Hypogonadotropic hypogonadism 4 with or without anosmia

Summary

Hypogonadotropic hypogonadism 4 with or without anosmia (MONDO:0012528) is a disease caused by PROK2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: PROK2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 14

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypogonadotropic hypogonadism 4 with or without anosmia
Mondo ID	MONDO:0012528
MeSH	C565696
OMIM	610628
DOID	DOID:0090077
UMLS	C3552343
MedGen	765257
GARD	0010772
Is cancer (heuristic)	no

Also known as: HH4 · hypogonadotropic hypogonadism 4 with or without anosmia · hypogonadotropic hypogonadism caused by mutation in PROK2 · KAL4 · Kallman syndrome 4 · Kallmann syndrome 4 · PROK2 hypogonadotropic hypogonadism

Data availability: 14 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Kallmann syndrome › hypogonadotropic hypogonadism 4 with or without anosmia

Related subtypes (17): hypogonadotropic hypogonadism 2 with or without anosmia, hypogonadotropic hypogonadism 3 with or without anosmia, hypogonadotropic hypogonadism 1 with or without anosmia, hypogonadotropic hypogonadism 5 with or without anosmia, hypogonadotropic hypogonadism 6 with or without anosmia, hypogonadotropic hypogonadism 8 with or without anosmia, hypogonadotropic hypogonadism 9 with or without anosmia, hypogonadotropic hypogonadism 11 with or without anosmia, hypogonadotropic hypogonadism 14 with or without anosmia, hypogonadotropic hypogonadism 15 with or without anosmia, hypogonadotropic hypogonadism 16 with or without anosmia, hypogonadotropic hypogonadism 17 with or without anosmia, hypogonadotropic hypogonadism 18 with or without anosmia, hypogonadotropic hypogonadism 19 with or without anosmia, hypogonadotropic hypogonadism 20 with or without anosmia, hypogonadotropic hypogonadism 21 with or without anosmia, hypogonadotropic hypogonadism 22 with or without anosmia

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

14 retrieved; paginated sample, class counts are floors:

4 conflicting classifications of pathogenicity, 4 likely pathogenic, 3 uncertain significance, 2 pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
156561	NM_001126128.2(PROK2):c.101G>A (p.Cys34Tyr)	PROK2	Pathogenic	no assertion criteria provided
3603	NM_001126128.2(PROK2):c.163del (p.Ser54_Ile55insTer)	PROK2	Pathogenic	criteria provided, multiple submitters, no conflicts
3893212	NM_001126128.2(PROK2):c.370_373del (p.Ile124fs)	PROK2	Likely pathogenic	criteria provided, single submitter
4538441	NM_001126128.2(PROK2):c.62del (p.Thr21fs)	PROK2	Likely pathogenic	no assertion criteria provided
4538450	NM_001126128.2(PROK2):c.286-1G>A	PROK2	Likely pathogenic	no assertion criteria provided
4759226	NM_001126128.2(PROK2):c.2T>C (p.Met1Thr)	PROK2	Likely pathogenic	criteria provided, single submitter
156560	NM_001126128.2(PROK2):c.70G>C (p.Ala24Pro)	PROK2	Conflicting classifications of pathogenicity	no assertion criteria provided
3604	NM_001126128.2(PROK2):c.217C>T (p.Arg73Cys)	PROK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
420068	NM_001126128.2(PROK2):c.297dup (p.Gly100fs)	PROK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
801987	NM_001126128.2(PROK2):c.-4C>A	PROK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2248655	NM_001126128.2(PROK2):c.185G>A (p.Gly62Asp)	PROK2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2309812	NM_001126128.2(PROK2):c.297del (p.Phe99fs)	PROK2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3601	NM_001126128.2(PROK2):c.94G>C (p.Gly32Arg)	PROK2	Uncertain significance	criteria provided, single submitter
378430	NM_001126128.2(PROK2):c.84C>G (p.Ala28=)	PROK2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
PROK2	Definitive	Semidominant	hypogonadotropic hypogonadism 4 with or without anosmia	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PROK2	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
PROK2	Orphanet:478	Kallmann syndrome

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
PROK2	HGNC:18455	ENSG00000163421	Q9HC23	Prokineticin-2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PROK2	Prokineticin-2	May function as an output molecule from the suprachiasmatic nucleus (SCN) that transmits behavioral circadian rhythm.

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)
PROK2	Other/Unknown	no		Prokineticin, Prokineticin_domain

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
blood	1
bone marrow	1
trabecular bone tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PROK2	159	broad	marker	blood, bone marrow, trabecular bone tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PROK2	1,217

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PROK2	Q9HC23	69.22

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Peptide ligand-binding receptors	1	74.2×	0.017	PROK2
G alpha (q) signalling events	1	57.4×	0.017	PROK2

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
positive regulation of smooth muscle contraction	1	936.2×	0.011	PROK2
endothelial cell proliferation	1	543.6×	0.011	PROK2
sensory perception of pain	1	374.5×	0.011	PROK2
circadian rhythm	1	244.2×	0.012	PROK2
neuropeptide signaling pathway	1	172.0×	0.014	PROK2
chemotaxis	1	135.9×	0.015	PROK2
positive regulation of cytosolic calcium ion concentration	1	117.0×	0.015	PROK2
angiogenesis	1	62.4×	0.024	PROK2
inflammatory response	1	37.7×	0.029	PROK2
G protein-coupled receptor signaling pathway	1	36.2×	0.029	PROK2
spermatogenesis	1	35.2×	0.029	PROK2
negative regulation of apoptotic process	1	34.8×	0.029	PROK2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PROK2	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	PROK2

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)
PROK2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.