thrombophilia due to protein S deficiency, autosomal dominant

Summary

thrombophilia due to protein S deficiency, autosomal dominant (MONDO:0012868) is a disease caused by PROS1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: PROS1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 166

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	thrombophilia due to protein S deficiency, autosomal dominant
Mondo ID	MONDO:0012868
MeSH	C567077
OMIM	612336
Orphanet	26349
DOID	DOID:0111900
UMLS	C3278211
MedGen	479841
GARD	0018568
MedDRA	10068370
Is cancer (heuristic)	no

Also known as: autosomal dominant hereditary thrombophilia due to congenital protein S deficiency · hereditary thrombophilia due to congenital protein S deficiency, autosomal dominant · THPH5 · thrombophilia 5 due to protein S deficiency, autosomal dominant · thrombophilia due to protein S deficiency, autosomal dominant

Data availability: 166 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › thrombophilia due to protein S deficiency, autosomal dominant

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid syndrome

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

166 retrieved; paginated sample, class counts are floors:

83 uncertain significance, 34 conflicting classifications of pathogenicity, 22 likely pathogenic, 10 pathogenic, 6 pathogenic/likely pathogenic, 5 likely benign, 4 benign/likely benign, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1048664	NM_000313.4(PROS1):c.740G>C (p.Cys247Ser)	PROS1	Pathogenic	criteria provided, single submitter
1330283	NM_000313.4(PROS1):c.1870+1G>C	PROS1	Pathogenic	criteria provided, multiple submitters, no conflicts
1330284	NM_000313.4(PROS1):c.76+2_76+3del	PROS1	Pathogenic	criteria provided, multiple submitters, no conflicts
13317	NM_000313.4(PROS1):c.773A>G (p.Asn258Ser)	PROS1	Pathogenic	no assertion criteria provided
13318	NM_000313.4(PROS1):c.586A>G (p.Lys196Glu)	PROS1	Pathogenic	criteria provided, multiple submitters, no conflicts
13319	PROS1, IVS10DS, G-A, +5	PROS1	Pathogenic	no assertion criteria provided
13320	NM_000313.4(PROS1):c.2031A>T (p.Ter677Tyr)	PROS1	Pathogenic	no assertion criteria provided
13321	NM_000313.4(PROS1):c.1324-9A>G	PROS1	Pathogenic	no assertion criteria provided
13322	NM_000313.4(PROS1):c.835C>T (p.Gln279Ter)	PROS1	Pathogenic	criteria provided, single submitter
1435151	NM_000313.4(PROS1):c.557G>A (p.Cys186Tyr)	PROS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29846	NM_000313.4(PROS1):c.1063C>T (p.Arg355Cys)	PROS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
503726	NM_000313.4(PROS1):c.1351C>T (p.Arg451Ter)	PROS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
581502	NM_000313.4(PROS1):c.77-1G>C	PROS1	Pathogenic	criteria provided, multiple submitters, no conflicts
627172	NM_000313.4(PROS1):c.1680T>A (p.Tyr560Ter)	PROS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
835217	NM_000313.4(PROS1):c.601+1G>A	PROS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
945955	NM_000313.4(PROS1):c.200A>C (p.Glu67Ala)	PROS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1048665	NM_000313.4(PROS1):c.1252A>T (p.Asn418Tyr)	PROS1	Likely pathogenic	criteria provided, single submitter
1064419	NM_000313.4(PROS1):c.1904T>C (p.Phe635Ser)	PROS1	Likely pathogenic	no assertion criteria provided
1330273	NM_000313.4(PROS1):c.595T>C (p.Cys199Arg)	PROS1	Likely pathogenic	criteria provided, single submitter
1330276	NM_000313.4(PROS1):c.154G>C (p.Gly52Arg)	PROS1	Likely pathogenic	criteria provided, single submitter
162509	NM_000313.4(PROS1):c.728-1G>A	PROS1	Likely pathogenic	criteria provided, single submitter
1677268	NM_000313.4(PROS1):c.1862G>T (p.Gly621Val)	PROS1	Likely pathogenic	criteria provided, single submitter
1684344	NM_000313.4(PROS1):c.1337T>C (p.Leu446Pro)	PROS1	Likely pathogenic	criteria provided, single submitter
2572156	NM_000313.4(PROS1):c.346+1G>T	PROS1	Likely pathogenic	criteria provided, single submitter
2627071	NM_000313.4(PROS1):c.1459G>C (p.Gly487Arg)	PROS1	Likely pathogenic	no assertion criteria provided
2627739	NM_000313.4(PROS1):c.346+2T>A	PROS1	Likely pathogenic	criteria provided, single submitter
2664772	NM_000313.4(PROS1):c.684C>G (p.Cys228Trp)	PROS1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2683968	NM_000313.4(PROS1):c.832G>T (p.Asp278Tyr)	PROS1	Likely pathogenic	criteria provided, single submitter
2683976	NM_000313.4(PROS1):c.1085A>G (p.Gln362Arg)	PROS1	Likely pathogenic	criteria provided, single submitter
3382058	NM_000313.4(PROS1):c.769_770del (p.Val257fs)	PROS1	Likely pathogenic	criteria provided, single submitter

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.