Spermatogenic failure 5

Summary

Spermatogenic failure 5 (MONDO:0009461) is a disease caused by AURKC (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: AURKC (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 30

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	spermatogenic failure 5
Mondo ID	MONDO:0009461
MeSH	C562903
OMIM	243060
Orphanet	137893
DOID	DOID:0070183
SNOMED CT	236806004
UMLS	C0403812
MedGen	98020
GARD	0012385
Is cancer (heuristic)	no

Also known as: macrocephalic sperm head syndrome · macrozoospermia · macrozoospermia with multiflagellar polyploid spermatozoa · male infertility due to large-headed multiflagellar polyploid spermatozoa · male infertility due to macrozoospermia · male infertility with large-headed, multiflagellar, polyploid spermatozoa · spermatogenic failure 5 · spermatogenic failure type 5 · SPGF5

Data availability: 30 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › spermatogenic failure › spermatogenic failure 5

Related subtypes (112): spermatogenic failure 6, spermatogenic failure 2, 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 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

30 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
1028940	NM_001015878.2(AURKC):c.744C>G (p.Tyr248Ter)	AURKC	Pathogenic	criteria provided, multiple submitters, no conflicts
6306	NM_001015878.2(AURKC):c.145del (p.Leu49fs)	AURKC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6307	NM_001015878.2(AURKC):c.686G>A (p.Cys229Tyr)	AURKC	Pathogenic	no assertion criteria provided
66088	NM_001015878.2(AURKC):c.436-2A>G	AURKC	Pathogenic	no assertion criteria provided
632323	NM_001015878.2(AURKC):c.94_101dup (p.Met35fs)	AURKC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330228	NM_001015878.2(AURKC):c.184C>T (p.Leu62Phe)	AURKC	Uncertain significance	criteria provided, single submitter
330229	NM_001015878.2(AURKC):c.351C>T (p.Tyr117=)	AURKC	Uncertain significance	criteria provided, single submitter
330231	NM_001015878.2(AURKC):c.436-4A>G	AURKC	Uncertain significance	criteria provided, multiple submitters, no conflicts
4818867	NM_001015878.2(AURKC):c.104+5G>T	AURKC	Uncertain significance	criteria provided, single submitter
893059	NM_001015878.2(AURKC):c.-53A>C	AURKC	Uncertain significance	criteria provided, single submitter
893060	NM_001015878.2(AURKC):c.-38G>T	AURKC	Uncertain significance	criteria provided, single submitter
893061	NM_001015878.2(AURKC):c.12C>G (p.Pro4=)	AURKC	Uncertain significance	criteria provided, single submitter
893062	NM_001015878.2(AURKC):c.209C>G (p.Ala70Gly)	AURKC	Uncertain significance	criteria provided, single submitter
893266	NM_001015878.2(AURKC):c.435+11G>A	AURKC	Uncertain significance	criteria provided, single submitter
893267	NM_001015878.2(AURKC):c.656A>C (p.Lys219Thr)	AURKC	Uncertain significance	criteria provided, single submitter
893268	NM_001015878.2(AURKC):c.675T>C (p.Ile225=)	AURKC	Uncertain significance	criteria provided, multiple submitters, no conflicts
893269	NM_001015878.2(AURKC):c.689A>G (p.Tyr230Cys)	AURKC	Uncertain significance	criteria provided, single submitter
893270	NM_001015878.2(AURKC):c.760-12T>C	AURKC	Uncertain significance	criteria provided, single submitter
893271	NM_001015878.2(AURKC):c.762A>G (p.Val254=)	AURKC	Uncertain significance	criteria provided, multiple submitters, no conflicts
894127	NM_001015878.2(AURKC):c.779T>C (p.Leu260Pro)	AURKC	Uncertain significance	criteria provided, single submitter
894128	NM_001015878.2(AURKC):c.780A>G (p.Leu260=)	AURKC	Uncertain significance	criteria provided, single submitter
894129	NM_001015878.2(AURKC):c.*6G>C	AURKC	Uncertain significance	criteria provided, single submitter
894485	NM_001015878.2(AURKC):c.-139C>T	AURKC	Uncertain significance	criteria provided, single submitter
894486	NM_001015878.2(AURKC):c.-84C>T	AURKC	Uncertain significance	criteria provided, single submitter
330224	NM_001015878.2(AURKC):c.-145G>C	AURKC	Benign	criteria provided, multiple submitters, no conflicts
330225	NM_001015878.2(AURKC):c.-128C>T	AURKC	Benign	criteria provided, multiple submitters, no conflicts
330230	NM_001015878.2(AURKC):c.396G>A (p.Leu132=)	AURKC	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
330232	NM_001015878.2(AURKC):c.621G>A (p.Pro207=)	AURKC	Likely benign	criteria provided, multiple submitters, no conflicts
893063	NM_001015878.2(AURKC):c.235A>G (p.Ile79Val)	AURKC	Benign	criteria provided, single submitter
894130	NM_001015878.2(AURKC):c.*38G>A	AURKC	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · 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
AURKC	Strong	Autosomal recessive	spermatogenic failure 5	5
DNAH8	Strong	Autosomal recessive	spermatogenic failure 46	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AURKC	Orphanet:137893	Male infertility due to large-headed multiflagellar polyploid spermatozoa

