thrombophilia, X-linked, due to factor 9 defect

Summary

thrombophilia, X-linked, due to factor 9 defect (MONDO:0010432) is a disease caused by F9 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: F9 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 380

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	thrombophilia, X-linked, due to factor 9 defect
Mondo ID	MONDO:0010432
MeSH	C567581
OMIM	300807
DOID	DOID:0111899
UMLS	C2749016
MedGen	411730
GARD	0024725
Is cancer (heuristic)	no

Also known as: deep venous thrombosis, protection against, X-linked recessive · THPH8 · thrombophilia 8, X-linked, due to factor IX defect, X-linked recessive · thrombophilia, X-linked, due to factor 9 defect · thrombophilia, X-linked, due to factor IX defect

Data availability: 380 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › blood coagulation disease › thrombophilia › inherited thrombophilia › thrombophilia, X-linked, due to factor 9 defect

Related subtypes (11): factor 5 excess with spontaneous thrombosis, thrombophilia due to thrombin defect, thrombophilia due to activated protein C resistance, thrombophilia, familial, due to decreased release of tissue plasminogen activator, heparin cofactor 2 deficiency, hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency, hereditary antithrombin deficiency, thrombomodulin-related bleeding disorder, hereditary thrombophilia due to congenital protein S deficiency, hereditary thrombophilia due to congenital protein C deficiency, thrombophilia, X-linked, due to factor 8 defect

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

380 retrieved; paginated sample, class counts are floors:

174 likely benign, 80 pathogenic, 41 uncertain significance, 32 benign, 25 likely pathogenic, 12 pathogenic/likely pathogenic, 9 conflicting classifications of pathogenicity, 6 benign/likely benign, 1 benign; association

ClinVar	Variant (HGVS)	Gene	Classification	Review
665638	NC_000023.10:g.(?138612860)(139587225_?)del	ATP11C	Pathogenic	criteria provided, single submitter
10572	NM_000133.4(F9):c.223C>T (p.Arg75Ter)	F9	Pathogenic	reviewed by expert panel
10573	NM_000133.4(F9):c.224G>A (p.Arg75Gln)	F9	Pathogenic	reviewed by expert panel
10578	NM_000133.4(F9):c.301C>G (p.Pro101Ala)	F9	Pathogenic	criteria provided, multiple submitters, no conflicts
10579	NM_000133.4(F9):c.316G>A (p.Gly106Ser)	F9	Pathogenic	reviewed by expert panel
10584	NM_000133.4(F9):c.571C>T (p.Arg191Cys)	F9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10585	NM_000133.4(F9):c.572G>A (p.Arg191His)	F9	Pathogenic	reviewed by expert panel
10587	NM_000133.4(F9):c.880C>T (p.Arg294Ter)	F9	Pathogenic	reviewed by expert panel
10590	NM_000133.4(F9):c.676C>T (p.Arg226Trp)	F9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10602	NM_000133.4(F9):c.881G>A (p.Arg294Gln)	F9	Pathogenic	reviewed by expert panel
10603	NM_000133.4(F9):c.892C>T (p.Arg298Ter)	F9	Pathogenic	criteria provided, multiple submitters, no conflicts
10607	NM_000133.4(F9):c.1025C>T (p.Thr342Met)	F9	Pathogenic	reviewed by expert panel
10608	NM_000133.4(F9):c.1058T>C (p.Val353Ala)	F9	Pathogenic	criteria provided, multiple submitters, no conflicts
10612	NM_000133.4(F9):c.1135C>T (p.Arg379Ter)	F9	Pathogenic	criteria provided, multiple submitters, no conflicts
10613	NM_000133.4(F9):c.1136G>A (p.Arg379Gln)	F9	Pathogenic	criteria provided, multiple submitters, no conflicts
10614	NM_000133.4(F9):c.1144T>C (p.Cys382Arg)	F9	Pathogenic	criteria provided, single submitter
10615	NM_000133.4(F9):c.1150C>T (p.Arg384Ter)	F9	Pathogenic	criteria provided, multiple submitters, no conflicts
10627	NM_000133.4(F9):c.1328T>C (p.Ile443Thr)	F9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10640	NM_000133.4(F9):c.484C>T (p.Arg162Ter)	F9	Pathogenic	criteria provided, multiple submitters, no conflicts
10646	NM_000133.4(F9):c.-17A>G	F9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10650	NM_000133.4(F9):c.1231A>G (p.Ser411Gly)	F9	Pathogenic	criteria provided, single submitter
10657	NM_000133.4(F9):c.82T>C (p.Cys28Arg)	F9	Pathogenic	criteria provided, single submitter
10668	NM_000133.4(F9):c.1151G>T (p.Arg384Leu)	F9	Pathogenic	no assertion criteria provided
1069182	NM_000133.4(F9):c.163T>A (p.Phe55Ile)	F9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070513	NM_000133.4(F9):c.839G>A (p.Gly280Asp)	F9	Pathogenic	criteria provided, single submitter
1070514	NM_000133.4(F9):c.1358G>A (p.Trp453Ter)	F9	Pathogenic	criteria provided, single submitter
1071157	NC_000023.10:g.(?138612860)(138613021_?)del	F9	Pathogenic	criteria provided, single submitter
1071223	NM_000133.4(F9):c.237_247del (p.Thr81fs)	F9	Pathogenic	criteria provided, single submitter
1076388	NM_000133.4(F9):c.191G>A (p.Cys64Tyr)	F9	Pathogenic	criteria provided, single submitter
1076389	NM_000133.4(F9):c.782G>A (p.Trp261Ter)	F9	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 4 · 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
F9	Strong	X-linked	thrombophilia, X-linked, due to factor 9 defect	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
F9	Orphanet:169793	Severe hemophilia B
F9	Orphanet:169796	Moderate hemophilia B
F9	Orphanet:169799	Mild hemophilia B
F9	Orphanet:177929	Bleeding disorder in hemophilia B carriers

