Hypogonadotropic hypogonadism 1 with or without anosmia

Summary

Hypogonadotropic hypogonadism 1 with or without anosmia (MONDO:0010635) is a disease caused by ANOS1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: ANOS1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 263

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypogonadotropic hypogonadism 1 with or without anosmia
Mondo ID	MONDO:0010635
OMIM	308700
DOID	DOID:0090094
NCIT	C75480
UMLS	C1563719
MedGen	295872
GARD	0003071
Is cancer (heuristic)	no

Also known as: ANOS1 hypogonadotropic hypogonadism · HH1 · hypogonadotropic hypogonadism 1 with or without anosmia · hypogonadotropic hypogonadism 1 with or without anosmia (Kallmann syndrome 1), X-linked recessive · hypogonadotropic hypogonadism caused by mutation in ANOS1 · KAL1 · Kallmann syndrome, type 1, X-linked · Kallmann syndrome, X-linked · KMS

Data availability: 263 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Kallmann syndrome › hypogonadotropic hypogonadism 1 with or without anosmia

Related subtypes (17): hypogonadotropic hypogonadism 2 with or without anosmia, hypogonadotropic hypogonadism 3 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

263 retrieved; paginated sample, class counts are floors:

90 uncertain significance, 63 pathogenic, 27 likely benign, 23 likely pathogenic, 23 benign, 19 conflicting classifications of pathogenicity, 14 benign/likely benign, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
10002	NM_000216.4(ANOS1):c.1842+412_*1083del	ANOS1	Pathogenic	no assertion criteria provided
10003	NM_000216.4(ANOS1):c.711G>A (p.Trp237Ter)	ANOS1	Pathogenic	no assertion criteria provided
10004	NM_000216.4(ANOS1):c.769C>T (p.Arg257Ter)	ANOS1	Pathogenic	criteria provided, single submitter
10005	NM_000216.4(ANOS1):c.774G>A (p.Trp258Ter)	ANOS1	Pathogenic	no assertion criteria provided
10006	NM_000216.4(ANOS1):c.831del (p.Ser278fs)	ANOS1	Pathogenic	no assertion criteria provided
10007	NG_007088.2:g.(37490_113516)_(149394_151790)del	ANOS1	Pathogenic	no assertion criteria provided
10008	NM_000216.4(ANOS1):c.1540G>A (p.Glu514Lys)	ANOS1	Pathogenic	no assertion criteria provided
10009	NM_000216.4(ANOS1):c.544_726+2del	ANOS1	Pathogenic	no assertion criteria provided
10010	NM_000216.4(ANOS1):c.95_105dup (p.Asp36fs)	ANOS1	Pathogenic	no assertion criteria provided
10011	NM_000216.4(ANOS1):c.784C>T (p.Arg262Ter)	ANOS1	Pathogenic	criteria provided, multiple submitters, no conflicts
10012	NG_007088.2:g.(37490_113516)_(202869_204133)del	ANOS1	Pathogenic	no assertion criteria provided
10014	NG_007088.2:g.(37490_113516)_(151921_166482)del	ANOS1	Pathogenic	no assertion criteria provided
10015	NM_000216.4(ANOS1):c.1062+1G>T	ANOS1	Pathogenic	no assertion criteria provided
1027379	NM_000216.4(ANOS1):c.774del (p.Trp258fs)	ANOS1	Pathogenic	no assertion criteria provided
1069737	NM_000216.4(ANOS1):c.1890_1891delinsTT (p.Arg631Ter)	ANOS1	Pathogenic	criteria provided, single submitter
1184534	NM_000216.4(ANOS1):c.67_92dup (p.Ala32fs)	ANOS1	Pathogenic	no assertion criteria provided
1341676	NM_000216.4(ANOS1):c.1063-1G>C	ANOS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1351117	NM_000216.4(ANOS1):c.1766G>A (p.Trp589Ter)	ANOS1	Pathogenic	criteria provided, single submitter
1356515	NM_000216.4(ANOS1):c.1756C>T (p.Gln586Ter)	ANOS1	Pathogenic	criteria provided, single submitter
1387367	NM_000216.4(ANOS1):c.171_181del (p.Gln57fs)	ANOS1	Pathogenic	criteria provided, single submitter
1390065	NC_000023.10:g.(?8501036)(8591731_?)del	ANOS1	Pathogenic	criteria provided, single submitter
140614	NM_000216.4(ANOS1):c.1A>G (p.Met1Val)	ANOS1	Pathogenic	criteria provided, single submitter
1408120	NM_000216.4(ANOS1):c.571C>T (p.Arg191Ter)	ANOS1	Pathogenic	criteria provided, single submitter
1437964	NM_000216.4(ANOS1):c.586C>T (p.Gln196Ter)	ANOS1	Pathogenic	criteria provided, single submitter
1439274	NM_000216.4(ANOS1):c.814C>T (p.Arg272Ter)	ANOS1	Pathogenic	criteria provided, single submitter
1451691	NM_000216.4(ANOS1):c.203del (p.Phe68fs)	ANOS1	Pathogenic	criteria provided, single submitter
1452668	NM_000216.4(ANOS1):c.1249C>T (p.Gln417Ter)	ANOS1	Pathogenic	criteria provided, single submitter
1460215	NM_000216.4(ANOS1):c.1862dup (p.Pro622fs)	ANOS1	Pathogenic	criteria provided, single submitter
180157	NM_000216.4(ANOS1):c.1369C>T (p.Arg457Ter)	ANOS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1999854	NM_000216.4(ANOS1):c.1828del (p.Gln610fs)	ANOS1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
ANOS1	Definitive	X-linked	hypogonadotropic hypogonadism 1 with or without anosmia	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ANOS1	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
ANOS1	HGNC:6211	ENSG00000011201	P23352	Anosmin-1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ANOS1	Anosmin-1	Has a dual branch-promoting and guidance activity, which may play an important role in the patterning of mitral and tufted cell collaterals to the olfactory cortex.

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
Antibody/Immunoglobulin	1	29.2×	0.034

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ANOS1	Antibody/Immunoglobulin	yes		FN3_dom, WAP_dom, Ig-like_fold

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
hair follicle	1
skeletal muscle tissue of rectus abdominis	1
visceral pleura	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ANOS1	268	broad	marker	visceral pleura, hair follicle, skeletal muscle tissue of rectus abdominis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ANOS1	1,182

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ANOS1	P23352	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
FGFR1 ligand binding and activation	1	5710.0×	0.001	ANOS1
Signaling by FGFR1	1	815.7×	0.003	ANOS1
FGFR1c ligand binding and activation	1	761.3×	0.003	ANOS1
Negative regulation of FGFR1 signaling	1	368.4×	0.004	ANOS1
Signaling by FGFR	1	346.1×	0.004	ANOS1
Signaling by Receptor Tyrosine Kinases	1	51.7×	0.023	ANOS1
Signal Transduction	1	10.2×	0.098	ANOS1

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
chemotaxis	1	135.9×	0.015	ANOS1
neuron differentiation	1	100.3×	0.015	ANOS1
axon guidance	1	90.6×	0.015	ANOS1
cell adhesion	1	37.5×	0.027	ANOS1

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
ANOS1	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	1	ANOS1
D	Druggable family + AlphaFold only, no drug	0
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)
ANOS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.