hereditary thrombophilia due to congenital protein S deficiency

Summary

hereditary thrombophilia due to congenital protein S deficiency (MONDO:0019144) is a disease with 1 cohort gene.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 3
• Phenotypes (HPO): 14

Clinical features

Signs & symptoms

Clinical features (HPO)

14 HPO clinical features (Orphanet curated; top 14 by frequency):

HPO ID	Term	Frequency
HP:0000979	Purpura	Very frequent (80-99%)
HP:0000488	Retinopathy	Frequent (30-79%)
HP:0000963	Thin skin	Frequent (30-79%)
HP:0001933	Subcutaneous hemorrhage	Frequent (30-79%)
HP:0002625	Deep venous thrombosis	Frequent (30-79%)
HP:0004418	Thrombophlebitis	Frequent (30-79%)
HP:0008065	Aplasia/Hypoplasia of the skin	Frequent (30-79%)
HP:0001000	Abnormality of skin pigmentation	Occasional (5-29%)
HP:0002204	Pulmonary embolism	Occasional (5-29%)
HP:0004420	Arterial thrombosis	Occasional (5-29%)
HP:0005293	Venous insufficiency	Occasional (5-29%)
HP:0100659	Abnormality of the cerebral vasculature	Occasional (5-29%)
HP:0100758	Gangrene	Occasional (5-29%)
HP:0200042	Skin ulcer	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary thrombophilia due to congenital protein S deficiency
Mondo ID	MONDO:0019144
Orphanet	743
DOID	DOID:0111905
ICD-11	1305244529
UMLS	C2584611
MedGen	748876
GARD	0016543
Is cancer (heuristic)	no

Also known as: autosomal recessive thrombophilia due to congenital protein S deficiency · hereditary thrombophilia due to congenital protein S deficiency

Data availability: 3 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › hematologic disorder › blood coagulation disease › thrombophilia › protein S deficiency › hereditary thrombophilia due to congenital protein S deficiency

Subtypes (2): thrombophilia due to protein S deficiency, autosomal dominant, thrombophilia due to protein S deficiency, autosomal recessive

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

3 retrieved; paginated sample, class counts are floors:

1 conflicting classifications of pathogenicity, 1 uncertain significance, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1684341	NM_000313.4(PROS1):c.1764_1765del (p.Pro589fs)	PROS1	Pathogenic	criteria provided, single submitter
13316	NM_000313.4(PROS1):c.1501T>C (p.Ser501Pro)	PROS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1421408	NM_000313.4(PROS1):c.449A>G (p.Gln150Arg)	PROS1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · 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
PROS1	Definitive	Autosomal dominant	thrombophilia due to protein S deficiency, autosomal dominant	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PROS1	Orphanet:743	Severe hereditary thrombophilia due to congenital protein S deficiency

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
PROS1	HGNC:9456	ENSG00000184500	P07225	Vitamin K-dependent protein S	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PROS1	Vitamin K-dependent protein S	Anticoagulant plasma protein; it is a cofactor to activated protein C in the degradation of coagulation factors Va and VIIIa.

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)
PROS1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, GLA_domain, EGF

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
bronchial epithelial cell	1
choroid plexus epithelium	1
synovial joint	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PROS1	276	ubiquitous	marker	choroid plexus epithelium, bronchial epithelial cell, synovial joint

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PROS1	1,129

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PROS1	P07225	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. 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×	0.002	PROS1
Defective cleavage of FV variant at R334	1	3806.7×	0.002	PROS1
Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus	1	1268.9×	0.002	PROS1
Gamma-carboxylation of protein precursors	1	1142.0×	0.002	PROS1
Removal of aminoterminal propeptides from gamma-carboxylated proteins	1	1142.0×	0.002	PROS1
Amplification and propagation of coagulation cascade	1	634.4×	0.003	PROS1
Initiation of coagulation cascade	1	475.8×	0.004	PROS1
Dengue Virus Attachment and Entry	1	259.6×	0.005	PROS1
Regulation of clotting cascade	1	233.1×	0.005	PROS1
Regulation of Complement cascade	1	233.1×	0.005	PROS1
Cell surface interactions at the vascular wall	1	95.2×	0.011	PROS1
Platelet degranulation	1	87.8×	0.011	PROS1

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
fibrinolysis	1	842.6×	0.004	PROS1
blood coagulation	1	173.7×	0.009	PROS1
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	78.4×	0.013	PROS1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PROS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	1	PROS1

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)
PROS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.