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
AURKC	HGNC:11391	ENSG00000105146	Q9UQB9	Aurora kinase C	gencc,clinvar
DNAH8	HGNC:2952	ENSG00000124721	Q96JB1	Dynein axonemal heavy chain 8	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AURKC	Aurora kinase C	Serine/threonine-protein kinase component of the chromosomal passenger complex (CPC), a complex that acts as a key regulator of mitosis.
DNAH8	Dynein axonemal heavy chain 8	Force generating protein component of the outer dynein arms (ODAs) in the sperm flagellum.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Kinase	1	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AURKC	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
DNAH8	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left testis	1
oocyte	1
secondary oocyte	1
adult organism	1
male germ line stem cell (sensu Vertebrata) in testis	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AURKC	173	broad	yes	oocyte, secondary oocyte, left testis
DNAH8	68	tissue_specific	marker	sperm, male germ line stem cell (sensu Vertebrata) in testis, adult organism

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AURKC	2,322
DNAH8	1,631

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AURKC	Q9UQB9	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DNAH8	Q96JB1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 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
mitotic spindle midzone assembly	1	766.0×	0.007	AURKC
cilium-dependent cell motility	1	702.2×	0.007	DNAH8
attachment of spindle microtubules to kinetochore	1	468.1×	0.007	AURKC
outer dynein arm assembly	1	366.4×	0.007	DNAH8
cilium movement involved in cell motility	1	337.0×	0.007	DNAH8
regulation of cytokinesis	1	210.7×	0.008	AURKC
positive regulation of cytokinesis	1	200.6×	0.008	AURKC
mitotic spindle organization	1	135.9×	0.010	AURKC
meiotic cell cycle	1	122.1×	0.010	AURKC
protein phosphorylation	1	34.0×	0.032	AURKC
cell division	1	23.1×	0.043	AURKC

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
AURKC	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AURKC	41	4
DNAH8	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	AURKC
AXITINIB	4	AURKC
SORAFENIB	4	AURKC
RUXOLITINIB	4	AURKC
VANDETANIB	4	AURKC
PAZOPANIB	4	AURKC
NINTEDANIB	4	AURKC
SUNITINIB	4	AURKC
ERLOTINIB	4	AURKC
QUIZARTINIB	4	AURKC
CRIZOTINIB	4	AURKC
MIDOSTAURIN	4	AURKC
LINIFANIB	3	AURKC
ORANTINIB	3	AURKC
CANERTINIB	3	AURKC
BARASERTIB	3	AURKC
CEDIRANIB	3	AURKC
DOVITINIB	3	AURKC
MOTESANIB	3	AURKC
LESTAURTINIB	3	AURKC
RUBOXISTAURIN	3	AURKC
CI-1040	2	AURKC
FORETINIB	2	AURKC
TANDUTINIB	2	AURKC
SU-014813	2	AURKC
ILORASERTIB	2	AURKC
DEFOSBARASERTIB	2	AURKC
DANUSERTIB	2	AURKC
R-406	2	AURKC
TOZASERTIB	2	AURKC

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
AURKC	358	Binding:358

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
AURKC	358

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 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)
FEDRATINIB	4	AURKC
AXITINIB	4	AURKC
SORAFENIB	4	AURKC
RUXOLITINIB	4	AURKC
VANDETANIB	4	AURKC
PAZOPANIB	4	AURKC
NINTEDANIB	4	AURKC
SUNITINIB	4	AURKC
ERLOTINIB	4	AURKC
QUIZARTINIB	4	AURKC
CRIZOTINIB	4	AURKC
MIDOSTAURIN	4	AURKC
LINIFANIB	3	AURKC
ORANTINIB	3	AURKC
CANERTINIB	3	AURKC
BARASERTIB	3	AURKC
CEDIRANIB	3	AURKC
DOVITINIB	3	AURKC
MOTESANIB	3	AURKC
LESTAURTINIB	3	AURKC
RUBOXISTAURIN	3	AURKC
CI-1040	2	AURKC
FORETINIB	2	AURKC
TANDUTINIB	2	AURKC
SU-014813	2	AURKC
ILORASERTIB	2	AURKC
DEFOSBARASERTIB	2	AURKC
DANUSERTIB	2	AURKC
R-406	2	AURKC
TOZASERTIB	2	AURKC

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	AURKC
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	DNAH8

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)
DNAH8	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.