Hereditary antithrombin deficiency

Summary

Hereditary antithrombin deficiency (MONDO:0013144) is a disease caused by SERPINC1 (GenCC Definitive), with 5 cohort genes and 12 clinical trials. Top therapeutic interventions include antithrombin alfa and antithrombin iii human.

At a glance

• Prevalence: 1-5 / 10 000 (Worldwide) [Orphanet-validated]
• Causal gene: SERPINC1 (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 420
• Phenotypes (HPO): 15
• Clinical trials: 12

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

15 HPO clinical features (Orphanet curated; top 15 by frequency):

HPO ID	Term	Frequency
HP:0001976	Reduced antithrombin III activity	Very frequent (80-99%)
HP:0040246	Reduced antithrombin antigen	Very frequent (80-99%)
HP:0002204	Pulmonary embolism	Frequent (30-79%)
HP:0002625	Deep venous thrombosis	Frequent (30-79%)
HP:0002638	Superficial thrombophlebitis	Frequent (30-79%)
HP:0004831	Recurrent thromboembolism	Frequent (30-79%)
HP:0031437	Pregnancy exposure	Frequent (30-79%)
HP:0004420	Arterial thrombosis	Occasional (5-29%)
HP:0005268	Spontaneous abortion	Occasional (5-29%)
HP:0012636	Retinal vein occlusion	Occasional (5-29%)
HP:0030242	Portal vein thrombosis	Occasional (5-29%)
HP:0030243	Hepatic vein thrombosis	Occasional (5-29%)
HP:0030248	Mesenteric venous thrombosis	Occasional (5-29%)
HP:0200067	Recurrent spontaneous abortion	Occasional (5-29%)
HP:0005305	Cerebral venous thrombosis	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary antithrombin deficiency
Mondo ID	MONDO:0013144
MeSH	D020152
OMIM	613118
Orphanet	82
DOID	DOID:3755
SNOMED CT	36351005
UMLS	C0272375
MedGen	75781
GARD	0006148
NORD	791
Is cancer (heuristic)	no

Also known as: antithrombin 3 deficiency · Antithrombin Deficiency · antithrombin III deficiency · AT3D · congenital antithrombin III deficiency · congenital AT-III deficiency · hereditary antithrombin deficiency · hereditary thrombophilia due to congenital antithrombin 3 deficiency · hereditary thrombophilia due to congenital antithrombin deficiency · inherited antithrombin deficiency · thrombophilia 7 due to antithrombin III deficiency · thrombophilia due to antithrombin 3 deficiency · thrombophilia due to antithrombin III deficiency

Data availability: 420 ClinVar variants · 105 ClinGen variant curations · 9 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › osteonecrosis › avascular necrosis › secondary avascular necrosis › hereditary antithrombin deficiency

Related subtypes (5): Gaucher disease type I, hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency, traumatic avascular necrosis, secondary non-traumatic avascular necrosis, osteonecrosis of the jaw

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

420 retrieved; paginated sample, class counts are floors:

