combined deficiency of factor V and factor VIII

Summary

combined deficiency of factor V and factor VIII (MONDO:0018175) is a disease with 2 cohort genes.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Cohort genes: 2
• Phenotypes (HPO): 18

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.5	Europe	Validated
Point prevalence	1-9 / 100 000	1	Iran, Islamic Republic of	Validated

Signs & symptoms

Clinical features (HPO)

18 HPO clinical features (Orphanet curated; top 18 by frequency):

HPO ID	Term	Frequency
HP:0003125	Reduced factor VIII activity	Very frequent (80-99%)
HP:0003225	Reduced coagulation factor V activity	Very frequent (80-99%)
HP:0003645	Prolonged partial thromboplastin time	Very frequent (80-99%)
HP:0008151	Prolonged prothrombin time	Very frequent (80-99%)
HP:0000225	Gingival bleeding	Frequent (30-79%)
HP:0000421	Epistaxis	Frequent (30-79%)
HP:0000978	Bruising susceptibility	Frequent (30-79%)
HP:0006298	Prolonged bleeding after dental extraction	Frequent (30-79%)
HP:0011889	Bleeding with minor or no trauma	Frequent (30-79%)
HP:0030137	Prolonged bleeding following circumcision	Frequent (30-79%)
HP:0000132	Menorrhagia	Occasional (5-29%)
HP:0000790	Hematuria	Occasional (5-29%)
HP:0002170	Intracranial hemorrhage	Occasional (5-29%)
HP:0002239	Gastrointestinal hemorrhage	Occasional (5-29%)
HP:0004846	Prolonged bleeding after surgery	Occasional (5-29%)
HP:0005261	Joint hemorrhage	Occasional (5-29%)
HP:0002149	Hyperuricemia	Very rare (<1-4%)
HP:0003077	Hyperlipidemia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	combined deficiency of factor V and factor VIII
Mondo ID	MONDO:0018175
Orphanet	35909
ICD-11	184219764
SNOMED CT	715559004
UMLS	C1856883
MedGen	384006
GARD	0016639
Is cancer (heuristic)	no

Also known as: combined deficiency of factor V and factor type VIII · F5F8D · familial multiple coagulation factor deficiency · FV and FVIII combined deficiency

Data availability: 2 GenCC gene-disease records.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › hematologic disorder › blood coagulation disease › coagulation protein disease › combined deficiency of factor V and factor VIII

Related subtypes (27): factor XIII deficiency, factor VII deficiency, factor X deficiency, thrombophilia due to activated protein C resistance, hypoplasminogenemia, congenital high-molecular-weight kininogen deficiency, congenital factor XII deficiency, alpha-2-plasmin inhibitor deficiency, Tatsumi factor deficiency, East Texas bleeding disorder, inherited prekallikrein deficiency, congenital plasminogen activator inhibitor type 1 deficiency, thrombomodulin-related bleeding disorder, congenital vitamin K-dependent coagulation factors deficiency, hemorrhagic disease due to alpha-1-antitrypsin Pittsburgh mutation, multiple sclerosis-ichthyosis-factor VIII deficiency syndrome, congenital fibrinogen deficiency, hemophilia, factor V deficiency, acquired coagulation factor deficiency, von Willebrand disease (hereditary or acquired), factor V short isoforms-related bleeding disorder, factor V amsterdam bleeding disorder, factor V atlanta bleeding disorder, combined deficiency of factor VII and factor X, plasminogen deficiency, type II, dysplasminogenemia

Subtypes (3): factor V and factor VIII, combined deficiency of, type 1, factor V and factor VIII, combined deficiency of, with normal protein C and protein C inhibitor, factor 5 and Factor VIII, combined deficiency of, 2

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · 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
LMAN1	Definitive	Autosomal recessive	factor V and factor VIII, combined deficiency of, type 1	5
MCFD2	Definitive	Autosomal recessive	factor 5 and Factor VIII, combined deficiency of, 2	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MCFD2	Orphanet:35909	Combined deficiency of factor V and factor VIII
LMAN1	Orphanet:35909	Combined deficiency of factor V and factor VIII

