Spermatogenic failure 88

Summary

Spermatogenic failure 88 (MONDO:0957821) is a disease with 3 cohort genes.

At a glance

• Cohort genes: 3
• ClinVar variants: 8

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	spermatogenic failure 88
Mondo ID	MONDO:0957821
OMIM	620547
DOID	DOID:0070587
UMLS	C5882706
MedGen	1845113
Is cancer (heuristic)	no

Data availability: 8 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 88

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, Y-linked, 2, 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 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

8 retrieved; paginated sample, class counts are floors:

7 pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
2626771	NM_144688.5(KASH5):c.1604T>A (p.Leu535Gln)	KASH5	Pathogenic	no assertion criteria provided
2626772	NM_144688.5(KASH5):c.590T>C (p.Leu197Pro)	KASH5	Pathogenic	no assertion criteria provided
2626773	NM_144688.5(KASH5):c.981_982del (p.Arg327fs)	KASH5	Pathogenic	no assertion criteria provided
2626774	NM_144688.5(KASH5):c.-95-2_798+248del	KASH5	Pathogenic	no assertion criteria provided
2626776	NM_144688.5(KASH5):c.1271_1274del (p.Arg424fs)	KASH5	Pathogenic	no assertion criteria provided
4277339	NM_001099218.3(RAD51AP2):c.2985del (p.Asn995fs)	RAD51AP2	Pathogenic	criteria provided, single submitter
4277340	NM_001302084.2(TOP6BL):c.25+1G>C	TOP6BL	Pathogenic	no assertion criteria provided
3064402	NM_144688.5(KASH5):c.302T>C (p.Met101Thr)	KASH5	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TOP6BL	Orphanet:254688	Complete hydatidiform mole

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
TOP6BL	HGNC:26197	ENSG00000173715	Q8N6T0	Type 2 DNA topoisomerase 6 subunit B-like	clinvar
KASH5	HGNC:26520	ENSG00000161609	Q8N6L0	Protein KASH5	clinvar
RAD51AP2	HGNC:34417	ENSG00000214842	Q09MP3	RAD51-associated protein 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TOP6BL	Type 2 DNA topoisomerase 6 subunit B-like	Component of a topoisomerase 6 complex specifically required for meiotic recombination.
KASH5	Protein KASH5	As a component of the LINC (LInker of Nucleoskeleton and Cytoskeleton) complex, involved in the connection between the nuclear lamina and the cytoskeleton.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TOP6BL	Other/Unknown	no		TopoVIB-like
KASH5	Other/Unknown	no		EF-hand-dom_pair, KASH5_CC, KASH5
RAD51AP2	Other/Unknown	no		RAD51_interact, RAD51-associated

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right testis	2
lower esophagus mucosa	1
skin of abdomen	1
skin of leg	1
left testis	1
testis	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TOP6BL	186	ubiquitous	marker	skin of abdomen, skin of leg, lower esophagus mucosa
KASH5	112	tissue_specific	marker	right testis, left testis, testis
RAD51AP2	64	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, right testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KASH5	1,547
RAD51AP2	453
TOP6BL	326

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KASH5	Q8N6L0	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TOP6BL	Q8N6T0	68.14
RAD51AP2	Q09MP3	33.74

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 3 evidence-associated genes (0 with Reactome annotation).

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
telomere localization	1	8426.0×	7e-04	KASH5
chromosome localization to nuclear envelope involved in homologous chromosome segregation	1	8426.0×	7e-04	KASH5
spindle localization	1	1685.2×	0.002	KASH5
meiotic DNA double-strand break formation	1	1203.7×	0.002	TOP6BL
meiotic telomere clustering	1	936.2×	0.003	KASH5
homologous chromosome pairing at meiosis	1	300.9×	0.006	KASH5
reciprocal meiotic recombination	1	280.9×	0.006	TOP6BL
spindle assembly	1	221.7×	0.007	KASH5
oogenesis	1	191.5×	0.007	KASH5
double-strand break repair via homologous recombination	1	78.0×	0.015	KASH5
actin filament organization	1	59.3×	0.018	KASH5
spermatogenesis	1	17.6×	0.056	KASH5

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
TOP6BL	0	0
KASH5	0	0
RAD51AP2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
E	Difficult family or no structure, no drug	3	TOP6BL, KASH5, RAD51AP2

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)
TOP6BL	0	—
KASH5	0	—
RAD51AP2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.