132 uncertain significance, 107 pathogenic, 106 likely benign, 54 likely pathogenic, 11 benign, 4 pathogenic/likely pathogenic, 4 conflicting classifications of pathogenicity, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1321896	Multiple alleles		Pathogenic	no assertion criteria provided
1321888	NC_000001.11:g.173888461_173971254del	LOC126805923	Pathogenic	no assertion criteria provided
1321898	NC_000001.11:g.173879820_173915405del	LOC126805923	Pathogenic	no assertion criteria provided
1321910	NC_000001.11:g.173881395_174342043del	LOC126805923	Pathogenic	no assertion criteria provided
1321891	NC_000001.11:g.173888460_174138926del	LOC126805924	Pathogenic	no assertion criteria provided
1321915	NC_000001.11:g.173884504_174418717del	LOC129388636	Pathogenic	no assertion criteria provided
1321897	NC_000001.11:g.172987296_174843232del	LOC129931934	Pathogenic	no assertion criteria provided
1321886	NC_000001.11:g.173501975_175305010del	LOC129931937	Pathogenic	no assertion criteria provided
1321899	NC_000001.11:g.173908511_174102900del	LOC129931942	Pathogenic	no assertion criteria provided
1321914	NC_000001.11:g.173878539_174421154del	LOC129931944	Pathogenic	no assertion criteria provided
1321890	NC_000001.11:g.173686375_176083118del	LOC129931965	Pathogenic	no assertion criteria provided
1321901	NC_000001.11:g.173912160_174154195del	RC3H1	Pathogenic	no assertion criteria provided
3247682	NC_000001.10:g.(?173873027)(173962123_?)del	RC3H1	Pathogenic	criteria provided, single submitter
100923	NM_000488.4(SERPINC1):c.1016G>A (p.Trp339Ter)	SERPINC1	Pathogenic	reviewed by expert panel
1321887	NC_000001.11:g.173896668_173942868del	SERPINC1	Pathogenic	no assertion criteria provided
1321892	NC_000001.11:g.173914640_173922032del	SERPINC1	Pathogenic	no assertion criteria provided
1321893	NM_000488.4(SERPINC1):c.84_409-536del	SERPINC1	Pathogenic	no assertion criteria provided
1321894	NM_000488.4(SERPINC1):c.408+948_763-386del	SERPINC1	Pathogenic	no assertion criteria provided
1321895	NM_000488.4(SERPINC1):c.42-486_1154-846del	SERPINC1	Pathogenic	no assertion criteria provided
1321900	NC_000001.11:g.173916704_173935703del	SERPINC1	Pathogenic	no assertion criteria provided
1321902	NM_000488.4(SERPINC1):c.763-379_1084del	SERPINC1	Pathogenic	no assertion criteria provided
1321903	NM_000488.4(SERPINC1):c.1154-898_1218+410del	SERPINC1	Pathogenic	no assertion criteria provided
1321904	NM_000488.4(SERPINC1):c.1154-40_1218+127dup	SERPINC1	Pathogenic	no assertion criteria provided
1321905	NM_000488.4(SERPINC1):c.1154-324_1218+475dup	SERPINC1	Pathogenic	no assertion criteria provided
1321907	NM_000488.4(SERPINC1):c.41+297_55del	SERPINC1	Pathogenic	no assertion criteria provided
1321909	NC_000001.11:g.173905922_173905923ins[NC_000006.11:56893618_56896059]	SERPINC1	Pathogenic	no assertion criteria provided
1321911	NC_000001.11:g.173879820_173925989del	SERPINC1	Pathogenic	no assertion criteria provided
1330272	NM_000488.4(SERPINC1):c.133C>T (p.Arg45Trp)	SERPINC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1330290	NM_000488.4(SERPINC1):c.436A>G (p.Lys146Glu)	SERPINC1	Pathogenic	criteria provided, single submitter
1335876	NC_000001.11:g.173908412_173919816dup	SERPINC1	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 1 · 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
SERPINC1	Definitive	Autosomal dominant	hereditary antithrombin deficiency	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SERPINC1	Orphanet:82	Hereditary thrombophilia due to congenital antithrombin deficiency

Cohort genes → proteins

5 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SERPINC1	HGNC:775	ENSG00000117601	P01008	Antithrombin-III	gencc,clinvar
RC3H1	HGNC:29434	ENSG00000135870	Q5TC82	Roquin-1	clinvar
SNORD74	HGNC:32734			small nucleolar RNA, C/D box 74	clinvar
SNORD75	HGNC:32735			small nucleolar RNA, C/D box 75	clinvar
SNORD76	HGNC:32736			small nucleolar RNA, C/D box 76	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SERPINC1	Antithrombin-III	Most important serine protease inhibitor in plasma that regulates the blood coagulation cascade.
RC3H1	Roquin-1	Post-transcriptional repressor of mRNAs containing a conserved stem loop motif, called constitutive decay element (CDE), which is often located in the 3’-UTR, as in HMGXB3, ICOS, IER3, NFKBID, NFKBIZ, PPP1R10, TNF, TNFRSF4 and in many more…

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 4 · 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	1.6×	0.476
Other/Unknown	4	1.4×	0.476

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SERPINC1	Other/Unknown	no		Serpin_fam, Serpin_CS, Serpin_dom
RC3H1	Transcription factor	no		Znf_CCCH, Znf_RING, Znf_RING/FYVE/PHD
SNORD74	Other/Unknown	no
SNORD75	Other/Unknown	no
SNORD76	Other/Unknown	no

Expression context

Cohort genes with no expression data: 3.

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	3

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	1
liver	1
right lobe of liver	1
ileal mucosa	1
tibialis anterior	1
upper leg skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SERPINC1	153	tissue_specific	marker	right lobe of liver, liver, adrenal tissue
RC3H1	260	ubiquitous	marker	tibialis anterior, upper leg skin, ileal mucosa
SNORD74
SNORD75
SNORD76

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RC3H1	3,135
SERPINC1	1,833
SNORD74	0
SNORD75	0
SNORD76	0

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 3

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SERPINC1	P01008	27
RC3H1	Q5TC82	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 5 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
R-HSA-140875	1	2855.0×	0.003	SERPINC1
R-HSA-140837	1	1427.5×	0.003	SERPINC1
R-HSA-140877	1	951.7×	0.003	SERPINC1
Fibrin formation	1	878.5×	0.003	SERPINC1
Amplification and propagation of coagulation cascade	1	634.4×	0.004	SERPINC1
Initiation of coagulation cascade	1	475.8×	0.004	SERPINC1
Regulation of clotting cascade	1	233.1×	0.007	SERPINC1
Post-translational protein phosphorylation	1	100.2×	0.015	SERPINC1
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	86.5×	0.015	SERPINC1
Hemostasis	1	36.0×	0.033	SERPINC1
Post-translational protein modification	1	19.2×	0.057	SERPINC1
Metabolism of proteins	1	12.4×	0.081	SERPINC1