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
MCFD2	HGNC:18451	ENSG00000180398	Q8NI22	Multiple coagulation factor deficiency protein 2	gencc
LMAN1	HGNC:6631	ENSG00000074695	P49257	Protein ERGIC-53	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MCFD2	Multiple coagulation factor deficiency protein 2	The MCFD2-LMAN1 complex forms a specific cargo receptor for the ER-to-Golgi transport of selected proteins.
LMAN1	Protein ERGIC-53	Mannose-specific lectin.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MCFD2	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
LMAN1	Other/Unknown	no		Lectin_leg, ConA-like_dom_sf, Intracellular_Lectin-GPT

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
adrenal tissue	1
parotid gland	1
seminal vesicle	1
germinal epithelium of ovary	1
gingival epithelium	1
jejunal mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MCFD2	295	ubiquitous	marker	parotid gland, seminal vesicle, adrenal tissue
LMAN1	280	ubiquitous	marker	germinal epithelium of ovary, jejunal mucosa, gingival epithelium

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LMAN1	2,474
MCFD2	881

Intra-cohort edges

A	B	Sources
LMAN1	MCFD2	intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LMAN1	P49257	18
MCFD2	Q8NI22	17

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. 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
Cargo concentration in the ER	2	335.9×	2e-04	MCFD2, LMAN1
COPII-mediated vesicle transport	2	163.1×	4e-04	MCFD2, LMAN1
ER to Golgi Anterograde Transport	2	132.8×	4e-04	MCFD2, LMAN1
Transport to the Golgi and subsequent modification	2	102.9×	4e-04	MCFD2, LMAN1
Asparagine N-linked glycosylation	2	60.1×	0.001	MCFD2, LMAN1
Membrane Trafficking	2	37.1×	0.002	MCFD2, LMAN1
Vesicle-mediated transport	2	34.8×	0.002	MCFD2, LMAN1
Post-translational protein modification	2	19.2×	0.006	MCFD2, LMAN1
Metabolism of proteins	2	12.4×	0.014	MCFD2, LMAN1
RHOD GTPase cycle	1	102.0×	0.019	LMAN1
RHOG GTPase cycle	1	74.2×	0.022	LMAN1
RHOC GTPase cycle	1	73.2×	0.022	LMAN1
RAC2 GTPase cycle	1	63.4×	0.023	LMAN1
RAC3 GTPase cycle	1	59.5×	0.023	LMAN1
RHOA GTPase cycle	1	37.3×	0.034	LMAN1
RHO GTPase cycle	1	30.1×	0.039	LMAN1
Signaling by Rho GTPases	1	17.1×	0.062	LMAN1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	16.7×	0.062	LMAN1
Signal Transduction	1	5.1×	0.187	LMAN1

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
positive regulation of organelle organization	1	2808.7×	0.003	LMAN1
obsolete negative regulation of protein targeting to mitochondrion	1	1404.3×	0.003	LMAN1
protein transport	2	43.9×	0.003	MCFD2, LMAN1
endoplasmic reticulum organization	1	210.7×	0.013	LMAN1
blood coagulation	1	86.9×	0.023	LMAN1
endoplasmic reticulum to Golgi vesicle-mediated transport	1	68.0×	0.023	LMAN1
Golgi organization	1	66.9×	0.023	LMAN1
protein folding	1	51.7×	0.025	LMAN1
vesicle-mediated transport	1	48.1×	0.025	MCFD2
gene expression	1	39.9×	0.027	MCFD2
in utero embryonic development	1	36.0×	0.028	LMAN1

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
MCFD2	0	0
LMAN1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
LMAN1	1	Binding:1

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	MCFD2, LMAN1

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)
MCFD2	0	—
LMAN1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.