DNAH12

Summary

DNAH12 (dynein axonemal heavy chain 12, HGNC:2943) is a protein-coding gene on chromosome 3p14.3, encoding Dynein axonemal heavy chain 12 (Q6ZR08). Involved in spermiogenesis.

Predicted to enable several functions, including ATP binding activity; ATP hydrolysis activity; and dynein intermediate chain binding activity. Predicted to be involved in microtubule-based movement. Predicted to be located in axoneme and microtubule. Predicted to be part of axonemal dynein complex.

Source: NCBI Gene 201625 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spermatogenic failure (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 520 total — 8 pathogenic
• Phenotypes (HPO): 12
• Druggable target: yes
• MANE Select transcript: NM_001366028

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2943
Approved symbol	DNAH12
Name	dynein axonemal heavy chain 12
Location	3p14.3
Locus type	gene with protein product
Status	Approved
Aliases	DLP12, Dnahc3, HL-19, hdhc3, DHC3, FLJ40427, FLJ44290
Ensembl gene	ENSG00000174844
Ensembl biotype	protein_coding
OMIM	603340
Entrez	201625

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 5 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000311202, ENST00000351747, ENST00000389536, ENST00000462713, ENST00000466540, ENST00000479363, ENST00000494758, ENST00000495027, ENST00000613504

RefSeq mRNA: 2 — MANE Select: NM_001366028 NM_001366028, NM_198564

CCDS: CCDS33771, CCDS93294

Canonical transcript exons

ENST00000495027 — 74 exons

Exon	Start	End
ENSE00001077076	57310717	57310950
ENSE00001181052	57309666	57309854
ENSE00001181064	57322343	57322483
ENSE00001273531	57301735	57301939
ENSE00001273538	57309151	57309254
ENSE00001273557	57323007	57323260
ENSE00001273561	57323469	57323619
ENSE00001273566	57334465	57334609
ENSE00001368141	57314494	57314631
ENSE00001651018	57421518	57421706
ENSE00001657743	57544197	57544344
ENSE00001801454	57468736	57468979
ENSE00001825636	57462690	57462875
ENSE00001869301	57425022	57425141
ENSE00001936228	57428633	57428821
ENSE00002213735	57523803	57523884
ENSE00002221437	57458099	57458220
ENSE00002221736	57446537	57446689
ENSE00002221864	57501321	57501412
ENSE00002228238	57470443	57470636
ENSE00002231326	57433645	57433828
ENSE00002237726	57433367	57433507
ENSE00002237908	57504016	57504204
ENSE00002241916	57508382	57508540
ENSE00002242801	57453247	57453403
ENSE00002245201	57444697	57444816
ENSE00002249541	57523583	57523609
ENSE00002250069	57445174	57445419
ENSE00002250749	57352085	57352225
ENSE00002252669	57483376	57483511
ENSE00002260362	57415426	57415564
ENSE00002260718	57459592	57459786
ENSE00002266709	57542701	57542903
ENSE00002266753	57472546	57472671
ENSE00002272684	57429691	57429774
ENSE00002280882	57509140	57509212
ENSE00002282782	57419367	57419518
ENSE00002287076	57408280	57408535
ENSE00002287778	57452843	57453015
ENSE00002288299	57404969	57405147
ENSE00002291999	57461489	57461689
ENSE00002292415	57454775	57454894
ENSE00002293793	57502323	57502479
ENSE00002297819	57510790	57510979
ENSE00002299352	57413746	57413912
ENSE00002301713	57457721	57458003
ENSE00002301838	57507643	57507838
ENSE00002302394	57471472	57471606
ENSE00002304775	57436951	57437060
ENSE00002318568	57489509	57489687
ENSE00002319550	57405653	57405952
ENSE00002321163	57446031	57446270
ENSE00003513229	57296847	57296984
ENSE00003533414	57296344	57296435
ENSE00003547191	57295525	57295592
ENSE00003558591	57334782	57334940
ENSE00003713616	57387086	57387219
ENSE00003715264	57380278	57380367
ENSE00003715970	57363594	57363786
ENSE00003716039	57384829	57385005
ENSE00003718959	57394171	57394332
ENSE00003724439	57366729	57366921
ENSE00003729954	57357176	57357348
ENSE00003734800	57376981	57377222
ENSE00003738915	57391872	57392066
ENSE00003739531	57382262	57382393
ENSE00003740540	57379158	57379298
ENSE00003742727	57385349	57385429
ENSE00003746474	57375818	57375965
ENSE00003750957	57368046	57368260
ENSE00003752477	57403309	57403501
ENSE00003753198	57386441	57386603
ENSE00003754460	57375371	57375516
ENSE00003933342	57293700	57293971