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
negative regulation of T-helper cell differentiation	1	8426.0×	0.002	RC3H1
regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay	1	8426.0×	0.002	RC3H1
negative regulation of germinal center formation	1	4213.0×	0.002	RC3H1
regulation of miRNA metabolic process	1	2808.7×	0.003	RC3H1
regulation of T cell receptor signaling pathway	1	2106.5×	0.003	RC3H1
regulation of germinal center formation	1	1404.3×	0.003	RC3H1
regulation of blood coagulation	1	936.2×	0.004	SERPINC1
negative regulation of T-helper 17 cell differentiation	1	936.2×	0.004	RC3H1
T follicular helper cell differentiation	1	702.2×	0.005	RC3H1
nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay	1	526.6×	0.005	RC3H1
P-body assembly	1	526.6×	0.005	RC3H1
negative regulation of activated T cell proliferation	1	526.6×	0.005	RC3H1
negative regulation of B cell proliferation	1	468.1×	0.005	RC3H1
lymph node development	1	401.2×	0.005	RC3H1
nuclear-transcribed mRNA catabolic process	1	383.0×	0.005	RC3H1
3’-UTR-mediated mRNA destabilization	1	383.0×	0.005	RC3H1
post-transcriptional regulation of gene expression	1	324.1×	0.005	RC3H1
B cell homeostasis	1	280.9×	0.006	RC3H1
nuclear-transcribed mRNA catabolic process, nonsense-mediated decay	1	234.1×	0.006	RC3H1
T cell homeostasis	1	227.7×	0.006	RC3H1
regulation of mRNA stability	1	210.7×	0.007	RC3H1
spleen development	1	200.6×	0.007	RC3H1
T cell proliferation	1	191.5×	0.007	RC3H1
cellular response to interleukin-1	1	140.4×	0.009	RC3H1
positive regulation of non-canonical NF-kappaB signal transduction	1	127.7×	0.009	RC3H1
blood coagulation	1	86.9×	0.013	SERPINC1
T cell receptor signaling pathway	1	75.9×	0.014	RC3H1
protein polyubiquitination	1	57.7×	0.018	RC3H1
ubiquitin-dependent protein catabolic process	1	37.1×	0.027	RC3H1

Therapeutics

Drugs indicated for this disease

1 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Antithrombin Alfa	Approved (phase 4)
Antithrombin Iii Human	Phase 3 (in late-stage trials)

Drug target analysis

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

Druggability breadth: 1 of 5 evidence-associated genes (20%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SERPINC1	1	3
RC3H1	0	0
SNORD74	0	0
SNORD75	0	0
SNORD76	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IDRAPARINUX SODIUM	3	SERPINC1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SERPINC1	19	Binding:19

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
IDRAPARINUX SODIUM	3	SERPINC1

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	SERPINC1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	RC3H1, SNORD74, SNORD75, SNORD76

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RC3H1	0	—
SNORD74	0	—
SNORD75	0	—
SNORD76	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 12.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	3
Not specified	3
PHASE2	2
PHASE4	1
PHASE2/PHASE3	1
PHASE1	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02278575	PHASE4	WITHDRAWN	Atenativ Effect on Uterine Blood Flow and Preeclampsia
NCT00319228	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	Safety, Pharmacokinetics and Efficacy of an ATIII Concentrate
NCT04918173	PHASE3	RECRUITING	Efficacy of Atenativ in Patients With Congenital Antithrombin Deficiency Undergoing Surgery or Delivery
NCT06096116	PHASE3	RECRUITING	Phase 3 Study on the Efficacy and Safety of Human Plasma Derived Antithrombin (Atenativ) in Heparin-Resistant Patients Scheduled to Undergo Cardiac Surgery Necessitating Cardiopulmonary Bypass
NCT00110513	PHASE3	COMPLETED	Recombinant Human Antithrombin (rhAT) in Patients With Hereditary Antithrombin Deficiency Undergoing Surgery or Delivery
NCT00823082	PHASE2	COMPLETED	Use of Antithrombin in Cardiac Surgery With Cardiopulmonary Bypass
NCT04899232	PHASE2	TERMINATED	Antithrombin III in Infectious Disease Caused by COVID-19
NCT00938288	PHASE1	COMPLETED	A Study of KW-3357 in Congenital Antithrombin Deficiency
NCT03090893	EARLY_PHASE1	WITHDRAWN	Response of Continuous Recombinant Antithrombin Infusion in Postcardiotomy ECMO Patients
NCT05891899	Not specified	NOT_YET_RECRUITING	Belgian Antithrombin Deficiency Registry
NCT02503267	Not specified	UNKNOWN	Incidence and Consequences of Disorders of Glycosylation in Patients With Conotruncal and Septal Heart Defects
NCT04879550	Not specified	COMPLETED	Prospective Investigation of Antithrombin III Deficiency in Adult Patients With ECMO

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ANTITHROMBIN ALFA	4	1
ANTITHROMBIN III HUMAN	3	5