thrombophilia due to protein S deficiency, autosomal recessive

Summary

thrombophilia due to protein S deficiency, autosomal recessive (MONDO:0013791) is a disease caused by PROS1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: PROS1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 444

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	thrombophilia due to protein S deficiency, autosomal recessive
Mondo ID	MONDO:0013791
OMIM	614514
UMLS	C3281092
MedGen	482722
GARD	0018569
Is cancer (heuristic)	no

Also known as: THPH6 · thrombophilia 5 due to protein S deficiency, autosomal recessive · thrombophilia due to protein S deficiency, autosomal recessive

Data availability: 444 ClinVar variants · 4 GenCC gene-disease records.

Disease family

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 › thrombophilia due to protein S deficiency, autosomal recessive

Related subtypes (1): thrombophilia due to protein S deficiency, autosomal dominant

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

444 retrieved; paginated sample, class counts are floors:

157 likely benign, 149 uncertain significance, 64 pathogenic, 37 conflicting classifications of pathogenicity, 14 likely pathogenic, 10 pathogenic/likely pathogenic, 9 benign, 4 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1457416	NC_000003.11:g.(?93593089)(93845334_?)del	ARL13B	Pathogenic	criteria provided, single submitter
472995	NC_000003.12:g.(?93874239)(94053268_?)del	LOC129937098	Pathogenic	criteria provided, single submitter
1066657	NM_000313.4(PROS1):c.1A>C (p.Met1Leu)	PROS1	Pathogenic	criteria provided, single submitter
1068259	NM_000313.4(PROS1):c.1871-2A>G	PROS1	Pathogenic	criteria provided, single submitter
1069092	NM_000313.4(PROS1):c.1084C>T (p.Gln362Ter)	PROS1	Pathogenic	criteria provided, single submitter
1069702	NM_000313.4(PROS1):c.181G>T (p.Glu61Ter)	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
13318	NM_000313.4(PROS1):c.586A>G (p.Lys196Glu)	PROS1	Pathogenic	criteria provided, multiple submitters, no conflicts
13322	NM_000313.4(PROS1):c.835C>T (p.Gln279Ter)	PROS1	Pathogenic	criteria provided, single submitter
1389448	NM_000313.4(PROS1):c.820A>T (p.Lys274Ter)	PROS1	Pathogenic	criteria provided, single submitter
1406689	NM_000313.4(PROS1):c.1871-1G>A	PROS1	Pathogenic	criteria provided, single submitter
1410953	NM_000313.4(PROS1):c.793dup (p.Cys265fs)	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
1452101	NM_000313.4(PROS1):c.3G>C (p.Met1Ile)	PROS1	Pathogenic	criteria provided, single submitter
1454860	NC_000003.11:g.(?93605147)(93617433_?)del	PROS1	Pathogenic	criteria provided, single submitter
1456211	NM_000313.4(PROS1):c.864C>A (p.Cys288Ter)	PROS1	Pathogenic	criteria provided, single submitter
1457418	NC_000003.11:g.(?93629453)(93692783_?)del	PROS1	Pathogenic	criteria provided, single submitter
1901307	NM_000313.4(PROS1):c.760C>T (p.Gln254Ter)	PROS1	Pathogenic	criteria provided, single submitter
1999459	NM_000313.4(PROS1):c.1977del (p.Asn659fs)	PROS1	Pathogenic	criteria provided, single submitter
216868	NM_000313.4(PROS1):c.967delinsGG (p.Phe323fs)	PROS1	Pathogenic	criteria provided, single submitter
219837	NM_000313.4(PROS1):c.1681C>T (p.Arg561Trp)	PROS1	Pathogenic	criteria provided, multiple submitters, no conflicts
2203406	NM_000313.4(PROS1):c.1518G>A (p.Trp506Ter)	PROS1	Pathogenic	criteria provided, single submitter
2694232	NM_000313.4(PROS1):c.1A>G (p.Met1Val)	PROS1	Pathogenic	criteria provided, single submitter
2731141	NM_000313.4(PROS1):c.77-2A>G	PROS1	Pathogenic	criteria provided, single submitter
2734546	NM_000313.4(PROS1):c.1465G>T (p.Gly489Ter)	PROS1	Pathogenic	criteria provided, single submitter
2734547	NM_000313.4(PROS1):c.1424G>T (p.Cys475Phe)	PROS1	Pathogenic	criteria provided, single submitter
2744826	NM_000313.4(PROS1):c.1726G>T (p.Glu576Ter)	PROS1	Pathogenic	criteria provided, single submitter
2807789	NM_000313.4(PROS1):c.1185_1188dup (p.Ile397Ter)	PROS1	Pathogenic	criteria provided, single submitter
2812037	NM_000313.4(PROS1):c.1179_1180dup (p.Ser394fs)	PROS1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 2 · 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
ARL13B	Orphanet:475	Isolated Joubert syndrome

