spermatogenic failure, Y-linked, 2

Summary

spermatogenic failure, Y-linked, 2 (MONDO:0010767) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 10

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	spermatogenic failure, Y-linked, 2
Mondo ID	MONDO:0010767
MeSH	C564030
OMIM	415000
DOID	DOID:0070187
UMLS	C1839071
MedGen	326394
GARD	0018504
Is cancer (heuristic)	no

Also known as: spermatogenic failure, Y-linked, 2 · spermatogenic failure, Y-linked, 2, Y-linked · spermatogenic failure, Y-linked, type 2 · SPGFY2

Data availability: 10 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › spermatogenic failure › spermatogenic failure, Y-linked, 2

Related subtypes (112): spermatogenic failure 6, spermatogenic failure 2, spermatogenic failure 5, spermatogenic failure 1, spermatogenic failure 4, spermatogenic failure, X-linked, 2, spermatogenic failure, Y-linked, 1, spermatogenic failure 3, spermatogenic failure 7, spermatogenic failure 8, spermatogenic failure 9, spermatogenic failure 10, spermatogenic failure 11, spermatogenic failure 12, spermatogenic failure 13, spermatogenic failure 14, spermatogenic failure 15, spermatogenic failure 16, spermatogenic failure 17, spermatogenic failure 30, spermatogenic failure 31, spermatogenic failure 32, spermatogenic failure 54, spermatogenic failure, X-linked, 4, spermatogenic failure, X-linked, 3, spermatogenic failure 33, spermatogenic failure 34, spermatogenic failure 55, spermatogenic failure 56, spermatogenic failure 57, spermatogenic failure 58, spermatogenic failure 59, spermatogenic failure 60, spermatogenic failure 61, spermatogenic failure 62, spermatogenic failure 63, spermatogenic failure 64, spermatogenic failure 65, spermatogenic failure 66, spermatogenic failure 67, spermatogenic failure 68, spermatogenic failure 69, spermatogenic failure 70, spermatogenic failure 71, spermatogenic failure 72, spermatogenic failure 73, spermatogenic failure 47, spermatogenic failure 48, spermatogenic failure 49, spermatogenic failure 50, spermatogenic failure 51, spermatogenic failure 52, spermatogenic failure 74, spermatogenic failure 75, spermatogenic failure 53, spermatogenic failure 76, spermatogenic failure 77, spermatogenic failure 35, spermatogenic failure 36, spermatogenic failure 37, spermatogenic failure 38, spermatogenic failure 39, spermatogenic failure 40, spermatogenic failure 41, spermatogenic failure 42, spermatogenic failure 43, spermatogenic failure 44, spermatogenic failure 45, spermatogenic failure 46, spermatogenic failure 18, spermatogenic failure 19, spermatogenic failure 20, spermatogenic failure 21, spermatogenic failure 22, spermatogenic failure 23, spermatogenic failure 24, spermatogenic failure 25, spermatogenic failure 26, spermatogenic failure 27, spermatogenic failure 28, spermatogenic failure 29, X-linked spermatogenic failure 1, spermatogenic failure 98, spermatogenic failure 78, spermatogenic failure 79, spermatogenic failure 80, spermatogenic failure, X-linked, 5, spermatogenic failure, X-linked, 6, spermatogenic failure 81, spermatogenic failure, X-linked, 7, spermatogenic failure 82, spermatogenic failure 83, spermatogenic failure 84, spermatogenic failure 85, spermatogenic failure 86, spermatogenic failure 87, spermatogenic failure 88, spermatogenic failure 89, spermatogenic failure 90, spermatogenic failure, X-linked, 8, spermatogenic failure 91, spermatogenic failure 92, spermatogenic failure 93, spermatogenic failure 94, spermatogenic failure 95, spermatogenic failure 96, spermatogenic failure 97, spermatogenic failure, X-linked, 9, spermatogenic failure 99, spermatogenic failure 100, spermatogenic failure 101, spermatogenic failure 102

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

10 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 2 pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
7136	NM_000492.4(CFTR):c.3909C>G (p.Asn1303Lys)	CFTR	Pathogenic	practice guideline
9757	NM_004654.4(USP9Y):c.773+3_773+6del	USP9Y	Pathogenic	no assertion criteria provided
1518294	NM_000492.4(CFTR):c.458G>A (p.Arg153Lys)	CFTR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2438504	NM_004654.4(USP9Y):c.3835C>G (p.Leu1279Val)	USP9Y	Uncertain significance	criteria provided, single submitter
2438505	NM_004654.4(USP9Y):c.5924C>T (p.Thr1975Ile)	USP9Y	Uncertain significance	criteria provided, single submitter
2627757	NM_004654.4(USP9Y):c.6343G>T (p.Gly2115Cys)	USP9Y	Uncertain significance	no assertion criteria provided
3381938	NM_004654.4(USP9Y):c.6845dup (p.Arg2283fs)	USP9Y	Uncertain significance	criteria provided, single submitter
3381939	NM_004654.4(USP9Y):c.1774del (p.Gln592fs)	USP9Y	Uncertain significance	criteria provided, single submitter
3383021	NM_004654.4(USP9Y):c.3842T>C (p.Val1281Ala)	USP9Y	Uncertain significance	criteria provided, single submitter
3383102	NM_004654.4(USP9Y):c.1256G>A (p.Arg419His)	USP9Y	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 7 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
USP9Y	Orphanet:1646	Chromosome Y microdeletion syndrome
CFTR	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
CFTR	Orphanet:48	Congenital bilateral absence of vas deferens
CFTR	Orphanet:498359	Aquagenic palmoplantar keratoderma
CFTR	Orphanet:586	Cystic fibrosis
CFTR	Orphanet:60033	Idiopathic bronchiectasis
CFTR	Orphanet:700124	Autosomal recessive hereditary chronic pancreatitis

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
USP9Y	HGNC:12633	ENSG00000114374	O00507	Ubiquitin carboxyl-terminal hydrolase 9Y	clinvar
CFTR	HGNC:1884	ENSG00000001626	P13569	Cystic fibrosis transmembrane conductance regulator	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
USP9Y	Ubiquitin carboxyl-terminal hydrolase 9Y	Deubiquitinase that mediates deubiquitination of target proteins.
CFTR	Cystic fibrosis transmembrane conductance regulator	Epithelial ion channel that plays an important role in the regulation of epithelial ion and water transport and fluid homeostasis.

