thrombophilia due to activated protein C resistance

Summary

thrombophilia due to activated protein C resistance (MONDO:0008560) is a disease caused by F5 (GenCC Strong), with 1 cohort gene and 2 clinical trials. Top therapeutic interventions include bevacizumab.

At a glance

• Causal gene: F5 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 95
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	thrombophilia due to activated protein C resistance
Mondo ID	MONDO:0008560
MeSH	D020016
OMIM	188055
DOID	DOID:0111902
SNOMED CT	421527008
UMLS	C1861171
MedGen	396074
GARD	0024631
Is cancer (heuristic)	no

Also known as: APC resistance · resistance, APC · THPH2 · thrombophilia 2 due to activated protein C resistance · thrombophilia due to activated protein C resistance

Data availability: 95 ClinVar variants · 3 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 › thrombophilia due to activated protein C resistance

Related subtypes (27): factor XIII deficiency, factor VII deficiency, factor X deficiency, 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, combined deficiency of factor V and factor VIII, 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

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

95 retrieved; paginated sample, class counts are floors:

50 uncertain significance, 21 conflicting classifications of pathogenicity, 8 likely pathogenic, 6 benign/likely benign, 4 pathogenic, 3 pathogenic/likely pathogenic, 1 benign, 1 drug response, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2734021	NM_000130.5(F5):c.3088C>T (p.Arg1030Ter)	F5	Pathogenic	criteria provided, multiple submitters, no conflicts
2866617	NM_000130.5(F5):c.5453del (p.Leu1818fs)	F5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2895285	NM_000130.5(F5):c.2021del (p.Lys674fs)	F5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
430053	NM_000130.5(F5):c.5037dup (p.Ser1680fs)	F5	Pathogenic	criteria provided, multiple submitters, no conflicts
627264	NM_000130.5(F5):c.1830_1831dup (p.His611fs)	F5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
645	NM_000130.5(F5):c.439G>T (p.Glu147Ter)	F5	Pathogenic	no assertion criteria provided
655	NM_000130.5(F5):c.1160T>C (p.Ile387Thr)	F5	Pathogenic	no assertion criteria provided
2431036	NM_000130.5(F5):c.413dup (p.Met138fs)	F5	Likely pathogenic	criteria provided, single submitter
2887062	NM_000130.5(F5):c.4962_4971+3del	F5	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3600169	NM_000130.5(F5):c.5816T>G (p.Leu1939Ter)	F5	Likely pathogenic	criteria provided, single submitter
3600193	NM_000130.5(F5):c.2846del (p.Leu949fs)	F5	Likely pathogenic	criteria provided, single submitter
3600196	NM_000130.5(F5):c.2079T>G (p.Tyr693Ter)	F5	Likely pathogenic	criteria provided, single submitter
3600213	NM_000130.5(F5):c.1297-1G>C	F5	Likely pathogenic	criteria provided, single submitter
3600215	NM_000130.5(F5):c.1059del (p.Phe353fs)	F5	Likely pathogenic	criteria provided, single submitter
4278197	NM_000130.5(F5):c.6584dup (p.Ile2196fs)	F5	Likely pathogenic	criteria provided, single submitter
642	NM_000130.4(F5):c.1601G>A (p.Arg534Gln)	F5	drug response	reviewed by expert panel
1771009	NM_000130.5(F5):c.136C>G (p.Arg46Gly)	F5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
255200	NM_000130.5(F5):c.2573A>G (p.Lys858Arg)	F5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
255210	NM_000130.5(F5):c.5290A>G (p.Met1764Val)	F5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
293607	NM_000130.5(F5):c.3442T>C (p.Ser1148Pro)	F5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
579171	NM_000130.5(F5):c.5265A>G (p.Ile1755Met)	F5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
627181	NM_000130.5(F5):c.5408A>G (p.His1803Arg)	F5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
627229	NM_000130.5(F5):c.1321C>T (p.Arg441Cys)	F5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
627349	NM_000130.5(F5):c.6179G>A (p.Gly2060Asp)	F5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
643	NM_000130.5(F5):c.1000A>G (p.Arg334Gly)	F5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
644	NM_000130.5(F5):c.1001G>C (p.Arg334Thr)	F5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
713561	NM_000130.5(F5):c.5245C>G (p.Leu1749Val)	F5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
716054	NM_000130.5(F5):c.3162A>C (p.Glu1054Asp)	F5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
787578	NM_000130.5(F5):c.4589A>C (p.Glu1530Ala)	F5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
870845	NM_000130.5(F5):c.3221A>G (p.Asn1074Ser)	F5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 6 · 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
F5	Strong	Autosomal dominant	thrombophilia due to activated protein C resistance	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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

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
F5	HGNC:3542	ENSG00000198734	P12259	Coagulation factor V	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
F5	Coagulation factor V	Central regulator of hemostasis.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
F5	Other/Unknown	no		FA58C, Cupredoxin, Galactose-bd-like_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
choroid plexus epithelium	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
F5	206	broad	marker	right lobe of liver, liver, choroid plexus epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
F5	1,754

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
F5	P12259	18

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
Defective cleavage of FV variant at a.a.534	1	3806.7×	0.001	F5
Defective cleavage of FV variant at R334	1	3806.7×	0.001	F5
Amplification and propagation of coagulation cascade	1	634.4×	0.005	F5
Initiation of coagulation cascade	1	475.8×	0.005	F5
Cargo concentration in the ER	1	335.9×	0.006	F5
Regulation of clotting cascade	1	233.1×	0.007	F5
COPII-mediated vesicle transport	1	163.1×	0.009	F5
Post-translational protein phosphorylation	1	100.2×	0.012	F5
Platelet degranulation	1	87.8×	0.012	F5
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	86.5×	0.012	F5

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
response to vitamin K	1	5617.3×	5e-04	F5
blood circulation	1	510.7×	0.003	F5
blood coagulation	1	173.7×	0.006	F5

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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

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

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

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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02982694	PHASE2	TERMINATED	Study With Atezolizumab Plus Bevacizumab in Patients With Chemotherapy Resistant, MSI-like, Colorectal Cancer
NCT05051826	Not specified	COMPLETED	Effect of Resistance Training in Water Combined With Land on Starting and Turning ,12-weeks Resistance Training

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
BEVACIZUMAB	4	1