atypical hemolytic-uremic syndrome with MCP/CD46 anomaly

Summary

atypical hemolytic-uremic syndrome with MCP/CD46 anomaly (MONDO:0013040) is a disease caused by CD46 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: CD46 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 108

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	atypical hemolytic-uremic syndrome with MCP/CD46 anomaly
Mondo ID	MONDO:0013040
OMIM	612922
Orphanet	93576
UMLS	C2752040
MedGen	414167
GARD	0018552
Is cancer (heuristic)	no

Also known as: aHUS with MCP/CD46 anomaly · AHUS2 · aHUS2 · atypical HUS with MCP/CD46 anomaly · D-HUS with MCP/CD46 anomaly · hemolytic uremic syndrome, atypical, susceptibility to, 2 · hemolytic uremic syndrome, atypical, susceptibility to, type 2 · hemolytic-uremic syndrome without diarrhea with MCP/CD46 anomaly · hemolytic-uremic syndrome without diarrhoea with MCP/CD46 anomaly

Data availability: 108 ClinVar variants · 4 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 MCP/CD46 anomaly

Related subtypes (4): atypical hemolytic-uremic syndrome with I factor 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

108 retrieved; paginated sample, class counts are floors:

50 uncertain significance, 17 conflicting classifications of pathogenicity, 10 pathogenic, 8 likely pathogenic, 8 benign, 6 pathogenic/likely pathogenic, 5 benign/likely benign, 2 likely benign, 1 pathogenic/likely pathogenic/pathogenic, low penetrance, 1 pathogenic/pathogenic, low penetrance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1163189	NM_172351.3(CD46):c.287-2A>G	CD46	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1333461	NM_172351.3(CD46):c.350_351dup (p.Glu118fs)	CD46	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1343345	NM_172351.3(CD46):c.820_821del (p.Ser274fs)	CD46	Pathogenic/Likely pathogenic/Pathogenic, low penetrance	criteria provided, multiple submitters, no conflicts
17044	NM_172351.3(CD46):c.800_801del (p.Thr267fs)	CD46	Pathogenic	criteria provided, single submitter
17047	NM_172351.3(CD46):c.98-1G>C	CD46	Pathogenic	criteria provided, single submitter
17048	NM_172351.3(CD46):c.175C>T (p.Arg59Ter)	CD46	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2078079	NM_172351.3(CD46):c.886del (p.Ala296fs)	CD46	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2577446	NM_172351.3(CD46):c.907del (p.Arg303fs)	CD46	Pathogenic	no assertion criteria provided
265981	NM_172351.3(CD46):c.776del (p.Gly259fs)	CD46	Pathogenic	no assertion criteria provided
3236244	NM_172351.3(CD46):c.126_127del (p.Glu42fs)	CD46	Pathogenic	criteria provided, single submitter
3236246	NM_172351.3(CD46):c.735del (p.Lys245fs)	CD46	Pathogenic	criteria provided, single submitter
369948	NM_172351.3(CD46):c.542_543del (p.Val180_Phe181insTer)	CD46	Pathogenic	no assertion criteria provided
3895475	NM_172351.3(CD46):c.1082+2T>A	CD46	Pathogenic	criteria provided, single submitter
4291201	NM_172351.3(CD46):c.381T>A (p.Cys127Ter)	CD46	Pathogenic/Pathogenic, low penetrance	criteria provided, multiple submitters, no conflicts
438672	NM_172351.3(CD46):c.685C>T (p.Arg229Ter)	CD46	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
505831	NM_172351.3(CD46):c.286+2T>G	CD46	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
635500	NM_172351.3(CD46):c.404del (p.Gly135fs)	CD46	Pathogenic	criteria provided, single submitter
829863	NM_172351.3(CD46):c.828G>A (p.Trp276Ter)	CD46	Pathogenic	criteria provided, multiple submitters, no conflicts
17045	NM_172351.3(CD46):c.811_816del (p.Asp271_Ser272del)	CD46	Likely pathogenic	criteria provided, single submitter
2584519	NM_172351.3(CD46):c.857-1G>A	CD46	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3068272	NM_172351.3(CD46):c.559G>C (p.Val187Leu)	CD46	Likely pathogenic	criteria provided, single submitter
3370412	NM_172351.3(CD46):c.351C>G (p.Tyr117Ter)	CD46	Likely pathogenic	no assertion criteria provided
3578197	NM_172351.3(CD46):c.518A>G (p.His173Arg)	CD46	Likely pathogenic	criteria provided, single submitter
3894572	NM_172351.3(CD46):c.422G>A (p.Cys141Tyr)	CD46	Likely pathogenic	criteria provided, single submitter
3895487	NM_172351.3(CD46):c.1019-2A>G	CD46	Likely pathogenic	criteria provided, single submitter
829903	NM_172351.3(CD46):c.714_715del (p.Gln238fs)	CD46	Likely pathogenic	criteria provided, single submitter
1162904	NM_172351.3(CD46):c.535G>C (p.Glu179Gln)	CD46	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1185017	NM_172351.3(CD46):c.198A>T (p.Lys66Asn)	CD46	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
17046	NM_172351.3(CD46):c.718T>C (p.Ser240Pro)	CD46	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
17049	NM_172351.3(CD46):c.104G>A (p.Cys35Tyr)	CD46	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
CD46	Definitive	Semidominant	atypical hemolytic-uremic syndrome with MCP/CD46 anomaly	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CD46	Orphanet:244242	HELLP syndrome
CD46	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
CD46	HGNC:6953	ENSG00000117335	P15529	Membrane cofactor protein	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CD46	Membrane cofactor protein	Acts as a cofactor for complement factor I, a serine protease which protects autologous cells against complement-mediated injury by cleaving C3b and C4b deposited on host tissue.

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)
CD46	Complement	yes		Sushi_SCR_CCP_dom, CD46, Sushi/SCR/CCP_sf

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
adrenal tissue	1
mucosa of paranasal sinus	1
palpebral conjunctiva	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CD46	295	ubiquitous	marker	palpebral conjunctiva, adrenal tissue, mucosa of paranasal sinus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CD46	1,780

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CD46	P15529	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Complement cascade	1	634.4×	0.006	CD46
Regulation of Complement cascade	1	233.1×	0.009	CD46
Innate Immune System	1	25.5×	0.052	CD46
Immune System	1	13.0×	0.077	CD46

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
obsolete sequestering of extracellular ligand from receptor	1	16852.0×	9e-04	CD46
negative regulation of complement activation, classical pathway	1	2407.4×	0.002	CD46
positive regulation of transforming growth factor beta production	1	2106.5×	0.002	CD46
positive regulation of memory T cell differentiation	1	1872.4×	0.002	CD46
T cell mediated immunity	1	991.3×	0.003	CD46
positive regulation of regulatory T cell differentiation	1	936.2×	0.003	CD46
regulation of Notch signaling pathway	1	842.6×	0.003	CD46
complement activation, classical pathway	1	543.6×	0.003	CD46
positive regulation of interleukin-10 production	1	401.2×	0.004	CD46
positive regulation of T cell proliferation	1	259.3×	0.006	CD46
single fertilization	1	183.2×	0.007	CD46
adaptive immune response	1	84.3×	0.015	CD46
negative regulation of gene expression	1	69.1×	0.017	CD46
positive regulation of gene expression	1	38.7×	0.028	CD46
innate immune response	1	33.6×	0.030	CD46

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CD46	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	CD46
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)
CD46	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.