Hypogonadotropic hypogonadism 3 with or without anosmia

Summary

Hypogonadotropic hypogonadism 3 with or without anosmia (MONDO:0009482) is a disease caused by PROKR2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: PROKR2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 122

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypogonadotropic hypogonadism 3 with or without anosmia
Mondo ID	MONDO:0009482
OMIM	244200
DOID	DOID:0090092
UMLS	C3550478
MedGen	763392
GARD	0003073
Is cancer (heuristic)	no

Also known as: HH3 · hypogonadotropic hypogonadism 3 with or without anosmia · hypogonadotropic hypogonadism caused by mutation in PROKR2 · KAL3 · Kallmann syndrome 3 · PROKR2 hypogonadotropic hypogonadism

Data availability: 122 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 3 with or without anosmia

Related subtypes (17): hypogonadotropic hypogonadism 2 with or without anosmia, hypogonadotropic hypogonadism 1 with or without anosmia, hypogonadotropic hypogonadism 4 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

122 retrieved; paginated sample, class counts are floors:

69 uncertain significance, 25 conflicting classifications of pathogenicity, 8 likely pathogenic, 8 likely benign, 5 benign, 4 benign/likely benign, 2 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2637789	NC_000020.10:g.(?5279863)(5283383_5294557)del	PROKR2	Pathogenic	criteria provided, single submitter
3452	NM_144773.4(PROKR2):c.58del (p.His20fs)	PROKR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3453	NM_144773.4(PROKR2):c.969G>A (p.Met323Ile)	PROKR2	Pathogenic	no assertion criteria provided
1184527	NM_144773.4(PROKR2):c.491G>A (p.Arg164Gln)	PROKR2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324963	NM_144773.4(PROKR2):c.691G>A (p.Glu231Lys)	PROKR2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2432848	NM_144773.4(PROKR2):c.201C>A (p.Cys67Ter)	PROKR2	Likely pathogenic	criteria provided, single submitter
2579639	NM_144773.4(PROKR2):c.948C>G (p.Tyr316Ter)	PROKR2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
267202	NM_144773.4(PROKR2):c.97T>C (p.Tyr33His)	PROKR2	Likely pathogenic	criteria provided, single submitter
3587501	NM_144773.4(PROKR2):c.1010dup (p.Asn338fs)	PROKR2	Likely pathogenic	criteria provided, single submitter
3587525	NM_144773.4(PROKR2):c.324del (p.Phe109fs)	PROKR2	Likely pathogenic	criteria provided, single submitter
4077446	NM_144773.4(PROKR2):c.896A>T (p.Asp299Val)	PROKR2	Likely pathogenic	criteria provided, single submitter
1012475	NM_144773.4(PROKR2):c.1058G>A (p.Arg353His)	PROKR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1303090	NM_144773.4(PROKR2):c.779C>T (p.Thr260Met)	PROKR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1386024	NM_144773.4(PROKR2):c.349C>T (p.Arg117Trp)	PROKR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
156562	NM_144773.4(PROKR2):c.253C>T (p.Arg85Cys)	PROKR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
156564	NM_144773.4(PROKR2):c.533G>C (p.Trp178Ser)	PROKR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
156565	NM_144773.4(PROKR2):c.743G>A (p.Arg248Gln)	PROKR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180158	NM_144773.4(PROKR2):c.563C>T (p.Ser188Leu)	PROKR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2041769	NM_144773.4(PROKR2):c.201C>T (p.Cys67=)	PROKR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2741590	NM_144773.4(PROKR2):c.472G>A (p.Val158Ile)	PROKR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2775885	NM_144773.4(PROKR2):c.604A>G (p.Ser202Gly)	PROKR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338862	NM_144773.4(PROKR2):c.337T>C (p.Tyr113His)	PROKR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338863	NM_144773.4(PROKR2):c.254G>T (p.Arg85Leu)	PROKR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338864	NM_144773.4(PROKR2):c.253C>G (p.Arg85Gly)	PROKR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338865	NM_144773.4(PROKR2):c.151G>A (p.Ala51Thr)	PROKR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3449	NM_144773.4(PROKR2):c.518T>G (p.Leu173Arg)	PROKR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3450	NM_144773.4(PROKR2):c.629A>G (p.Gln210Arg)	PROKR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3451	NM_144773.4(PROKR2):c.254G>A (p.Arg85His)	PROKR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
633661	NM_144773.4(PROKR2):c.332T>G (p.Met111Arg)	PROKR2	Conflicting classifications of pathogenicity	no assertion criteria provided
803597	NM_144773.4(PROKR2):c.889G>A (p.Val297Ile)	PROKR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 4 · 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
PROKR2	Definitive	Autosomal dominant	hypogonadotropic hypogonadism 3 with or without anosmia	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PROKR2	Orphanet:3157	Septo-optic dysplasia spectrum
PROKR2	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
PROKR2	Orphanet:478	Kallmann syndrome
PROKR2	Orphanet:95496	Pituitary stalk interruption 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
PROKR2	HGNC:15836	ENSG00000101292	Q8NFJ6	Prokineticin receptor 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PROKR2	Prokineticin receptor 2	Receptor for prokineticin 2.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
GPCR	1	23.9×	0.042

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PROKR2	GPCR	yes		GPCR_Rhodpsn, NPY_rcpt, GPCR_Rhodpsn_7TM

Expression context

Cohort genes with no expression data: 0.

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
cortical plate	1
ganglionic eminence	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PROKR2	32	tissue_specific	yes	cortical plate, ganglionic eminence, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PROKR2	844

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PROKR2	Q8NFJ6	78.50

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	PROKR2
G alpha (q) signalling events	1	57.4×	0.017	PROKR2

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
cellular response to hormone stimulus	1	383.0×	0.006	PROKR2
circadian rhythm	1	244.2×	0.006	PROKR2
G protein-coupled receptor signaling pathway	1	36.2×	0.028	PROKR2

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
PROKR2	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
PROKR2	9	Functional:5, Binding:4

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	1	PROKR2
E	Difficult family or no structure, no drug	0

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)
PROKR2	9	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.