Spermatogenic failure 18

Summary

Spermatogenic failure 18 (MONDO:0054615) is a disease caused by DNAH1 (GenCC Strong), with 4 cohort genes.

At a glance

• Causal gene: DNAH1 (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 2,388

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	spermatogenic failure 18
Mondo ID	MONDO:0054615
OMIM	617576
DOID	DOID:0070165
UMLS	C4539783
MedGen	1617309
GARD	0018402
Is cancer (heuristic)	no

Also known as: spermatogenic failure 18 · SPGF18

Data availability: 2,388 ClinVar variants · 2 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 18

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 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

600 retrieved; paginated sample, class counts are floors:

280 uncertain significance, 258 likely benign, 25 benign, 16 pathogenic, 7 benign/likely benign, 7 conflicting classifications of pathogenicity, 5 likely pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1033365	NM_015512.5(DNAH1):c.9352C>T (p.Arg3118Ter)	DNAH1	Pathogenic	criteria provided, multiple submitters, no conflicts
1060963	NM_015512.5(DNAH1):c.7066C>T (p.Arg2356Trp)	DNAH1	Pathogenic	criteria provided, single submitter
1068985	NM_015512.5(DNAH1):c.2921_2939dup (p.Arg981fs)	DNAH1	Pathogenic	criteria provided, single submitter
1251942	NM_015512.5(DNAH1):c.3772C>T (p.Gln1258Ter)	DNAH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1401790	NM_015512.5(DNAH1):c.7864C>T (p.Arg2622Ter)	DNAH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1421082	NM_015512.5(DNAH1):c.2005_2014del (p.Gly669fs)	DNAH1	Pathogenic	criteria provided, single submitter
1451711	NM_015512.5(DNAH1):c.3107G>A (p.Trp1036Ter)	DNAH1	Pathogenic	criteria provided, single submitter
1455501	NM_015512.5(DNAH1):c.4167C>A (p.Tyr1389Ter)	DNAH1	Pathogenic	criteria provided, single submitter
1459903	NM_015512.5(DNAH1):c.2602C>T (p.Arg868Ter)	DNAH1	Pathogenic	criteria provided, multiple submitters, no conflicts
1905119	NM_015512.5(DNAH1):c.5547C>A (p.Tyr1849Ter)	DNAH1	Pathogenic	criteria provided, single submitter
1914975	NM_015512.5(DNAH1):c.5308C>T (p.Arg1770Ter)	DNAH1	Pathogenic	criteria provided, single submitter
1965274	NM_015512.5(DNAH1):c.7559C>G (p.Ser2520Ter)	DNAH1	Pathogenic	criteria provided, single submitter
1988199	NM_015512.5(DNAH1):c.526C>T (p.Gln176Ter)	DNAH1	Pathogenic	criteria provided, single submitter
2002471	NM_015512.5(DNAH1):c.2926del (p.Ala976fs)	DNAH1	Pathogenic	criteria provided, single submitter
2021302	NM_015512.5(DNAH1):c.8626-1G>C	DNAH1	Pathogenic	criteria provided, single submitter
2029087	NM_015512.5(DNAH1):c.202_203del (p.Pro68fs)	DNAH1	Pathogenic	criteria provided, single submitter
2033207	NM_015512.5(DNAH1):c.7342del (p.Gln2448fs)	DNAH1	Pathogenic	criteria provided, single submitter
2036895	NM_015512.5(DNAH1):c.3583C>T (p.Gln1195Ter)	DNAH1	Pathogenic	criteria provided, single submitter
1483312	NM_015512.5(DNAH1):c.3980+1G>C	DNAH1	Likely pathogenic	criteria provided, single submitter
1504260	NM_015512.5(DNAH1):c.5611-1G>A	DNAH1	Likely pathogenic	criteria provided, single submitter
1973856	NM_015512.5(DNAH1):c.3480+1G>C	DNAH1	Likely pathogenic	criteria provided, single submitter
1993908	NM_015512.5(DNAH1):c.9621+1G>T	DNAH1	Likely pathogenic	criteria provided, single submitter
2027844	NM_015512.5(DNAH1):c.7198+1G>A	DNAH1	Likely pathogenic	criteria provided, single submitter
1301732	NM_015512.5(DNAH1):c.3002G>A (p.Arg1001His)	DNAH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1385471	NM_015512.5(DNAH1):c.11971G>A (p.Val3991Ile)	DNAH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1402087	NM_015512.5(DNAH1):c.10534A>G (p.Asn3512Asp)	DNAH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1416117	NM_015512.5(DNAH1):c.9302A>G (p.Lys3101Arg)	DNAH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1453969	NM_015512.5(DNAH1):c.46C>T (p.Gln16Ter)	DNAH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1489252	NM_015512.5(DNAH1):c.7978G>A (p.Val2660Ile)	DNAH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1493548	NM_015512.5(DNAH1):c.6212T>G (p.Leu2071Arg)	DNAH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
DNAH1	Strong	Autosomal recessive	spermatogenic failure 18	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DNAH1	Orphanet:244	Primary ciliary dyskinesia
DNAH1	Orphanet:276234	Non-syndromic male infertility due to sperm motility disorder
STK36	Orphanet:244	Primary ciliary dyskinesia
CFAP251	Orphanet:276234	Non-syndromic male infertility due to sperm motility disorder