Expression profiles

Bgee: expression breadth ubiquitous, 174 present calls, max score 99.45.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.5463 / max 177.5234, expressed in 103 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
42649	0.5174	100
42650	0.0182	9
42648	0.0107	4

Top tissues by expression

252 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
bronchial epithelial cell	CL:0002328	99.45	gold quality
bronchus	UBERON:0002185	98.63	gold quality
right uterine tube	UBERON:0001302	97.65	gold quality
mucosa of paranasal sinus	UBERON:0005030	97.31	gold quality
oviduct epithelium	UBERON:0004804	97.00	gold quality
sperm	CL:0000019	94.47	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	94.20	gold quality
epithelium of nasopharynx	UBERON:0001951	88.90	gold quality
nasopharynx	UBERON:0001728	88.88	gold quality
buccal mucosa cell	CL:0002336	87.74	silver quality
nasal cavity epithelium	UBERON:0005384	86.72	gold quality
secondary oocyte	CL:0000655	86.02	gold quality
fallopian tube	UBERON:0003889	85.30	gold quality
left testis	UBERON:0004533	83.80	gold quality
right testis	UBERON:0004534	83.32	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.48	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.80	gold quality
testis	UBERON:0000473	81.79	gold quality
oocyte	CL:0000023	79.15	gold quality
tibialis anterior	UBERON:0001385	78.71	gold quality
right lung	UBERON:0002167	77.14	gold quality
nasal cavity mucosa	UBERON:0001826	76.84	gold quality
pancreatic ductal cell	CL:0002079	76.17	gold quality
caput epididymis	UBERON:0004358	74.88	gold quality
ileal mucosa	UBERON:0000331	71.18	gold quality
trachea	UBERON:0003126	70.02	gold quality
endothelial cell	CL:0000115	69.77	silver quality
left uterine tube	UBERON:0001303	68.68	gold quality
islet of Langerhans	UBERON:0000006	64.90	gold quality
body of pancreas	UBERON:0001150	63.73	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-ANND-2	yes	3188.60
E-HCAD-15	yes	2138.15
E-CURD-114	yes	1059.74
E-HCAD-1	yes	28.55
E-MTAB-10287	yes	25.29
E-GEOD-130148	yes	13.70
E-MTAB-9388	yes	6.39
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 2)

• We show that EGF relocates to the cell centre in a dynein-dependent fashion, concomitant with the sorting away of transferrin receptor, although it remains in Rab5-positive early endosomes. (PMID:17173037)
• Dynein will initiate translocation of late endosomes to microtubule minus ends only after interacting with betaIII spectrin, which requires the activities of Rab7-RILP and ORP1L. (PMID:17283181)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	dnah12	ENSDARG00000059987
mus_musculus	Dnah12	ENSMUSG00000021879
rattus_norvegicus	Dnah12	ENSRNOG00000059865

Paralogs (15): DNAH9 (ENSG00000007174), DNAH5 (ENSG00000039139), DNAH11 (ENSG00000105877), DNAH1 (ENSG00000114841), DNAH6 (ENSG00000115423), DNAH7 (ENSG00000118997), DNAH8 (ENSG00000124721), DNAH3 (ENSG00000158486), DNHD1 (ENSG00000179532), DNAH2 (ENSG00000183914), DNAH14 (ENSG00000185842), DYNC2H1 (ENSG00000187240), DNAH17 (ENSG00000187775), DYNC1H1 (ENSG00000197102), DNAH10 (ENSG00000197653)

Protein

Protein identifiers

Dynein axonemal heavy chain 12 — Q6ZR08 (reviewed: Q6ZR08)

Alternative names: Axonemal beta dynein heavy chain 12, Axonemal dynein heavy chain 12-like protein, Axonemal dynein heavy chain 7-like protein, Ciliary dynein heavy chain 12, Dynein axonemal heavy chain 7-like, Dynein heavy chain domain-containing protein 2

All UniProt accessions (5): Q6ZR08, E9PG32, H7C5N3, H7C5S4, J3QTM1

UniProt curated annotations — full annotation on UniProt →

Function. Involved in spermiogenesis. Plays a role in the proper organization of axoneme in sperm flagella, but not in cilia, by recruiting DNAH1 and DNALI1 to flagellum.

