DMRT1

Summary

DMRT1 (doublesex and mab-3 related transcription factor 1, HGNC:2934) is a protein-coding gene on chromosome 9p24.3, encoding Doublesex- and mab-3-related transcription factor 1 (Q9Y5R6). Transcription factor that plays a key role in male sex determination and differentiation by controlling testis development and male germ cell proliferation.

This gene is found in a cluster with two other members of the gene family, having in common a zinc finger-like DNA-binding motif (DM domain). The DM domain is an ancient, conserved component of the vertebrate sex-determining pathway that is also a key regulator of male development in flies and nematodes. This gene exhibits a gonad-specific and sexually dimorphic expression pattern. Defective testicular development and XY feminization occur when this gene is hemizygous.

Source: NCBI Gene 1761 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spermatogenic failure (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 17
• Clinical variants (ClinVar): 200 total — 13 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 4
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_021951

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2934
Approved symbol	DMRT1
Name	doublesex and mab-3 related transcription factor 1
Location	9p24.3
Locus type	gene with protein product
Status	Approved
Aliases	DMT1, CT154
Ensembl gene	ENSG00000137090
Ensembl biotype	protein_coding
OMIM	602424
Entrez	1761

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 retained_intron

ENST00000382276, ENST00000564322, ENST00000569227

RefSeq mRNA: 2 — MANE Select: NM_021951 NM_001363767, NM_021951

CCDS: CCDS6442, CCDS87636

Canonical transcript exons

ENST00000382276 — 5 exons

Exon	Start	End
ENSE00000681836	893912	894195
ENSE00000812987	916763	916907
ENSE00001491530	967985	969090
ENSE00003458315	841697	842192
ENSE00003599359	846960	847143

Expression profiles

Bgee: expression breadth broad, 23 present calls, max score 93.06.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0965 / max 80.7442, expressed in 7 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
95806	0.0544	5
95807	0.0142	3
95808	0.0105	3
95805	0.0087	3
95809	0.0087	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	93.06	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.19	gold quality
buccal mucosa cell	CL:0002336	88.73	gold quality
right testis	UBERON:0004534	87.21	gold quality
testis	UBERON:0000473	86.72	gold quality
left testis	UBERON:0004533	85.62	gold quality
adult organism	UBERON:0007023	85.51	gold quality
secondary oocyte	CL:0000655	61.32	gold quality
choroid plexus epithelium	UBERON:0003911	60.59	silver quality
oocyte	CL:0000023	59.23	gold quality
cartilage tissue	UBERON:0002418	59.13	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	55.73	gold quality
tibia	UBERON:0000979	55.41	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
hair follicle	UBERON:0002073	49.18	gold quality
quadriceps femoris	UBERON:0001377	49.14	gold quality
oviduct epithelium	UBERON:0004804	49.03	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
myocardium	UBERON:0002349	48.87	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality
nasal cavity mucosa	UBERON:0001826	48.80	gold quality
vastus lateralis	UBERON:0001379	48.65	gold quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
CA1 field of hippocampus	UBERON:0003881	48.50	gold quality
left ventricle myocardium	UBERON:0006566	48.24	gold quality
orbitofrontal cortex	UBERON:0004167	48.20	gold quality
epithelial cell of pancreas	CL:0000083	48.08	gold quality
upper arm skin	UBERON:0004263	48.06	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.10

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

9 targets.

Target	Regulation
CYP11B2
CYP19A1
DMRT1
HSD3B2
NR5A1
PRG4
SLC11A2
SOHLH1	Activation
STRA8	Repression

Upstream regulators (CollecTRI, top): DMRT1, EGR1, FOXL2, SOX17, SOX5, SP1, SP3

miRNA regulators (miRDB)

77 targeting DMRT1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-10393-5P	99.65	68.01	1368

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 21)