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DNAH1	HGNC:2940	ENSG00000114841	Q9P2D7	Dynein axonemal heavy chain 1	gencc,clinvar
STK36	HGNC:17209	ENSG00000163482	Q9NRP7	Serine/threonine-protein kinase 36	clinvar
CFAP251	HGNC:28506	ENSG00000158023	Q8TBY9	Cilia- and flagella-associated protein 251	clinvar
DNAH3	HGNC:2949	ENSG00000158486	Q8TD57	Dynein axonemal heavy chain 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DNAH1	Dynein axonemal heavy chain 1	Force generating protein of cilia required for sperm flagellum motility.
STK36	Serine/threonine-protein kinase 36	Serine/threonine protein kinase which plays an important role in the sonic hedgehog (Shh) pathway by regulating the activity of GLI transcription factors.
CFAP251	Cilia- and flagella-associated protein 251	Involved in spermatozoa motility.
DNAH3	Dynein axonemal heavy chain 3	Force generating protein of respiratory cilia.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.25

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	6.9×	0.318
Scaffold/PPI	1	4.3×	0.318
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DNAH1	Other/Unknown	no		Dhc_D6_P-loop, Dhc_linker, Dhc_D4
STK36	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
CFAP251	Scaffold/PPI	no		WD40_rpt, Quinoprotein_ADH-like_sf, EF-hand-dom_pair
DNAH3	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dhc_linker

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bronchial epithelial cell	3
bronchus	3
right uterine tube	3
adenohypophysis	1
left testis	1
epithelium of bronchus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DNAH1	183	tissue_specific	marker	right uterine tube, bronchial epithelial cell, bronchus
STK36	218	ubiquitous	marker	right uterine tube, adenohypophysis, left testis
CFAP251	177	broad	marker	right uterine tube, bronchial epithelial cell, bronchus
DNAH3	156	tissue_specific	marker	bronchial epithelial cell, epithelium of bronchus, bronchus

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DNAH1	1,699
DNAH3	1,268
CFAP251	1,050
STK36	884

Intra-cohort edges

A	B	Sources
CFAP251	DNAH1	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DNAH1	Q9P2D7	2
CFAP251	Q8TBY9	1
DNAH3	Q8TD57	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
STK36	Q9NRP7	81.22

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cilium-dependent cell motility	2	702.2×	4e-05	DNAH1, DNAH3
inner dynein arm assembly	2	443.5×	5e-05	DNAH1, DNAH3
epithelial cilium movement involved in extracellular fluid movement	2	383.0×	5e-05	DNAH1, STK36
flagellated sperm motility	2	58.5×	0.002	DNAH1, CFAP251
obsolete regulation of DNA-binding transcription factor activity	1	383.0×	0.008	STK36
cilium movement involved in cell motility	1	168.5×	0.015	DNAH3
axoneme assembly	1	135.9×	0.015	STK36
sperm axoneme assembly	1	117.0×	0.015	DNAH1
positive regulation of smoothened signaling pathway	1	105.3×	0.015	STK36
cilium movement	1	98.0×	0.015	CFAP251
post-embryonic development	1	51.4×	0.026	STK36
smoothened signaling pathway	1	45.3×	0.027	STK36
brain development	1	19.9×	0.057	STK36
cilium assembly	1	18.4×	0.057	STK36
protein phosphorylation	1	17.0×	0.058	STK36

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) 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
STK36	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
STK36	19	4
DNAH1	0	0
CFAP251	0	0
DNAH3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	STK36
SORAFENIB	4	STK36
NERATINIB	4	STK36
BOSUTINIB	4	STK36
PAZOPANIB	4	STK36
DASATINIB	4	STK36
ERLOTINIB	4	STK36
GEFITINIB	4	STK36
CANERTINIB	3	STK36
LESTAURTINIB	3	STK36
FORETINIB	2	STK36
DEFOSBARASERTIB	2	STK36
R-406	2	STK36
RAF-265	2	STK36
PELITINIB	2	STK36
R-1487	1	STK36
BMS-387032	1	STK36
GSK-690693	1	STK36
AST-487	1	STK36

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
STK36	77	Binding:77

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

19 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	STK36
SORAFENIB	4	STK36
NERATINIB	4	STK36
BOSUTINIB	4	STK36
PAZOPANIB	4	STK36
DASATINIB	4	STK36
ERLOTINIB	4	STK36
GEFITINIB	4	STK36
CANERTINIB	3	STK36
LESTAURTINIB	3	STK36
FORETINIB	2	STK36
DEFOSBARASERTIB	2	STK36
R-406	2	STK36
RAF-265	2	STK36
PELITINIB	2	STK36
R-1487	1	STK36
BMS-387032	1	STK36
GSK-690693	1	STK36
AST-487	1	STK36

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	STK36
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	DNAH1, CFAP251, DNAH3

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)
DNAH1	0	—
CFAP251	0	—
DNAH3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.