factor V and factor VIII, combined deficiency of, type 1

Summary

factor V and factor VIII, combined deficiency of, type 1 (MONDO:0009206) is a disease caused by LMAN1 (GenCC Definitive), with 4 cohort genes. The dominant Reactome pathway is Cargo concentration in the ER (3 cohort genes).

At a glance

• Causal gene: LMAN1 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 111

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	factor V and factor VIII, combined deficiency of, type 1
Mondo ID	MONDO:0009206
OMIM	227300
SNOMED CT	84048006
UMLS	C4551981
MedGen	1637212
GARD	0018630
Is cancer (heuristic)	no

Also known as: combined deficiency of factor V and factor VIII caused by mutation in LMAN1 · combined factor V and VIII deficiency · F5F8D1 · factor 5 and Factor VIII, combined deficiency of, 1 · factor V and factor VIII, combined deficiency of, 1 · factor V and factor VIII, combined deficiency of, type 1 · LMAN1 combined deficiency of factor V and factor VIII

Data availability: 111 ClinVar variants · 4 GenCC gene-disease records.

Disease family

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 › factor V and factor VIII, combined deficiency of, type 1

Related subtypes (2): 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

ClinVar germline variants

111 retrieved; paginated sample, class counts are floors:

67 uncertain significance, 16 benign, 8 conflicting classifications of pathogenicity, 7 pathogenic, 6 likely pathogenic, 4 likely benign, 2 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1802256	NM_005570.4(LMAN1):c.349C>T (p.Arg117Ter)	LMAN1	Pathogenic	criteria provided, single submitter
3383188	NM_005570.4(LMAN1):c.1366C>T (p.Arg456Ter)	LMAN1	Pathogenic	criteria provided, single submitter
627401	NM_005570.4(LMAN1):c.904A>T (p.Lys302Ter)	LMAN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8062	NM_005570.4(LMAN1):c.89dup (p.Asp31fs)	LMAN1	Pathogenic	no assertion criteria provided
8063	NM_005570.4(LMAN1):c.1149+2T>C	LMAN1	Pathogenic	no assertion criteria provided
8064	NM_005570.4(LMAN1):c.796del (p.Gln266fs)	LMAN1	Pathogenic	no assertion criteria provided
8065	NM_005570.4(LMAN1):c.1356del (p.Asn452_Leu453insTer)	LMAN1	Pathogenic	criteria provided, single submitter
8066	NM_005570.4(LMAN1):c.2T>C (p.Met1Thr)	LMAN1	Pathogenic	no assertion criteria provided
3583381	NM_005570.4(LMAN1):c.822G>A (p.Pro274=)	LMAN1	Likely pathogenic	criteria provided, single submitter
3583382	NM_005570.4(LMAN1):c.49_86dup (p.Gly30fs)	LMAN1	Likely pathogenic	criteria provided, single submitter
3583383	NM_005570.4(LMAN1):c.15del (p.Arg5fs)	LMAN1	Likely pathogenic	criteria provided, single submitter
4849411	NM_005570.4(LMAN1):c.478-11_483delinsATTTTTTTAGGAAAAA	LMAN1	Likely pathogenic	criteria provided, single submitter
2865	NM_139279.6(MCFD2):c.149+5G>A	MCFD2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
627205	NM_139279.6(MCFD2):c.379_380dup (p.Asp127fs)	MCFD2	Likely pathogenic	criteria provided, single submitter
4263259	NM_001377304.1(GFI1B):c.958C>T (p.Arg320Trp)	GFI1B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4278325	NM_001377304.1(GFI1B):c.887G>T (p.Arg296Leu)	GFI1B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
327568	NM_005570.4(LMAN1):c.1392G>A (p.Pro464=)	LMAN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
327570	NM_005570.4(LMAN1):c.1221-4T>C	LMAN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
327572	NM_005570.4(LMAN1):c.846G>A (p.Ser282=)	LMAN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
327580	NM_005570.4(LMAN1):c.27C>G (p.Leu9=)	LMAN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
800356	NM_005570.4(LMAN1):c.1178T>C (p.Val393Ala)	LMAN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
891804	NM_005570.4(LMAN1):c.477+10T>C	LMAN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4086144	NM_000130.5(F5):c.4664G>T (p.Arg1555Met)	F5	Uncertain significance	criteria provided, single submitter
4277957	NM_001377304.1(GFI1B):c.701C>T (p.Thr234Met)	GFI1B	Uncertain significance	criteria provided, single submitter
327540	NM_005570.4(LMAN1):c.*2923C>T	LMAN1	Uncertain significance	criteria provided, single submitter
327541	NM_005570.4(LMAN1):c.*2893G>A	LMAN1	Uncertain significance	criteria provided, single submitter
327542	NM_005570.4(LMAN1):c.*2650G>A	LMAN1	Uncertain significance	criteria provided, single submitter
327543	NM_005570.4(LMAN1):c.*2602G>T	LMAN1	Uncertain significance	criteria provided, single submitter
327546	NM_005570.4(LMAN1):c.*2259A>T	LMAN1	Uncertain significance	criteria provided, single submitter
327549	NM_005570.4(LMAN1):c.*2044A>G	LMAN1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 10 · 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