• Comparison of genomic and mRNA sequences show that DMRT1b and c result from exonization of intronic sequences, including the exonization of an Alu element. All 99 Alu elements are non-randomly distributed among the non-coding regions on both directions. (PMID:16617334)
• Analysis of germ cell tumors reveals gene expression changes correlated to DMRT1 levels. (PMID:20007774)
• Studies identified three new susceptibility loci DMRT1, TERT and ATF7IP associated with testicular germ cell cancer. (PMID:20543847)
• Chromosome 9p loss is the hallmark of squamous cell carcinoma, and DMRT1, DMRT3 and DOCK8 genes at 9p24.3 might be of interest for the study of the pathophysiology of SCC as potential targets for therapeutic measures. (PMID:20596660)
• There is evidence that DMT1 expression and function respond rapidly to changes in dietary iron content (PMID:21462105)
• Findings continue to corroborate that genes influencing male germ cell development and differentiation have emerged as the major players in inherited TGCT susceptibility. (PMID:21551455)
• variants in or near BAK1, DMRT1, TERT-CLPTM1L, and KITLG predispose to familial and bilateral TGCT. (PMID:21617256)
• The biological importance of the changes in expression of DMRT1 in Sertoli cells remains to be established, but it is consistent with DMRT1 reinforcing the inhibition of meiosis in the testis. (PMID:22899867)
• neither DMRT1 nor FGF9 abnormalities are frequently involved in dysgenetic male gonad development in patients with non-syndromic 46,XY disorder of sex development. (PMID:22939835)
• Meiosis signalling is dysregulated in carcinoma in situ (CIS) cells and that a key regulator of the mitosis-meiosis switch, DMRT1, is expressed in ’early-stage’ CIS cells but is down-regulated with further invasive transformation. (PMID:23303528)
• The combined results indicate that DMRT1 loss-of-function mutations are a risk factor and potential genetic cause of human spermatogenic failure (PMID:23555275)
• Point mutations of DMRT1 may be rarely associated with male infertility. (PMID:24934491)
• The role of DMT1 in mitochondrial iron acquisition by immunofluorescence with mitochondrial markers in cells and isolated mitochondria, as well as flow cytometric quantification of DMT1-positive mitochondria from an inducible expression system. (PMID:25483589)
• These show that DMRT proteins use a unique binding interaction, inserting two adjacent antiparallel recognition helices into a widened DNA major groove to make base-specific contacts. (PMID:26005864)
• The results suggest a role of changes in DMRT1 dosage in non-obstructive azoospermia potentially also through a process of gene misregulation, even though DMRT1 deleterious variants seem to be rare. (PMID:26139570)
• DMRT1 might influence sex-specific patterns of childhood asthma, and its expression in testis tissue and lung macrophages suggests a potential involvement in hormone or immune cell regulation. (PMID:26906082)
• Report differential expression of DMRT1 in normal human spermatogenesis, testicular mixed germ cell-sex cord stromal tumor, spermatocytic tumor, and seminoma. (PMID:30067948)
• DMRT1 is required for testicular differentiation in humans. DMRT1 repression results in alterations in expression of key genes involved in gonadal development. Repression of DMRT1 results in focal dysgenesis in the human fetal testis (PMID:30272154)
• Functional assessment of DMRT1 variants and their pathogenicity for isolated male infertility. (PMID:36572623)
• DMRT1 regulates human germline commitment. (PMID:37709822)
• Diversity of transactivation regions of DMRT1 in vertebrates. (PMID:39432160)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	dmrt1	ENSDARG00000007349
mus_musculus	Dmrt1	ENSMUSG00000024837
rattus_norvegicus	Dmrt1	ENSRNOG00000016075
caenorhabditis_elegans		WBGENE00019521
caenorhabditis_elegans		WBGENE00022060

Paralogs (8): DMRT3 (ENSG00000064218), DMRTC2 (ENSG00000142025), DMRTA2 (ENSG00000142700), DMRTB1 (ENSG00000143006), DMRT2 (ENSG00000173253), DMRTA1 (ENSG00000176399), DMRTC1B (ENSG00000184911), DMRTC1 (ENSG00000269502)

Protein

Protein identifiers

Doublesex- and mab-3-related transcription factor 1 — Q9Y5R6 (reviewed: Q9Y5R6)

Alternative names: DM domain expressed in testis protein 1

All UniProt accessions (2): Q9Y5R6, H3BN61

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that plays a key role in male sex determination and differentiation by controlling testis development and male germ cell proliferation. Plays a central role in spermatogonia by inhibiting meiosis in undifferentiated spermatogonia and promoting mitosis, leading to spermatogonial development and allowing abundant and continuous production of sperm. Acts both as a transcription repressor and activator: prevents meiosis by restricting retinoic acid (RA)-dependent transcription and repressing STRA8 expression and promotes spermatogonial development by activating spermatogonial differentiation genes, such as SOHLH1. Also plays a key role in postnatal sex maintenance by maintaining testis determination and preventing feminization: represses transcription of female promoting genes such as FOXL2 and activates male-specific genes. May act as a tumor suppressor. May also play a minor role in oogenesis.

