KASH5

Summary

KASH5 (KASH domain containing 5, HGNC:26520) is a protein-coding gene on chromosome 19q13.33, encoding Protein KASH5 (Q8N6L0). As a component of the LINC (LInker of Nucleoskeleton and Cytoskeleton) complex, involved in the connection between the nuclear lamina and the cytoskeleton.

Predicted to enable dynein complex binding activity. Predicted to be involved in several processes, including cytoskeleton organization; homologous chromosome segregation; and spindle localization. Predicted to act upstream of or within several processes, including double-strand break repair via homologous recombination; meiotic telomere clustering; and spermatogenesis. Predicted to be located in chromosome; membrane; and nuclear envelope. Predicted to be part of meiotic nuclear membrane microtubule tethering complex. Predicted to be active in chromosome; meiotic spindle pole; and nuclear outer membrane. Implicated in primary ovarian insufficiency and spermatogenic failure 88.

Source: NCBI Gene 147872 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 111 total — 6 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 11
• MANE Select transcript: NM_144688

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26520
Approved symbol	KASH5
Name	KASH domain containing 5
Location	19q13.33
Locus type	gene with protein product
Status	Approved
Aliases	FLJ32658
Ensembl gene	ENSG00000161609
Ensembl biotype	protein_coding
OMIM	618125
Entrez	147872

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 7 retained_intron, 6 protein_coding, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000447857, ENST00000593362, ENST00000593631, ENST00000593725, ENST00000594043, ENST00000594905, ENST00000595828, ENST00000596130, ENST00000596419, ENST00000596771, ENST00000596862, ENST00000597993, ENST00000598730, ENST00000600570, ENST00000600895

RefSeq mRNA: 1 — MANE Select: NM_144688 NM_144688

CCDS: CCDS46140

Canonical transcript exons

ENST00000447857 — 20 exons

Exon	Start	End
ENSE00001116437	49417015	49417079
ENSE00001116438	49414951	49414996
ENSE00001116443	49388249	49388327
ENSE00001676735	49417159	49417266
ENSE00003092601	49417369	49417990
ENSE00003462286	49406886	49406963
ENSE00003478698	49409753	49409875
ENSE00003481249	49397651	49397717
ENSE00003503230	49395106	49395292
ENSE00003503842	49390789	49390926
ENSE00003514399	49397982	49398143
ENSE00003524159	49412968	49413026
ENSE00003569583	49409196	49409283
ENSE00003606601	49394476	49394580
ENSE00003614789	49399457	49399507
ENSE00003640983	49395769	49395833
ENSE00003641829	49399025	49399142
ENSE00003651179	49407240	49407296
ENSE00003682708	49407612	49407671
ENSE00003689399	49408967	49409031

Expression profiles

Bgee: expression breadth ubiquitous, 112 present calls, max score 96.41.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1406 / max 104.6517, expressed in 22 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
176977	0.0510	4
176975	0.0453	11
176978	0.0312	7
176976	0.0131	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	96.41	gold quality
left testis	UBERON:0004533	96.26	gold quality
testis	UBERON:0000473	92.83	gold quality
pancreatic ductal cell	CL:0002079	88.26	silver quality
right hemisphere of cerebellum	UBERON:0014890	87.47	gold quality
cerebellar hemisphere	UBERON:0002245	87.43	gold quality
cerebellar cortex	UBERON:0002129	87.19	gold quality
sperm	CL:0000019	86.56	silver quality
cerebellum	UBERON:0002037	84.94	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.05	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.47	gold quality
secondary oocyte	CL:0000655	76.73	silver quality
adult organism	UBERON:0007023	70.38	gold quality
body of pancreas	UBERON:0001150	69.92	gold quality
ileal mucosa	UBERON:0000331	62.76	gold quality
deltoid	UBERON:0001476	60.20	gold quality
pancreas	UBERON:0001264	59.86	gold quality
epithelial cell of pancreas	CL:0000083	58.08	gold quality
skin of hip	UBERON:0001554	54.56	silver quality
cardiac muscle of right atrium	UBERON:0003379	54.34	gold quality
left ventricle myocardium	UBERON:0006566	54.23	gold quality
kidney epithelium	UBERON:0004819	53.93	gold quality
oocyte	CL:0000023	53.82	silver quality
upper arm skin	UBERON:0004263	53.52	gold quality
quadriceps femoris	UBERON:0001377	51.85	gold quality
myocardium	UBERON:0002349	50.25	gold quality
granulocyte	CL:0000094	49.45	silver quality
vastus lateralis	UBERON:0001379	48.84	gold quality
lower lobe of lung	UBERON:0008949	47.77	silver quality
nasal cavity epithelium	UBERON:0005384	47.03	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.08

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

32 targeting KASH5, 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-4533	100.00	69.48	2758
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-7157-5P	99.66	69.33	1829
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-885-5P	99.59	68.59	879
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-942-5P	99.41	68.40	1977
HSA-MIR-130A-5P	99.33	70.26	2623
HSA-MIR-500A-5P	98.76	69.13	1241
HSA-MIR-423-5P	98.69	67.48	1522
HSA-MIR-3184-5P	98.56	67.13	1491
HSA-MIR-4450	98.26	68.35	725
HSA-MIR-4768-3P	98.16	66.02	2330
HSA-MIR-637	97.91	64.05	1517
HSA-MIR-4723-3P	97.67	65.91	1017
HSA-MIR-6769B-3P	97.41	65.53	1036