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LMAN1	Orphanet:35909	Combined deficiency of factor V and factor VIII
MCFD2	Orphanet:35909	Combined deficiency of factor V and factor VIII
F5	Orphanet:131	Budd-Chiari syndrome
F5	Orphanet:326	Congenital factor V deficiency
F5	Orphanet:329217	Cerebral sinovenous thrombosis
F5	Orphanet:391320	East Texas bleeding disorder
F5	Orphanet:599579	Factor V Amsterdam bleeding disorder
F5	Orphanet:600194	Factor V Atlanta bleeding disorder
GFI1B	Orphanet:140957	Autosomal dominant macrothrombocytopenia
GFI1B	Orphanet:734	Alpha delta granule deficiency

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
LMAN1	HGNC:6631	ENSG00000074695	P49257	Protein ERGIC-53	gencc,clinvar
MCFD2	HGNC:18451	ENSG00000180398	Q8NI22	Multiple coagulation factor deficiency protein 2	clinvar
F5	HGNC:3542	ENSG00000198734	P12259	Coagulation factor V	clinvar
GFI1B	HGNC:4238	ENSG00000165702	Q5VTD9	Zinc finger protein Gfi-1b	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LMAN1	Protein ERGIC-53	Mannose-specific lectin.
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.
F5	Coagulation factor V	Central regulator of hemostasis.
GFI1B	Zinc finger protein Gfi-1b	Essential proto-oncogenic transcriptional regulator necessary for development and differentiation of erythroid and megakaryocytic lineages.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 3 · 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
Transcription factor	1	2.1×	0.404
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LMAN1	Other/Unknown	no		Lectin_leg, ConA-like_dom_sf, Intracellular_Lectin-GPT
MCFD2	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
F5	Other/Unknown	no		FA58C, Cupredoxin, Galactose-bd-like_sf
GFI1B	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
germinal epithelium of ovary	1
gingival epithelium	1
jejunal mucosa	1
adrenal tissue	1
parotid gland	1
seminal vesicle	1
choroid plexus epithelium	1
liver	1
right lobe of liver	1
monocyte	1
sperm	1
trabecular bone tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LMAN1	280	ubiquitous	marker	germinal epithelium of ovary, jejunal mucosa, gingival epithelium
MCFD2	295	ubiquitous	marker	parotid gland, seminal vesicle, adrenal tissue
F5	206	broad	marker	right lobe of liver, liver, choroid plexus epithelium
GFI1B	126	tissue_specific	marker	sperm, trabecular bone tissue, monocyte

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LMAN1	2,474
F5	1,754
GFI1B	1,554
MCFD2	881

Intra-cohort edges

A	B	Sources
F5	LMAN1	string_interaction
F5	MCFD2	string_interaction
LMAN1	MCFD2	intact, string_interaction

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LMAN1	P49257	18
F5	P12259	18
MCFD2	Q8NI22	17