Subunit / interactions. Consists of at least two heavy chains and a number of intermediate and light chains. Interacts (via the stem region) with DNALI1. Interacts with DNAH1. Interacts with radial spoke-associated proteins DNAJB13, RSPH1 and RSPH9.

Subcellular location. Cell projection. Cilium. Flagellum.

Tissue specificity. Detected in sperm (at protein level).

Disease relevance. Spermatogenic failure 100 (SPGF100) [MIM:621209] An autosomal recessive, male infertility disorder characterized by asthenoteratozoospermia with reduced sperm progressive motility, and multiple morphologic abnormalities of the sperm flagella. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Dynein heavy chains probably consist of an N-terminal stem (which binds cargo and interacts with other dynein components), and the head or motor domain. The motor contains six tandemly-linked AAA domains in the head, which form a ring. A stalk-like structure (formed by two of the coiled coil domains) protrudes between AAA 4 and AAA 5 and terminates in a microtubule-binding site. A seventh domain may also contribute to this ring; it is not clear whether the N-terminus or the C-terminus forms this extra domain. There are four well-conserved and two non-conserved ATPase sites, one per AAA domain. Probably only one of these (within AAA 1) actually hydrolyzes ATP, the others may serve a regulatory function.

Similarity. Belongs to the dynein heavy chain family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q6ZR08-1	1	yes
Q6ZR08-4	4
Q6ZR08-2	2
Q6ZR08-3	3

RefSeq proteins (2): NP_001352957, NP_940966 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003593	AAA+_ATPase	Domain
IPR004273	Dhc_D6_P-loop	Domain
IPR013602	Dhc_linker	Domain
IPR024317	Dhc_D4	Domain
IPR026983	DHC	Family
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR035699	Dhc_AAA	Domain
IPR041228	Dhc_C	Domain
IPR041466	Dhc_AAA5_ext	Domain
IPR041589	DNAH3_AAA_lid_1	Domain
IPR041658	AAA_lid_11	Domain
IPR042219	AAA_lid_11_sf	Homologous_superfamily
IPR042222	Dynein_2_N	Homologous_superfamily
IPR042228	Dynein_linker_3	Homologous_superfamily
IPR043157	Dynein_AAA1S	Homologous_superfamily
IPR043160	Dynein_C_barrel	Homologous_superfamily

Pfam: PF03028, PF08393, PF12774, PF12775, PF12780, PF17852, PF17857, PF18198, PF18199

UniProt features (48 total): sequence variant 21, region of interest 7, splice variant 7, binding site 4, sequence conflict 4, short sequence motif 2, coiled-coil region 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

No AlphaFold model available for Q6ZR08 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (4): 1253–1260; 1534–1541; 1892–1899; 2257–2264

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 115 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, GOBP_MALE_GAMETE_GENERATION, GOBP_AXONEMAL_DYNEIN_COMPLEX_ASSEMBLY, SENGUPTA_NASOPHARYNGEAL_CARCINOMA_DN, GOBP_CILIUM_ORGANIZATION, GOBP_CILIUM_MOVEMENT, GOMF_CYTOSKELETAL_MOTOR_ACTIVITY, GOBP_CILIUM_OR_FLAGELLUM_DEPENDENT_CELL_MOTILITY, GOBP_ORGANELLE_ASSEMBLY, GOBP_CELLULAR_PROCESS_INVOLVED_IN_REPRODUCTION_IN_MULTICELLULAR_ORGANISM, GOBP_MICROTUBULE_BUNDLE_FORMATION, MYB_Q3, BASAKI_YBX1_TARGETS_DN, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, GOBP_MOTILE_CILIUM_ASSEMBLY

GO Biological Process (6): spermatid development (GO:0007286), sperm axoneme assembly (GO:0007288), axonemal dynein complex assembly (GO:0070286), cilium movement (GO:0003341), microtubule-based movement (GO:0007018), inner dynein arm assembly (GO:0036159)

GO Molecular Function (6): ATP binding (GO:0005524), minus-end-directed microtubule motor activity (GO:0008569), dynein intermediate chain binding (GO:0045505), dynein light intermediate chain binding (GO:0051959), nucleotide binding (GO:0000166), ATP hydrolysis activity (GO:0016887)

