Pregnancy loss, recurrent, susceptibility to, 3

Summary

Pregnancy loss, recurrent, susceptibility to, 3 (MONDO:0013729) is a disease with 3 cohort genes.

At a glance

• Cohort genes: 3
• ClinVar variants: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pregnancy loss, recurrent, susceptibility to, 3
Mondo ID	MONDO:0013729
OMIM	614391
UMLS	C3280674
MedGen	482304
Is cancer (heuristic)	no

Also known as: ANXA5 pregnancy loss, recurrent, susceptibility · pregnancy loss, recurrent, susceptibility caused by mutation in ANXA5 · pregnancy loss, recurrent, susceptibility to, 3 · pregnancy loss, recurrent, susceptibility to, type 3 · RPRGL3

Data availability: 4 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease susceptibility › inherited disease susceptibility › pregnancy loss, recurrent, susceptibility › pregnancy loss, recurrent, susceptibility to, 3

Related subtypes (3): pregnancy loss, recurrent, susceptibility to, 1, pregnancy loss, recurrent, susceptibility to, 2, pregnancy loss, recurrent, 4

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

4 retrieved; paginated sample, class counts are floors:

2 pathogenic, 1 risk factor, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
684614	NM_017419.3(ASIC5):c.680G>T (p.Arg227Ile)	ASIC5	Pathogenic	no assertion criteria provided
1184734	NM_138694.4(PKHD1):c.8743G>T (p.Glu2915Ter)	PKHD1	Pathogenic	no assertion criteria provided
29691	Multiple alleles		risk factor	no assertion criteria provided
3235034	NM_001154.4(ANXA5):c.652G>C (p.Gly218Arg)	ANXA5	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · 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
ANXA5	Moderate	Autosomal dominant	pregnancy loss, recurrent, susceptibility to, 3	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PKHD1	Orphanet:53035	Caroli disease
PKHD1	Orphanet:731	Autosomal recessive polycystic kidney disease

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ANXA5	HGNC:543	ENSG00000164111	P08758	Annexin A5	gencc,clinvar
ASIC5	HGNC:17537	ENSG00000256394	Q9NY37	Bile acid-sensitive ion channel	clinvar
PKHD1	HGNC:9016	ENSG00000170927	P08F94	Fibrocystin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ANXA5	Annexin A5	This protein is an anticoagulant protein that acts as an indirect inhibitor of the thromboplastin-specific complex, which is involved in the blood coagulation cascade.
ASIC5	Bile acid-sensitive ion channel	Forms bile acid-gated sodium channels and may play a role in bile acid-dependent absorption and secretion by epithelial cells of the bile ducts.
PKHD1	Fibrocystin	Promotes ciliogenesis in renal epithelial cells and therefore participates in the tubules formation and/ or ensures the maintenance of the architecture of the lumen of the kidney.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Antibody/Immunoglobulin	1	9.7×	0.199
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ANXA5	Other/Unknown	no		Annexin, ANX5, Annexin_repeat_CS
ASIC5	Other/Unknown	no		ENaC
PKHD1	Antibody/Immunoglobulin	yes		IPT_dom, PbH1, Pectin_lyase_fold/virulence

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)	1
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
smooth muscle tissue	1
stromal cell of endometrium	1
buccal mucosa cell	1
duodenum	1
jejunal mucosa	1
kidney epithelium	1
metanephros cortex	1
renal medulla	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ANXA5	305	ubiquitous	marker	stromal cell of endometrium, smooth muscle tissue, calcaneal tendon
ASIC5	17	tissue_specific	yes	buccal mucosa cell, duodenum, jejunal mucosa
PKHD1	51	tissue_specific	marker	kidney epithelium, renal medulla, metanephros cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ANXA5	6,084
PKHD1	1,211
ASIC5	360

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ANXA5	P08758	17
ASIC5	Q9NY37	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PKHD1	P08F94

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 3 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
Response to elevated platelet cytosolic Ca2+	1	81.6×	0.032	ANXA5
Stimuli-sensing channels	1	68.0×	0.032	ASIC5
Platelet activation, signaling and aggregation	1	52.9×	0.032	ANXA5
Ion channel transport	1	48.0×	0.032	ASIC5
Platelet degranulation	1	43.9×	0.032	ANXA5
Hemostasis	1	18.0×	0.064	ANXA5
Transport of small molecules	1	12.6×	0.078	ASIC5

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of cholangiocyte proliferation	1	5617.3×	0.005	PKHD1
negative regulation of coagulation	1	1404.3×	0.008	ANXA5
regulation of establishment of planar polarity	1	936.2×	0.008	PKHD1
homeostatic process	1	561.7×	0.008	PKHD1
establishment of centrosome localization	1	561.7×	0.008	PKHD1
regulation of cell-matrix adhesion	1	432.1×	0.008	PKHD1
regulation of cell-cell adhesion	1	401.2×	0.008	PKHD1
negative regulation of epithelial cell apoptotic process	1	401.2×	0.008	PKHD1
negative regulation of apoptotic process	2	23.2×	0.008	ANXA5, PKHD1
epithelial cell morphogenesis	1	312.1×	0.009	PKHD1
regulation of TOR signaling	1	312.1×	0.009	PKHD1
regulation of centrosome duplication	1	244.2×	0.009	PKHD1
branching morphogenesis of an epithelial tube	1	244.2×	0.009	PKHD1
cell-cell junction organization	1	208.1×	0.010	PKHD1
sodium ion import across plasma membrane	1	208.1×	0.010	ASIC5
regulation of ERK1 and ERK2 cascade	1	193.7×	0.010	PKHD1
establishment of mitotic spindle orientation	1	160.5×	0.010	PKHD1
neuronal action potential	1	160.5×	0.010	ASIC5
obsolete negative regulation of NF-kappaB transcription factor activity	1	119.5×	0.013	PKHD1
regulation of cell adhesion	1	102.1×	0.015	PKHD1
negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	87.8×	0.016	PKHD1
positive regulation of epithelial cell proliferation	1	81.4×	0.017	PKHD1
sodium ion transmembrane transport	1	67.7×	0.019	ASIC5
blood coagulation	1	57.9×	0.021	ANXA5
intracellular calcium ion homeostasis	1	48.4×	0.024	PKHD1
kidney development	1	46.8×	0.024	PKHD1
cell-cell adhesion	1	33.8×	0.033	PKHD1
cilium assembly	1	24.5×	0.043	PKHD1
positive regulation of cell population proliferation	1	11.2×	0.090	PKHD1
signal transduction	1	5.3×	0.176	ANXA5

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ANXA5	0	0
ASIC5	0	0
PKHD1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ANXA5	7	Binding:7

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	1	PKHD1
E	Difficult family or no structure, no drug	2	ANXA5, ASIC5

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ANXA5	7	—
ASIC5	0	—
PKHD1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.