Subcellular location. Nucleus.

Tissue specificity. Testis-specific. Expressed in prostate cancer (at protein level).

Disease relevance. Testicular germ cell tumor (TGCT) [MIM:273300] A common malignancy in males representing 95% of all testicular neoplasms. TGCTs have various pathologic subtypes including: unclassified intratubular germ cell neoplasia, seminoma (including cases with syncytiotrophoblastic cells), spermatocytic seminoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, and teratoma. The disease may be caused by variants affecting the gene represented in this entry. 46,XY sex reversal 4 (SRXY4) [MIM:154230] A condition characterized by male-to-female sex reversal in the presence of a normal 46,XY karyotype. Patients display complete or partial gonadal dysgenesis and a chromosome 9p deletion. The disease may be caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the DMRT family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9Y5R6-1	1, DMRT1a	yes
Q9Y5R6-2	2, DMRT1b
Q9Y5R6-3	3, DMRT1c

RefSeq proteins (2): NP_001350696, NP_068770* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001275	DM_DNA-bd	Domain
IPR022114	DMRT1-like	Family
IPR026607	DMRT	Family
IPR036407	DM_DNA-bd_sf	Homologous_superfamily

Pfam: PF00751, PF12374

UniProt features (17 total): splice variant 4, sequence variant 4, compositionally biased region 4, region of interest 2, chain 1, DNA-binding region 1, modified residue 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4YJ0	X-RAY DIFFRACTION	3.81

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y5R6-F1	57.76	0.16

Functional residue map

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

Post-translational modifications (1): 339

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9690406	Transcriptional regulation of testis differentiation

MSigDB gene sets: 183 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, GOBP_POSITIVE_REGULATION_OF_MITOTIC_NUCLEAR_DIVISION, E2F_Q4_01, GOBP_NEGATIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_POSITIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_EPITHELIUM_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_REGULATION_OF_NUCLEAR_DIVISION, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOBP_REGULATION_OF_MEIOTIC_NUCLEAR_DIVISION, AAGCCAT_MIR135A_MIR135B, GOBP_SERTOLI_CELL_DEVELOPMENT, GOBP_MALE_SEX_DETERMINATION, GOBP_OOGENESIS, MODULE_511

GO Biological Process (24): negative regulation of transcription by RNA polymerase II (GO:0000122), cell morphogenesis (GO:0000902), male germ cell proliferation (GO:0002176), regulation of transcription by RNA polymerase II (GO:0006357), meiosis I (GO:0007127), spermatogenesis (GO:0007283), sex differentiation (GO:0007548), primordial germ cell migration (GO:0008354), male sex determination (GO:0030238), intracellular signal transduction (GO:0035556), negative regulation of meiotic nuclear division (GO:0045835), positive regulation of mitotic nuclear division (GO:0045840), positive regulation of transcription by RNA polymerase II (GO:0045944), male sex differentiation (GO:0046661), oocyte development (GO:0048599), Sertoli cell differentiation (GO:0060008), Sertoli cell development (GO:0060009), positive regulation of meiosis I (GO:0060903), regulation of nodal signaling pathway (GO:1900107), positive regulation of male gonad development (GO:2000020), developmental process involved in reproduction (GO:0003006), regulation of DNA-templated transcription (GO:0006355), male gonad development (GO:0008584), cell differentiation (GO:0030154)