GO Cellular Component (10): axonemal dynein complex (GO:0005858), microtubule (GO:0005874), sperm flagellum (GO:0036126), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), cilium (GO:0005929), dynein complex (GO:0030286), motile cilium (GO:0031514), inner dynein arm (GO:0036156), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
axoneme assembly	2
protein binding	2
cellular anatomical structure	2
germ cell development	1
spermatid differentiation	1
developmental process involved in reproduction	1
sperm flagellum assembly	1
protein-containing complex assembly	1
microtubule-based movement	1
microtubule-based process	1
axonemal dynein complex assembly	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
microtubule motor activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
ribonucleoside triphosphate phosphatase activity	1
ATP-dependent activity	1
axoneme	1
dynein complex	1
microtubule cytoskeleton	1
polymeric cytoskeletal fiber	1
9+2 motile cilium	1
intracellular anatomical structure	1
intracellular membraneless organelle	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
microtubule associated complex	1
catalytic complex	1
cilium	1
axonemal dynein complex	1

Protein interactions and networks

STRING

1243 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DNAH12	DNAH1	Q9P2D7	954
DNAH12	DNAH6	Q9C0G6	953
DNAH12	M9MMK7	M9MMK7	919
DNAH12	DNAH5	Q8TE73	860
DNAH12	DNAH9	Q9NYC9	590
DNAH12	DNAH2	Q9P225	580
DNAH12	DNAI2	Q9GZS0	579
DNAH12	DNAI1	Q9UI46	571
DNAH12	DLGAP4	Q9Y2H0	545
DNAH12	DNAAF1	Q8NEP3	534
DNAH12	DNALI1	O14645	529
DNAH12	DYNC2H1	Q8NCM8	508
DNAH12	CCDC40	Q4G0X9	500
DNAH12	DNAH10	Q8IVF4	479
DNAH12	DNAAF6	Q9NQM4	470

IntAct

5 interactions, top by confidence:

A	B	Type	Score
DNAH12	OCIAD2	psi-mi:“MI:0915”(physical association)	0.400
P		psi-mi:“MI:0914”(association)	0.350
MAK	CNOT1	psi-mi:“MI:0914”(association)	0.350
COQ8B	DNAJB6	psi-mi:“MI:0914”(association)	0.350

BioGRID (20): DNAH12 (Affinity Capture-MS), DNAH12 (Proximity Label-MS), DNAH12 (Proximity Label-MS), DNAH12 (Affinity Capture-MS), DNAH12 (Affinity Capture-MS), DNAH12 (Proximity Label-MS), DNAH12 (Affinity Capture-MS), DNAH12 (Affinity Capture-MS), DNAH12 (Affinity Capture-MS), DNAH12 (Affinity Capture-MS), DNAH12 (Affinity Capture-MS), DNAH12 (Affinity Capture-MS), GAPDH (Cross-Linking-MS (XL-MS)), PPIA (Cross-Linking-MS (XL-MS)), DNAH12 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A1B0GVH7, A2RRP1, D3YVL2, E9Q8T7, O55007, O88480, P0C6F1, P37276, P38650, Q0KK59, Q14204, Q3UHQ6, Q3UMB5, Q3V0Q1, Q4R7B1, Q5R414, Q5SQX6, Q5T0N1, Q5ZLS8, Q63164, Q63170, Q642P2, Q69Z23, Q6GYP7, Q6GYQ0, Q6ZR08, Q7L576, Q7TMB8, Q8BW94, Q8IVF4, Q8K2A7, Q8TD57, Q8TDY2, Q8TEV9, Q8WVF1, Q8WXX0, Q91XQ0, Q923J6, Q95LN2, Q96F07

Diamond homologs: E9Q8T7, F1SC07, M0R8U1, P0C6F1, P23098, P39057, Q39565, Q39575, Q39610, Q3V0Q1, Q63164, Q63170, Q69Z23, Q6ZR08, Q8BW94, Q8IVF4, Q8TD57, Q8TE73, Q8VHE6, Q8WXX0, Q91XQ0, Q923J6, Q96DT5, Q96JB1, Q9C0G6, Q9MBF8, Q9NYC9, Q9P225, Q9P2D7, Q9SMH3, Q9UFH2, P34036, P36022, P37276, P38650, P45443, P45444, P78716, Q14204, Q19020

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

520 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	0
Uncertain significance	457
Likely benign	18
Benign	15

