
3584178	NM_000064.4(C3):c.1003+1G>A	C3	Likely pathogenic	criteria provided, single submitter
3584182	NM_000064.4(C3):c.774-1G>T	C3	Likely pathogenic	criteria provided, single submitter
3584194	NM_000064.4(C3):c.276del (p.Asn93fs)	C3	Likely pathogenic	criteria provided, single submitter
4279900	NM_000064.4(C3):c.683-1G>T	C3	Likely pathogenic	criteria provided, single submitter
1402622	NM_000064.4(C3):c.1887G>A (p.Pro629=)	C3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1408822	NM_000064.4(C3):c.1215C>T (p.Gly405=)	C3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1430457	NM_000064.4(C3):c.1686G>A (p.Ser562=)	C3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1606550	NM_000064.4(C3):c.2441-16G>T	C3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1627203	NM_000064.4(C3):c.1923C>T (p.Asp641=)	C3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1630092	NM_000064.4(C3):c.683-4C>G	C3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1674240	NM_000064.4(C3):c.987C>T (p.Thr329=)	C3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1678448	NM_000064.4(C3):c.3131G>A (p.Gly1044Glu)	C3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
17062	NM_000064.4(C3):c.3343G>A (p.Asp1115Asn)	C3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2069494	NM_000064.4(C3):c.4947C>T (p.Leu1649=)	C3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3012516	NM_000064.4(C3):c.3155-17CT[3]	C3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330269	NM_000064.4(C3):c.4941G>A (p.Gln1647=)	C3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330271	NM_000064.4(C3):c.4855A>C (p.Ser1619Arg)	C3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330272	NM_000064.4(C3):c.4850+12C>A	C3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · 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
C3	Definitive	Autosomal dominant	atypical hemolytic-uremic syndrome with C3 anomaly	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
C3	Orphanet:280133	Complement component 3 deficiency
C3	Orphanet:544472	Atypical hemolytic uremic syndrome with complement gene abnormality

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
C3	HGNC:1318	ENSG00000125730	P01024	Complement C3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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: 1 · 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	268.0×	0.004

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
C3	Complement	yes	3.4.21.47	Anaphylatoxin/fibulin, Netrin_domain, Macroglobln_a2

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
palpebral conjunctiva	1
parietal pleura	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
C3	289	ubiquitous	marker	parietal pleura, right lobe of liver, palpebral conjunctiva

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
C3	3,199

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
C3	P01024	75

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Alternative complement activation	1	2284.0×	0.004	C3
Activation of C3 and C5	1	1268.9×	0.004	C3
Purinergic signaling in leishmaniasis infection	1	423.0×	0.008	C3
Regulation of Complement cascade	1	233.1×	0.011	C3
Post-translational protein phosphorylation	1	100.2×	0.017	C3
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	1	87.2×	0.017	C3
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	86.5×	0.017	C3
Peptide ligand-binding receptors	1	74.2×	0.017	C3
G alpha (i) signalling events	1	39.0×	0.029	C3
Neutrophil degranulation	1	23.1×	0.043	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 1 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 triglyceride biosynthetic process	1	8426.0×	9e-04	C3
complement-dependent cytotoxicity	1	8426.0×	9e-04	C3
positive regulation of type IIa hypersensitivity	1	5617.3×	9e-04	C3
positive regulation of activation of membrane attack complex	1	5617.3×	9e-04	C3
oviduct epithelium development	1	5617.3×	9e-04	C3
vertebrate eye-specific patterning	1	5617.3×	9e-04	C3
complement-mediated synapse pruning	1	4213.0×	0.001	C3
positive regulation of apoptotic cell clearance	1	2407.4×	0.002	C3
positive regulation of D-glucose transmembrane transport	1	2106.5×	0.002	C3
positive regulation of lipid storage	1	1404.3×	0.002	C3
positive regulation of phagocytosis, engulfment	1	1296.3×	0.002	C3
complement activation, GZMK pathway	1	1296.3×	0.002	C3
neuron remodeling	1	1203.7×	0.002	C3
complement receptor mediated signaling pathway	1	1123.5×	0.002	C3
positive regulation of G protein-coupled receptor signaling pathway	1	1053.2×	0.002	C3
complement activation, alternative pathway	1	991.3×	0.002	C3
amyloid-beta clearance	1	936.2×	0.002	C3
positive regulation of receptor-mediated endocytosis	1	802.5×	0.002	C3
complement activation	1	624.1×	0.003	C3
complement activation, classical pathway	1	543.6×	0.003	C3
positive regulation of vascular endothelial growth factor production	1	495.6×	0.003	C3
B cell activation	1	455.5×	0.003	C3
positive regulation of protein phosphorylation	1	276.3×	0.005	C3
fatty acid metabolic process	1	193.7×	0.006	C3
response to bacterium	1	193.7×	0.006	C3
positive regulation of angiogenesis	1	115.4×	0.010	C3
immune response	1	47.1×	0.024	C3
inflammatory response	1	37.7×	0.028	C3
G protein-coupled receptor signaling pathway	1	36.2×	0.029	C3
signal transduction	1	16.1×	0.062	C3

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
C3	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
C3	15	Binding:15

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
C3	3.4.21.47	alternative-complement-pathway C3/C5 convertase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	C3
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.