GO Molecular Function (11): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), cis-regulatory region sequence-specific DNA binding (GO:0000987), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), chromatin binding (GO:0003682), identical protein binding (GO:0042802), metal ion binding (GO:0046872), sequence-specific double-stranded DNA binding (GO:1990837), RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA binding (GO:0003677), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (4): chromatin (GO:0000785), female germ cell nucleus (GO:0001674), nucleus (GO:0005634), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
developmental process involved in reproduction	4
regulation of transcription by RNA polymerase II	3
transcription by RNA polymerase II	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
meiotic nuclear division	2
multicellular organism development	2
intracellular anatomical structure	2
male gonad development	2
transcription cis-regulatory region binding	2
cellular anatomical structure	2
negative regulation of DNA-templated transcription	1
anatomical structure morphogenesis	1
germ cell proliferation	1
regulation of DNA-templated transcription	1
meiotic telophase I	1
meiosis I cell cycle process	1
male gamete generation	1
gamete generation	1
cell migration	1
sex determination	1
signal transduction	1
negative regulation of cell cycle process	1
regulation of meiotic nuclear division	1
negative regulation of meiotic cell cycle	1
negative regulation of nuclear division	1
regulation of mitotic nuclear division	1
positive regulation of nuclear division	1
positive regulation of cell cycle process	1
mitotic nuclear division	1
positive regulation of DNA-templated transcription	1
sex differentiation	1
germ cell development	1
oocyte differentiation	1
epithelial cell differentiation	1
epithelial cell development	1
Sertoli cell differentiation	1
meiosis I	1
positive regulation of meiotic nuclear division	1
regulation of meiosis I	1
regulation of activin receptor signaling pathway	1

Protein interactions and networks

STRING

1496 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DMRT1	KANK1	Q14678	916
DMRT1	SRY	Q05066	912
DMRT1	SOX3	P35714	885
DMRT1	AMH	P03971	847
DMRT1	DOCK8	Q8NF50	846
DMRT1	SOX9	P48436	841
DMRT1	FOXL2	P58012	833
DMRT1	ATF7IP	Q6VMQ6	777
DMRT1	NR0B1	P51843	732
DMRT1	CYP19A1	P11511	718
DMRT1	CLPTM1L	Q96KA5	717
DMRT1	NR5A1	Q13285	702
DMRT1	KITLG	P21583	685
DMRT1	STRA8	Q7Z7C7	674
DMRT1	NANOS2	P60321	659

IntAct

9 interactions, top by confidence:

A	B	Type	Score
DMRT1	DMRT1	psi-mi:“MI:0407”(direct interaction)	0.610
DMRT1	DMRT1	psi-mi:“MI:0915”(physical association)	0.610
DMRT1	Dlg4	psi-mi:“MI:0407”(direct interaction)	0.440
DMRT1	TRIM29	psi-mi:“MI:0915”(physical association)	0.370
DMRT1	ATE1	psi-mi:“MI:0914”(association)	0.350
SLC26A1	CLGN	psi-mi:“MI:0914”(association)	0.350
SLC39A14	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (8): NANOS3 (Phenotypic Enhancement), MECR (Affinity Capture-MS), PIEZO1 (Affinity Capture-MS), ATE1 (Affinity Capture-MS), TRIM68 (Affinity Capture-MS), DMRT1 (Affinity Capture-MS), DMRT1 (Affinity Capture-MS), TRIM29 (Two-hybrid)

ESM2 similar proteins: A1XSY8, O08656, O43474, P08046, P08151, P08152, P08154, P09022, P09027, P10070, P11161, P13360, P15976, P17679, P18146, P19544, P22561, P26632, P26633, P31249, P40656, P43300, P43301, P43429, P46153, P47806, P49639, P49952, P50476, P51774, Q05159, Q06889, Q07424, Q08427, Q0VGT2, Q29W20, Q60793, Q61169, Q6NW96, Q6P0J3

Diamond homologs: A2A9A2, A2A9I7, A4QNP7, A6QQ94, A8TSS9, B0I1G7, B7ZS42, C0LZJ1, D4A218, F6W2R2, G5EEJ1, J7FCF0, O18214, P23023, P57690, P83758, P85119, Q18248, Q19291, Q2I327, Q2MJB4, Q32LE6, Q3LH63, Q4AE28, Q5UU75, Q5VZB9, Q6YHU8, Q71MM5, Q76L87, Q801F8, Q80WT2, Q8BG36, Q8CFG4, Q8CGW9, Q8IXT2, Q8JIR6, Q90WM5, Q96MA1, Q96SC8, Q9DFI0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	13
Likely pathogenic	9
Uncertain significance	105
Likely benign	30
Benign	38