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
PROS1	HGNC:9456	ENSG00000184500	P07225	Vitamin K-dependent protein S	gencc,clinvar
ARL13B	HGNC:25419	ENSG00000169379	Q3SXY8	ADP-ribosylation factor-like protein 13B	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.
ARL13B	ADP-ribosylation factor-like protein 13B	Cilium-specific protein required to control the microtubule-based, ciliary axoneme structure.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PROS1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, GLA_domain, EGF
ARL13B	Other/Unknown	no		Small_GTP-bd, Small_GTPase_ARF/SAR, P-loop_NTPase

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
bronchial epithelial cell	2
choroid plexus epithelium	1
synovial joint	1
calcaneal tendon	1
secondary oocyte	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
ARL13B	237	ubiquitous	marker	secondary oocyte, calcaneal tendon, bronchial epithelial cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ARL13B	2,558
PROS1	1,129

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PROS1	P07225	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ARL13B	Q3SXY8	72.92

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 28. 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
ARL13B-mediated ciliary trafficking of INPP5E	1	1903.3×	0.005	ARL13B
Defective cleavage of FV variant at a.a.534	1	1903.3×	0.005	PROS1
Defective cleavage of FV variant at R334	1	1903.3×	0.005	PROS1
Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus	1	634.4×	0.008	PROS1
Gamma-carboxylation of protein precursors	1	571.0×	0.008	PROS1
Removal of aminoterminal propeptides from gamma-carboxylated proteins	1	571.0×	0.008	PROS1
Amplification and propagation of coagulation cascade	1	317.2×	0.013	PROS1
Chaperone Mediated Autophagy	1	248.3×	0.013	ARL13B
Initiation of coagulation cascade	1	237.9×	0.013	PROS1
Late endosomal microautophagy	1	163.1×	0.015	ARL13B
Selective autophagy	1	139.3×	0.015	ARL13B
Dengue Virus Attachment and Entry	1	129.8×	0.015	PROS1
Cargo trafficking to the periciliary membrane	1	124.1×	0.015	ARL13B
Aggrephagy	1	124.1×	0.015	ARL13B
Regulation of clotting cascade	1	116.5×	0.015	PROS1
Regulation of Complement cascade	1	116.5×	0.015	PROS1
RHOJ GTPase cycle	1	100.2×	0.016	ARL13B
RHOQ GTPase cycle	1	90.6×	0.017	ARL13B
Autophagy	1	74.2×	0.020	ARL13B
Macroautophagy	1	57.7×	0.024	ARL13B
Cilium Assembly	1	54.4×	0.024	ARL13B
Cell surface interactions at the vascular wall	1	47.6×	0.027	PROS1
Platelet degranulation	1	43.9×	0.028	PROS1
Organelle biogenesis and maintenance	1	33.0×	0.035	ARL13B
RHO GTPase cycle	1	30.1×	0.037	ARL13B
Signaling by Rho GTPases	1	17.1×	0.061	ARL13B
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	16.7×	0.061	ARL13B
Signal Transduction	1	5.1×	0.187	ARL13B

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
interneuron migration from the subpallium to the cortex	1	8426.0×	0.002	ARL13B
formation of radial glial scaffolds	1	2106.5×	0.002	ARL13B
receptor localization to non-motile cilium	1	1685.2×	0.002	ARL13B
neural tube patterning	1	1404.3×	0.002	ARL13B
left/right axis specification	1	601.9×	0.004	ARL13B
fibrinolysis	1	421.3×	0.005	PROS1
dorsal/ventral pattern formation	1	210.7×	0.009	ARL13B
non-motile cilium assembly	1	145.3×	0.011	ARL13B
heart looping	1	133.8×	0.011	ARL13B
smoothened signaling pathway	1	90.6×	0.014	ARL13B
blood coagulation	1	86.9×	0.014	PROS1
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	39.2×	0.027	PROS1
cilium assembly	1	36.8×	0.027	ARL13B

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

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
PROS1	0	0
ARL13B	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	2	PROS1, ARL13B

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PROS1	0	—
ARL13B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.