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
3899930	NM_001366028.2(DNAH12):c.4166C>T (p.Pro1389Leu)	Pathogenic
3899931	NM_001366028.2(DNAH12):c.6533C>G (p.Ser2178Ter)	Pathogenic
3899932	DNAH12, GLN2077TER	Pathogenic
3899933	DNAH12, ARG3002CYS	Pathogenic
3899934	DNAH12, ILE816MET	Pathogenic
3899935	DNAH12, IVS, G-C, -1	Pathogenic
3899936	DNAH12, IVS, G-A, +5	Pathogenic
3899937	DNAH12, 2-BP DEL, 944TT	Pathogenic

SpliceAI

10449 predictions. Top by Δscore:

Variant	Effect	Δscore
3:57293973:T:C	acceptor_gain	1.0000
3:57293973:T:TC	acceptor_gain	1.0000
3:57295523:A:AC	donor_gain	1.0000
3:57295524:C:CC	donor_gain	1.0000
3:57295591:CA:C	acceptor_gain	1.0000
3:57295593:C:CC	acceptor_gain	1.0000
3:57296339:CTGA:C	donor_loss	1.0000
3:57296340:TGACC:T	donor_loss	1.0000
3:57296341:GACC:G	donor_loss	1.0000
3:57296342:A:T	donor_loss	1.0000
3:57296343:C:CA	donor_loss	1.0000
3:57309149:A:AC	donor_gain	1.0000
3:57309150:C:CC	donor_gain	1.0000
3:57309255:C:CC	acceptor_gain	1.0000
3:57309859:C:CT	acceptor_gain	1.0000
3:57309860:A:T	acceptor_gain	1.0000
3:57322347:T:A	donor_gain	1.0000
3:57322484:C:CC	acceptor_gain	1.0000
3:57323467:ACTGG:A	donor_gain	1.0000
3:57323468:CTGGC:C	donor_gain	1.0000
3:57405016:A:AC	donor_gain	1.0000
3:57405147:CC:C	acceptor_loss	1.0000
3:57405733:A:C	donor_gain	1.0000
3:57408409:A:AC	donor_gain	1.0000
3:57408410:C:CC	donor_gain	1.0000
3:57419385:AAAT:A	donor_gain	1.0000
3:57421681:C:CT	acceptor_gain	1.0000
3:57421682:A:T	acceptor_gain	1.0000
3:57433506:CA:C	acceptor_gain	1.0000
3:57433508:C:CC	acceptor_gain	1.0000

AlphaMissense

26229 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:57323029:A:G	L2586P	1.000
3:57323033:A:G	W2585R	1.000
3:57323033:A:T	W2585R	1.000
3:57323138:A:G	W2550R	1.000
3:57323138:A:T	W2550R	1.000
3:57428806:G:T	R1671S	1.000
3:57428807:A:C	S1670R	1.000
3:57428807:A:T	S1670R	1.000
3:57428809:T:G	S1670R	1.000
3:57428817:G:T	A1667D	1.000
3:57429760:A:C	S1642R	1.000
3:57429760:A:T	S1642R	1.000
3:57429762:T:G	S1642R	1.000
3:57429767:A:G	L1640P	1.000
3:57429773:A:G	L1638P	1.000
3:57433381:C:G	D1633H	1.000
3:57433391:G:C	N1629K	1.000
3:57433391:G:T	N1629K	1.000
3:57433408:A:G	W1624R	1.000
3:57433408:A:T	W1624R	1.000
3:57433441:A:G	W1613R	1.000
3:57433441:A:T	W1613R	1.000
3:57433505:C:A	W1591C	1.000
3:57433505:C:G	W1591C	1.000
3:57433507:A:G	W1591R	1.000
3:57433507:A:T	W1591R	1.000
3:57433670:C:T	G1582E	1.000
3:57446035:A:G	L1369P	1.000
3:57446073:A:C	N1356K	1.000
3:57446073:A:T	N1356K	1.000

dbSNP variants (sampled 300 via entrez): RS1000013510 (3:57402456 A>C,G), RS1000037265 (3:57359013 A>G), RS1000046305 (3:57514446 A>G), RS1000046472 (3:57354305 G>C), RS1000050778 (3:57527801 T>C), RS1000051546 (3:57484449 T>A,C), RS1000092494 (3:57395967 T>A), RS1000092885 (3:57322878 C>A,T), RS1000098453 (3:57353948 G>A,T), RS1000098509 (3:57434851 A>G), RS1000114477 (3:57376690 T>A,C), RS1000130430 (3:57371668 C>T), RS1000130881 (3:57488881 A>G), RS1000150867 (3:57434605 A>T), RS1000165466 (3:57376338 G>A,C)