Top pathogenic / likely-pathogenic (22)

Variant ID	HGVS	Classification
144708	GRCh38/hg38 9p24.3-24.2(chr9:204193-4210335)x1	Pathogenic
147488	GRCh38/hg38 9p24.3(chr9:204193-1592365)x1	Pathogenic
148184	GRCh38/hg38 9p24.3-24.2(chr9:204104-3367760)x1	Pathogenic
148849	GRCh38/hg38 9p24.3-24.2(chr9:204104-3755031)x1	Pathogenic
1527474	GRCh37/hg19 9p24.3-24.2(chr9:203861-3226591)	Pathogenic
154196	GRCh38/hg38 9p24.3-24.2(chr9:203861-4585050)x1	Pathogenic
154563	GRCh38/hg38 9p24.3-24.2(chr9:266045-3346702)x1	Pathogenic
395051	GRCh37/hg19 9p24.3-24.2(chr9:213161-3497920)x1	Pathogenic
4279409	GRCh37/hg19 9p24.3-24.2(chr9:203862-4420171)x1	Pathogenic
57352	GRCh38/hg38 9p24.3-24.2(chr9:220253-3793376)x1	Pathogenic
59066	GRCh38/hg38 9p24.3-24.2(chr9:280255-3905421)x1	Pathogenic
689070	GRCh37/hg19 9p24.3-24.2(chr9:203861-2978707)x1	Pathogenic
983185	GRCh37/hg19 9p24.3-24.2(chr9:204090-2430905)x1	Pathogenic
1244251	NM_021951.3(DMRT1):c.344T>A (p.Met115Lys)	Likely pathogenic
2673165	NM_021951.3(DMRT1):c.315C>G (p.Cys105Trp)	Likely pathogenic
2690943	NM_021951.3(DMRT1):c.395G>A (p.Gly132Asp)	Likely pathogenic
2690944	NM_021951.3(DMRT1):c.425C>T (p.Ala142Val)	Likely pathogenic
2690945	NM_021951.3(DMRT1):c.982A>G (p.Ser328Gly)	Likely pathogenic
3376120	NM_021951.3(DMRT1):c.968-11_977del	Likely pathogenic
3376121	NM_021951.3(DMRT1):c.879C>G (p.Tyr293Ter)	Likely pathogenic
3376122	NM_021951.3(DMRT1):c.146dup (p.Ser50fs)	Likely pathogenic
393463	NM_021951.3(DMRT1):c.332G>T (p.Arg111Met)	Likely pathogenic

SpliceAI

1328 predictions. Top by Δscore:

Variant	Effect	Δscore
9:846954:TTCCA:T	acceptor_loss	1.0000
9:846955:TCCA:T	acceptor_loss	1.0000
9:846956:CCAGG:C	acceptor_loss	1.0000
9:846957:CA:C	acceptor_loss	1.0000
9:846958:A:AC	acceptor_loss	1.0000
9:846959:G:GT	acceptor_loss	1.0000
9:893905:A:AG	acceptor_gain	1.0000
9:893906:A:G	acceptor_gain	1.0000
9:893908:TTA:T	acceptor_loss	1.0000
9:893910:A:AG	acceptor_gain	1.0000
9:893910:A:T	acceptor_loss	1.0000
9:893910:AGAG:A	acceptor_gain	1.0000
9:893910:AGAGG:A	acceptor_gain	1.0000
9:893911:G:GA	acceptor_gain	1.0000
9:893911:GA:G	acceptor_gain	1.0000
9:893911:GAGG:G	acceptor_gain	1.0000
9:893911:GAGGG:G	acceptor_gain	1.0000
9:916757:A:AG	acceptor_gain	1.0000
9:916758:A:AG	acceptor_gain	1.0000
9:916759:G:GG	acceptor_gain	1.0000
9:916759:GCA:G	acceptor_gain	1.0000
9:916761:A:AG	acceptor_gain	1.0000
9:916762:G:GG	acceptor_gain	1.0000
9:916874:G:GT	donor_gain	1.0000
9:916892:G:GT	donor_gain	1.0000
9:916903:GAGCG:G	donor_gain	1.0000
9:916905:GCG:G	donor_gain	1.0000
9:916908:G:GA	donor_loss	1.0000
9:916908:G:GG	donor_gain	1.0000
9:916909:TAGG:T	donor_loss	1.0000