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GFI1B	Q5VTD9	64.09

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 27. Enrichment computed across 4 evidence-associated genes (3 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 3 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	3	335.9×	7e-07	LMAN1, MCFD2, F5
COPII-mediated vesicle transport	3	163.1×	3e-06	LMAN1, MCFD2, F5
ER to Golgi Anterograde Transport	2	88.5×	0.002	LMAN1, MCFD2
Transport to the Golgi and subsequent modification	2	68.6×	0.002	LMAN1, MCFD2
Defective cleavage of FV variant at a.a.534	1	1268.9×	0.003	F5
Defective cleavage of FV variant at R334	1	1268.9×	0.003	F5
Asparagine N-linked glycosylation	2	40.1×	0.003	LMAN1, MCFD2
Membrane Trafficking	2	24.7×	0.007	LMAN1, MCFD2
Vesicle-mediated transport	2	23.2×	0.007	LMAN1, MCFD2
Amplification and propagation of coagulation cascade	1	211.5×	0.013	F5
Initiation of coagulation cascade	1	158.6×	0.015	F5
Post-translational protein modification	2	12.8×	0.018	LMAN1, MCFD2
Regulation of clotting cascade	1	77.7×	0.027	F5
RHOD GTPase cycle	1	68.0×	0.028	LMAN1
RHOG GTPase cycle	1	49.4×	0.032	LMAN1
RHOC GTPase cycle	1	48.8×	0.032	LMAN1
Metabolism of proteins	2	8.2×	0.032	LMAN1, MCFD2
RAC2 GTPase cycle	1	42.3×	0.035	LMAN1
RAC3 GTPase cycle	1	39.6×	0.036	LMAN1
Post-translational protein phosphorylation	1	33.4×	0.040	F5
Platelet degranulation	1	29.3×	0.042	F5
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	28.8×	0.042	F5
RHOA GTPase cycle	1	24.9×	0.047	LMAN1
RHO GTPase cycle	1	20.0×	0.055	LMAN1
Signaling by Rho GTPases	1	11.4×	0.090	LMAN1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	11.2×	0.090	LMAN1
Signal Transduction	1	3.4×	0.267	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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
blood coagulation	2	86.9×	0.004	LMAN1, F5
positive regulation of organelle organization	1	1404.3×	0.004	LMAN1
response to vitamin K	1	1404.3×	0.004	F5
obsolete negative regulation of protein targeting to mitochondrion	1	702.2×	0.006	LMAN1
regulation of hemopoiesis	1	383.0×	0.009	GFI1B
protein transport	2	21.9×	0.009	LMAN1, MCFD2
blood circulation	1	127.7×	0.020	F5
endoplasmic reticulum organization	1	105.3×	0.021	LMAN1
negative regulation of G1/S transition of mitotic cell cycle	1	89.6×	0.022	GFI1B
endoplasmic reticulum to Golgi vesicle-mediated transport	1	34.0×	0.048	LMAN1
Golgi organization	1	33.4×	0.048	LMAN1
protein folding	1	25.9×	0.053	LMAN1
chromatin organization	1	24.8×	0.053	GFI1B
vesicle-mediated transport	1	24.1×	0.053	MCFD2
gene expression	1	20.0×	0.059	MCFD2
in utero embryonic development	1	18.0×	0.061	LMAN1
negative regulation of transcription by RNA polymerase II	1	4.4×	0.220	GFI1B
regulation of transcription by RNA polymerase II	1	2.9×	0.302	GFI1B

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
F5	EDOXABAN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
F5	2	4
LMAN1	0	0
MCFD2	0	0
GFI1B	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
EDOXABAN	4	F5
RAZAXABAN	2	F5

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
F5	10	Binding:10
LMAN1	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

2 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.

Compound	Max phase	Cohort target (bioactivity)
EDOXABAN	4	F5
RAZAXABAN	2	F5

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	F5
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	3	LMAN1, MCFD2, GFI1B

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MCFD2	0	F5
LMAN1	1	—
GFI1B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.