Disease associations

OMIM: gene MIM:603340 | disease phenotypes: MIM:614111, MIM:621209

GenCC curated gene-disease

Disease	Classification	Inheritance
oligoasthenoteratozoospermia	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
spermatogenic failure	Definitive	AR

Mondo (4): pyruvate dehydrogenase E1-beta deficiency (MONDO:0013580), spermatogenic failure 100 (MONDO:0978302), megacolon (MONDO:0001273), oligoasthenoteratozoospermia (MONDO:0850098)

Orphanet (2): Pyruvate dehydrogenase E1-beta deficiency (Orphanet:255138), Pyruvate dehydrogenase deficiency (Orphanet:765)

HPO phenotypes

12 total (12 of 12 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000798	Oligozoospermia
HP:0003251	Male infertility
HP:0011462	Young adult onset
HP:0012207	Reduced sperm motility
HP:0032558	Absent sperm flagella
HP:0032559	Short sperm flagella
HP:0032560	Coiled sperm flagella
HP:0033393	Irregularly shaped sperm tail
HP:0034011	Reduced progressive sperm motility
HP:0034811	Bent sperm flagella
HP:6000135	Low semen volume

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST006481_15	Lung function (FEV1)	5.000000e-09
GCST006481_39	Lung function (FEV1)	8.000000e-07
GCST008892_3	Working memory	1.000000e-06
GCST90000025_943	Appendicular lean mass	3.000000e-09
GCST90002394_245	Monocyte percentage of white cells	3.000000e-11

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004314	forced expiratory volume
EFO:0004335	short-term memory
EFO:0004980	appendicular lean mass
EFO:0007989	monocyte percentage of leukocytes

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008531	Megacolon	C06.405.469.158.701
C566729	Pyruvate Dehydrogenase E1-Beta Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066282 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs112830684	DNAH12		0.00	0

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.13	Kd	7.34	nM	CHEMBL5653589
7.75	ED50	17.58	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148246: Binding affinity to human DNAH12 incubated for 45 mins by Kinobead based pull down assay	kd	0.0073	uM

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, decreases methylation, increases methylation, affects methylation	4
sodium arsenite	decreases expression, increases expression	2
Tobacco Smoke Pollution	decreases expression	2
methyleugenol	decreases expression	1
propionaldehyde	increases expression	1
2,3-pentanedione	decreases expression	1
beta-lapachone	decreases expression	1
2-amino-9H-pyrido(2,3-b)indole	decreases expression	1
butyraldehyde	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
pentanal	increases expression	1
tebuconazole	increases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
quinocetone	increases expression	1
bisphenol S	decreases methylation	1
theaflavin-3,3’-digallate	affects expression	1
Air Pollutants	increases abundance, increases expression	1
Aldehydes	increases expression	1
Diacetyl	decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Lipopolysaccharides	affects response to substance, increases expression, affects cotreatment	1
Phthalic Acids	decreases methylation	1
Smoke	increases abundance, increases expression	1
Valproic Acid	decreases expression	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	decreases expression	1
Okadaic Acid	decreases expression	1
Acrylamide	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651288	Binding	Binding affinity to human DNAH12 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

9 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT07579858	PHASE3	COMPLETED	PRP Improves Blastocyst Formation in ICSI Cycles
NCT05200663	PHASE2	UNKNOWN	Efficacy Comparison of Tamoxifen and Tamoxifen With Antioxidants on Semen Quality of Male With Idiopathic Infertility
NCT02752555	Not specified	UNKNOWN	Severe Male Factor Infertility Management
NCT06088693	Not specified	COMPLETED	The Role of Electroacupuncture With Standard Therapy on Sperm Analysis and SOD Levels in Oligozoospermia.
NCT07286279	Not specified	COMPLETED	Identifying Candidates for Limited Dissection at Microdissection TESE.
NCT07345455	Not specified	RECRUITING	Probiotics on Sperm Quality in Male Infertility Patients
NCT05257005	Not specified	UNKNOWN	Natural History Study of Pyruvate Dehydrogenase Deficiency
NCT04340856	Not specified	COMPLETED	Retrospective, Uncontrolled Cohort Study on the Therapy of Chronic Megalon
NCT07470892	Not specified	NOT_YET_RECRUITING	Preoperative Fish Oil PN and Prognosis After Constipation Surgery