AlphaMissense

2444 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:842077:G:T	R80M	1.000
9:842170:G:T	R111M	1.000
9:846967:T:C	L121P	1.000
9:846973:G:T	R123M	1.000
9:846974:G:C	R123S	1.000
9:846974:G:T	R123S	1.000
9:842073:T:A	C79S	0.999
9:842073:T:C	C79R	0.999
9:842074:G:C	C79S	0.999
9:842077:G:C	R80T	0.999
9:842078:G:C	R80S	0.999
9:842078:G:T	R80S	0.999
9:842081:C:A	N81K	0.999
9:842081:C:G	N81K	0.999
9:842084:C:A	H82Q	0.999
9:842084:C:G	H82Q	0.999
9:842101:T:A	L88H	0.999
9:842105:G:C	K89N	0.999
9:842105:G:T	K89N	0.999
9:842114:G:C	K92N	0.999
9:842114:G:T	K92N	0.999
9:842127:T:A	W97R	0.999
9:842127:T:C	W97R	0.999
9:842129:G:C	W97C	0.999
9:842129:G:T	W97C	0.999
9:842151:T:A	C105S	0.999
9:842151:T:C	C105R	0.999
9:842152:G:C	C105S	0.999
9:842158:T:C	L107P	0.999
9:842170:G:C	R111T	0.999

dbSNP variants (sampled 300 via entrez): RS1000025679 (9:850913 C>T), RS1000054978 (9:903551 T>G), RS1000055270 (9:847046 C>G,T), RS1000063870 (9:857378 T>C), RS1000068415 (9:866198 G>A,T), RS1000070100 (9:953680 A>G), RS1000100670 (9:885566 T>C,G), RS1000110941 (9:948470 G>C), RS1000132915 (9:881329 G>A), RS1000141189 (9:851114 G>A), RS1000149993 (9:874684 A>G), RS1000162097 (9:919917 T>C), RS1000200081 (9:945405 C>G,T), RS1000209055 (9:892628 T>C), RS1000218084 (9:885152 C>T)

Disease associations

OMIM: gene MIM:602424 | disease phenotypes: MIM:618282, MIM:154230, MIM:400044

GenCC curated gene-disease

Disease	Classification	Inheritance
46,XY disorder of sex development	Strong	Autosomal dominant
46,XX disorder of sex development	Limited	Autosomal dominant
azoospermia	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
spermatogenic failure	Definitive	AD

Mondo (7): hyper-IgE recurrent infection syndrome 3, autosomal recessive (MONDO:0032654), male infertility (MONDO:0005372), 46,XY sex reversal 4 (MONDO:0007938), 46,XY complete gonadal dysgenesis (MONDO:0010765), 46,XX disorder of sex development (MONDO:0017576), 46 XY differences of sex development (MONDO:0020040), azoospermia (MONDO:0100459)

Orphanet (3): Autosomal recessive hyper-IgE syndrome due to ZNF341 deficiency (Orphanet:641368), Male infertility with azoospermia or oligozoospermia due to single gene mutation (Orphanet:399805), 46,XY complete gonadal dysgenesis (Orphanet:242)

HPO phenotypes

4 total (4 of 4 shown, HPO-id order):

HPO	Term
HP:0000037	Male pseudohermaphroditism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000147	Polycystic ovaries
HP:0008733	Dysplastic testis