Protein-family classification

Druggable: 2 · 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
Transporter	1	38.9×	0.051
Protease	1	18.3×	0.054

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
USP9Y	Protease	yes		Peptidase_C19_UCH, ARM-type_fold, USP_CS
CFTR	Transporter	yes	2.7.4.3	ABC_transporter-like_ATP-bd, AAA+_ATPase, CFTR/ABCC7

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
male germ line stem cell (sensu Vertebrata) in testis	1
metanephros cortex	1
right lung	1
body of pancreas	1
gall bladder	1
pancreas	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
USP9Y	254	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, right lung, metanephros cortex
CFTR	193	broad	marker	body of pancreas, gall bladder, pancreas

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CFTR	7,664
USP9Y	955

Intra-cohort edges

A	B	Sources
CFTR	USP9Y	intact

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CFTR	P13569	58

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
USP9Y	O00507	79.64

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 2 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
RHO GTPases regulate CFTR trafficking	1	3806.7×	0.003	CFTR
Chaperone Mediated Autophagy	1	496.5×	0.008	CFTR
Late endosomal microautophagy	1	326.3×	0.008	CFTR
Aggrephagy	1	248.3×	0.008	CFTR
Developmental Lineage of Pancreatic Ductal Cells	1	228.4×	0.008	CFTR
Defective CFTR causes cystic fibrosis	1	219.6×	0.008	CFTR
RHOQ GTPase cycle	1	181.3×	0.009	CFTR
ABC-family protein mediated transport	1	121.5×	0.011	CFTR
Cargo recognition for clathrin-mediated endocytosis	1	104.8×	0.012	CFTR
Clathrin-mediated endocytosis	1	85.2×	0.013	CFTR
Ub-specific processing proteases	1	53.1×	0.019	CFTR

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
intracellular pH elevation	1	2808.7×	0.005	CFTR
transepithelial water transport	1	1685.2×	0.005	CFTR
positive regulation of enamel mineralization	1	1685.2×	0.005	CFTR
membrane hyperpolarization	1	936.2×	0.006	CFTR
multicellular organismal-level water homeostasis	1	842.6×	0.006	CFTR
amelogenesis	1	702.2×	0.006	CFTR
cellular response to forskolin	1	561.7×	0.006	CFTR
water transport	1	495.6×	0.006	CFTR
bicarbonate transport	1	401.2×	0.006	CFTR
cholesterol transport	1	366.4×	0.006	CFTR
sperm capacitation	1	337.0×	0.006	CFTR
cholesterol biosynthetic process	1	210.7×	0.009	CFTR
cellular response to cAMP	1	145.3×	0.013	CFTR
chloride transmembrane transport	1	118.7×	0.014	CFTR
BMP signaling pathway	1	100.3×	0.015	USP9Y
protein deubiquitination	1	88.7×	0.015	USP9Y
transmembrane transport	1	84.3×	0.015	CFTR
response to endoplasmic reticulum stress	1	83.4×	0.015	CFTR
establishment of localization in cell	1	80.2×	0.015	CFTR
transforming growth factor beta receptor signaling pathway	1	79.5×	0.015	USP9Y
regulation of protein stability	1	62.9×	0.018	USP9Y
cell migration	1	30.8×	0.035	USP9Y
spermatogenesis	1	17.6×	0.058	USP9Y
proteolysis	1	17.1×	0.058	USP9Y

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CFTR	IVACAFTOR

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CFTR	14	4
USP9Y	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IVACAFTOR	4	CFTR
LUMACAFTOR	4	CFTR
TEZACAFTOR	4	CFTR
ELEXACAFTOR	4	CFTR
GLYBURIDE	4	CFTR
RUTIN	3	CFTR
BAMOCAFTOR	3	CFTR
QUERCETIN	3	CFTR
GALICAFTOR	2	CFTR
GENISTEIN	2	CFTR
ICENTICAFTOR	2	CFTR
NAVOCAFTOR	2	CFTR
RISELCAFTOR	2	CFTR
GLPG-2737	2	CFTR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CFTR	520	Binding:497, Functional:17, ADMET:5, Toxicity:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CFTR	2.7.4.3, 5.6.1.6	adenylate kinase, channel-conductance-controlling ATPase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CFTR	520

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
CFTR	1

Chemical tractability of cohort targets

14 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.

Compound	Max phase	Cohort target (bioactivity)
IVACAFTOR	4	CFTR
LUMACAFTOR	4	CFTR
TEZACAFTOR	4	CFTR
ELEXACAFTOR	4	CFTR
GLYBURIDE	4	CFTR
RUTIN	3	CFTR
BAMOCAFTOR	3	CFTR
QUERCETIN	3	CFTR
GALICAFTOR	2	CFTR
GENISTEIN	2	CFTR
ICENTICAFTOR	2	CFTR
NAVOCAFTOR	2	CFTR
RISELCAFTOR	2	CFTR
GLPG-2737	2	CFTR

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CFTR
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	USP9Y
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)
USP9Y	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.