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
F9	HGNC:3551	ENSG00000101981	P00740	Coagulation factor IX	gencc,clinvar
ATP11C	HGNC:13554	ENSG00000101974	Q8NB49	Phospholipid-transporting ATPase IG	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
F9	Coagulation factor IX	Factor IX is a vitamin K-dependent plasma protein that participates in the intrinsic pathway of blood coagulation by converting factor X to its active form in the presence of Ca(2+) ions, phospholipids, and factor VIIIa.
ATP11C	Phospholipid-transporting ATPase IG	Catalytic component of a P4-ATPase flippase complex which catalyzes the hydrolysis of ATP coupled to the transport of aminophospholipids, phosphatidylserines (PS) and phosphatidylethanolamines (PE), from the outer to the inner leaflet of t…

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

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
Protease	1	18.3×	0.108
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
F9	Protease	yes	3.4.21.22	EGF-type_Asp/Asn_hydroxyl_site, GLA_domain, EGF
ATP11C	Transcription factor	no	7.6.2.1	P_typ_ATPase, P-type_ATPase_IV, ATPase_P-typ_transduc_dom_A_sf

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
liver	1
right lobe of liver	1
secondary oocyte	1
calcaneal tendon	1
male germ line stem cell (sensu Vertebrata) in testis	1
seminal vesicle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
F9	45	tissue_specific	marker	right lobe of liver, liver, secondary oocyte
ATP11C	250	ubiquitous	marker	seminal vesicle, calcaneal tendon, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP11C	1,740
F9	1,451

Intra-cohort edges

A	B	Sources
ATP11C	F9	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
F9	P00740	56
ATP11C	Q8NB49	13

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. 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
Defective F9 secretion	1	5710.0×	0.002	F9
Defective gamma-carboxylation of F9	1	2855.0×	0.002	F9
Defective factor IX causes thrombophilia	1	1903.3×	0.002	F9
Defective cofactor function of FVIIIa variant	1	1903.3×	0.002	F9
Defective F9 variant does not activate FX	1	1903.3×	0.002	F9
Defective F9 activation	1	951.7×	0.003	F9
Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus	1	634.4×	0.003	F9
Gamma-carboxylation of protein precursors	1	571.0×	0.003	F9
Removal of aminoterminal propeptides from gamma-carboxylated proteins	1	571.0×	0.003	F9
FXIIa, PKa-dependent activation of coagulation pathway	1	571.0×	0.003	F9
Amplification and propagation of coagulation cascade	1	317.2×	0.005	F9
Protein hydroxylation	1	271.9×	0.005	F9
Initiation of coagulation cascade	1	237.9×	0.005	F9
Regulation of clotting cascade	1	116.5×	0.010	F9
Ion transport by P-type ATPases	1	103.8×	0.011	ATP11C
Ion channel transport	1	48.0×	0.022	ATP11C
Transport of small molecules	1	12.6×	0.078	ATP11C

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
zymogen activation	1	337.0×	0.008	F9
phospholipid translocation	1	312.1×	0.008	ATP11C
monoatomic ion transmembrane transport	1	104.0×	0.014	ATP11C
blood coagulation	1	86.9×	0.014	F9
proteolysis	1	17.1×	0.058	F9

Therapeutics

Drug target analysis

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

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
F9	2	2
ATP11C	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LETAXABAN	2	F9
RAZAXABAN	2	F9

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
F9	108	Binding:107, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
F9	3.4.21.22	coagulation factor IXa
ATP11C	7.6.2.1	P-type phospholipid transporter

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
F9	108

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

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)
LETAXABAN	2	F9
RAZAXABAN	2	F9

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	1	F9
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ATP11C

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)
ATP11C	0	F9

Clinical trials & evidence

Clinical trials

Clinical trials: 0.