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST000701_5	Testicular germ cell cancer	1.000000e-23
GCST001067_1	Testicular cancer	9.000000e-10
GCST001067_2	Testicular cancer	1.000000e-11
GCST001762_370	Obesity-related traits	3.000000e-06
GCST001850_29	Major depressive disorder	4.000000e-06
GCST002022_9	Testicular germ cell tumor	2.000000e-26
GCST002023_11	Testicular germ cell tumor	4.000000e-07
GCST003542_195	Night sleep phenotypes	4.000000e-06
GCST003542_8	Night sleep phenotypes	3.000000e-08
GCST004635_20	Testicular germ cell tumor	2.000000e-45
GCST004713_26	Testicular germ cell tumor	1.000000e-32
GCST004713_27	Testicular germ cell tumor	7.000000e-41
GCST004713_5	Testicular germ cell tumor	2.000000e-23
GCST004858_13	Dupuytren’s disease	4.000000e-26
GCST006462_32	Uterine fibroids	4.000000e-18
GCST008514_12	Peginterferon alfa-2a treatment response in chronic hepatitis B infection	8.000000e-06
GCST009190_12	Medial orbital frontal cortex volume	9.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0003939	energy intake
EFO:0004229	Dupuytren Contracture
EFO:0010103	response to peginterferon alfa-2a

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D058489	46, XX Disorders of Sex Development	C12.050.351.875.253.064; C12.200.706.316.064; C12.800.316.064; C16.131.939.316.064; C19.391.119.064
D053713	Azoospermia	C12.100.500.430.380; C12.100.750.700.380; C12.200.294.430.380
D058490	Disorder of Sex Development, 46,XY	C12.050.351.875.253.096; C12.200.706.316.096; C12.800.316.096; C16.131.939.316.096; C19.391.119.096
D006061	Gonadal Dysgenesis, 46,XY	C12.050.351.875.253.096.687; C12.050.351.875.253.309.388; C12.200.706.316.096.687; C12.200.706.316.309.388; C12.800.316.096.687; C12.800.316.309.388; C16.131.939.316.096.687; C16.131.939.316.309.388; C19.391.119.096.687; C19.391.119.309.388
D007248	Infertility, Male	C12.100.500.430; C12.100.750.700; C12.200.294.430
C567887	46,XY Sex Reversal 4 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression	3
bufotalin	increases expression	1
sodium arsenite	affects methylation	1
N-acetyl-4-benzoquinoneimine	affects response to substance	1
entinostat	increases expression	1
abrine	increases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	increases methylation	1
Demecolcine	increases expression	1
Methotrexate	decreases expression	1
Silicon Dioxide	increases expression	1
Tunicamycin	increases expression	1
Okadaic Acid	increases expression	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A0Z5	SEES3-1V human DMRT1, clone1	Embryonic stem cell	Male
CVCL_A0Z6	SEES3-1V human DMRT1, clone2	Embryonic stem cell	Male
CVCL_A0Z7	SEES3-1V human DMRT1, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02307994	PHASE4	UNKNOWN	Clinical Research on Effectiveness and Safety of Treatment of Severe Oligospermia or Azoospermia With uFSH
NCT02202382	PHASE4	COMPLETED	Effects of Korean Red Ginseng on Male Infertility
NCT02204826	PHASE4	COMPLETED	Effects of Korean Red Ginseng on Semen Parameters in Male Infertility Patients: a Randomized, Placebo-controlled, Double-blind Clinical Study
NCT03802864	PHASE4	COMPLETED	Post-operative Pain Control of Testicular Sperm Extraction Using Liposomal Bupivacaine
NCT06100432	PHASE4	ACTIVE_NOT_RECRUITING	Effect of Eurycoma Longifolia (DLBS5055) and Multivitamins (Vitamin C+Vitamin E+ β-carotene) for Infertile Males
NCT07523022	PHASE4	ENROLLING_BY_INVITATION	Comparison of the Effect of Gonadotropin and Clomiphene Citrate Treatment on Sperm Parameters and the Outcome of Assisted Reproductive Procedures in Subfertile Men Based on the APHRODITE Groups
NCT02275169	PHASE3	UNKNOWN	FSH Treatment for Non-obstructive Azoospermic Patients
NCT00975117	PHASE3	COMPLETED	Spermotrend in the Treatment of Male Infertility
NCT01407432	PHASE3	COMPLETED	Impact of Folates in the Care of the Male Infertility
NCT01895816	PHASE3	COMPLETED	Herbal Tonic Fertile Supplement(ZO2C5)
NCT02605070	PHASE3	TERMINATED	Pilot Study on the Effects of FSH Treatment on the Epigenetic Characteristics of Spermatozoa in Infertile Patients With Severe Oligozoospermia
NCT07402759	PHASE3	ACTIVE_NOT_RECRUITING	Impact of tdrd9 Gene Mutations in the Therapeutic Response to L-carnitine in Oligoasthenozoospermic Men
NCT02544191	PHASE2	UNKNOWN	GnRHa Combined With hCG and hMG for Treatment of Patients With Non-obstructive Azoospermia
NCT03762967	PHASE2	UNKNOWN	Autologous Adipose-Derived Adult Stromal Vascular Cell Administration for Male Patients With Infertility
NCT01880086	PHASE2	COMPLETED	Clomiphene Citrate for the Treatment of Low Testosterone Associated With Chronic Opioid Pain Medication Administration
NCT02061384	PHASE2	COMPLETED	RA-2 13-cis Retinoic Acid (Isotretinoin)
NCT02421887	PHASE2	COMPLETED	Males, Antioxidants, and Infertility Trial
NCT05200663	PHASE2	UNKNOWN	Efficacy Comparison of Tamoxifen and Tamoxifen With Antioxidants on Semen Quality of Male With Idiopathic Infertility
NCT05290558	PHASE2	ACTIVE_NOT_RECRUITING	The Therapeutic Effects of Bu Shen Yi Jing Pill on Semen Quality in Sub Fertile Males: a Randomized Controlled Trial
NCT06091969	PHASE2	NOT_YET_RECRUITING	Supplementation for Male Subfertility
NCT01595308	PHASE1	COMPLETED	A Pilot Study to Evaluate the Effect of Pomegranate Juice on Semen Parameters in Healthy Male Volunteers
NCT02122211	PHASE1	COMPLETED	Choline Dehydrogenase and Sperm Function: Effects of Betaine
NCT02575924	PHASE1	UNKNOWN	Influence of Culture Media on Clinical Outcomes in Poor Responders or Severe Male Infertility
NCT04463316	Not specified	RECRUITING	GROWing Up With Rare GENEtic Syndromes
NCT06723938	Not specified	RECRUITING	Phenotypic and Genotypic Characterisation of a Large, Multicentre Italian Cohort of 46, XY DSD Patients
NCT02041910	PHASE1/PHASE2	UNKNOWN	Testicular Injection of Autologous Stem Cells for Treatment of Patients With Azoospermia
NCT00282477	Not specified	UNKNOWN	Trial to Evaluate Erectile Function, Fertility and Sperm Count in Male Cyclists Compared to Age Matched Controls
NCT00484081	Not specified	COMPLETED	Microdissection Testicular Sperm Extraction (MicroTESE) and IVF-ICSI Outcome in Non-Obstructive Azoospermia (NOA)
NCT00548977	Not specified	COMPLETED	Genetic Studies Spermatogenic Failure
NCT01375062	Not specified	COMPLETED	Obtaining Undifferentiated Cells From Testis Biopsy
NCT01509482	Not specified	COMPLETED	Insulin Resistance in Idiopathic Oligospermia and Azoospermia
NCT02008799	Not specified	UNKNOWN	Intra Testicular Artery Injection of Bone Marrow Stem Cell in Management of Azoospermia
NCT02339272	Not specified	COMPLETED	Study of Synapsis and Recombination in Male Meiosis and the Implications in Infertility
NCT02414295	Not specified	COMPLETED	Sperm Production in Kleinfelter Syndrome Patients After Mesenchymal Stem Cell Injection
NCT02418832	Not specified	RECRUITING	Testis Needle Aspiration of Sperm in Men With Azoospermia
NCT02617173	Not specified	UNKNOWN	The Effect of Low Electrical Current on Testicular Spermatocyte Count
NCT02773498	Not specified	TERMINATED	Comparison of Medical Results of Testicular Sperm Extraction by Conventional Surgery and Microsurgical Track
NCT03497728	Not specified	TERMINATED	Detection of Microdeletions in the Azoospermia Factor (AZF) Regions in Infertile Male Patients
NCT04675164	Not specified	COMPLETED	Laser Assisted Sperm Selection of Viable Immotile Testicular Sperm in Azoospermic Infertile Men
NCT05479474	Not specified	RECRUITING	Platelet Rich Plasma Testis Treatment for Infertile Men