Literature-anchored findings (GeneRIF, showing 6)

• Structural Analysis of Different LINC Complexes Reveals Distinct Binding Modes. (PMID:33058875)
• A human infertility-associated KASH5 variant promotes mitochondrial localization. (PMID:33980926)
• Homozygous missense mutation in CCDC155 disrupts the transmembrane distribution of CCDC155 and SUN1, resulting in non-obstructive azoospermia and premature ovarian insufficiency in humans. (PMID:35587281)
• Novel bi-allelic variants in KASH5 are associated with meiotic arrest and non-obstructive azoospermia. (PMID:35674372)
• Homozygous Variant in KASH5 Causes Premature Ovarian Insufficiency by Disordered Meiotic Homologous Pairing. (PMID:35708642)
• A homozygous KASH5 frameshift mutation causes diminished ovarian reserve, recurrent miscarriage, and non-obstructive azoospermia in humans. (PMID:36864840)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Kash5	ENSMUSG00000038292
rattus_norvegicus	Kash5	ENSRNOG00000025378

Paralogs (31): DUSP13B (ENSG00000079393), DUSP12 (ENSG00000081721), SSH1 (ENSG00000084112), DUSP3 (ENSG00000108861), PTPMT1 (ENSG00000110536), DUSP16 (ENSG00000111266), EPM2A (ENSG00000112425), DUSP22 (ENSG00000112679), DUSP1 (ENSG00000120129), DUSP4 (ENSG00000120875), STYXL1 (ENSG00000127952), DUSP9 (ENSG00000130829), DUSP26 (ENSG00000133878), DUSP5 (ENSG00000138166), DUSP6 (ENSG00000139318), SSH2 (ENSG00000141298), DUSP10 (ENSG00000143507), DUSP15 (ENSG00000149599), DUSP2 (ENSG00000158050), DUSP19 (ENSG00000162999), DUSP7 (ENSG00000164086), DUSP18 (ENSG00000167065), SSH3 (ENSG00000172830), DUSP8 (ENSG00000184545), DUSP28 (ENSG00000188542), DUSP29 (ENSG00000188716), DUSP21 (ENSG00000189037), STYX (ENSG00000198252), STYXL2 (ENSG00000198842), DUSP14 (ENSG00000276023), DUSP13A (ENSG00000293543)

Protein

Protein identifiers

Protein KASH5 — Q8N6L0 (reviewed: Q8N6L0)

Alternative names: Coiled-coil domain-containing protein 155, KASH domain-containing protein 5

All UniProt accessions (7): Q8N6L0, M0QX09, M0QXT3, M0QXW9, M0QZT9, M0QZW6, M0R1C7

UniProt curated annotations — full annotation on UniProt →

Function. As a component of the LINC (LInker of Nucleoskeleton and Cytoskeleton) complex, involved in the connection between the nuclear lamina and the cytoskeleton. The nucleocytoplasmic interactions established by the LINC complex play an important role in the transmission of mechanical forces across the nuclear envelope and in nuclear movement and positioning. Required for telomere attachment to nuclear envelope in the prophase of meiosis. Required for rapid telomere prophase movements implicating a SUN1/2:KASH5 LINC complex in which SUN1 and SUN2 seem to act at least partial redundantly. Required for homolog pairing during meiotic prophase in spermatocytes and probably oocytes. Essential for male and female gametogenesis. Recruits cytoplasmic dynein to telomere attachment sites at the nuclear envelope in spermatocytes. In oocytes is involved in meiotic resumption and spindle formation.

Subunit / interactions. Core component the LINC complex which is composed of inner nuclear membrane SUN domain-containing proteins coupled to outer nuclear membrane KASH domain-containing nesprins. SUN and KASH domain-containing proteins seem to bind each other promiscuously; however, differentially expression of LINC complex constituents is giving rise to specific assemblies. At least SUN1/2-containing core LINC complexes are proposed to be hexameric composed of three protomers of each KASH and SUN domain-containing protein. Interacts with SUN1; this interaction mediates its telomere localization by forming a SUN1:KASH5 LINC complex. Component of a probable SUN2:KASH5 LINC complex. Self-associates. Interacts with DYNC1H1, DCTN1, DYNC1I1/2 and PAFAH1B1; suggesting the association with the dynein-dynactin motor complex.

Subcellular location. Nucleus outer membrane. Nucleus. Chromosome. Telomere. Nucleus envelope.

Tissue specificity. Expressed in testis (at protein level).

Disease relevance. Spermatogenic failure 88 (SPGF88) [MIM:620547] An autosomal recessive male infertility disorder characterized by non-obstructive azoospermia due to primary spermatogenic arrest. The disease is caused by variants affecting the gene represented in this entry. Premature ovarian failure 22 (POF22) [MIM:620548] A form of premature ovarian failure, an ovarian disorder defined as the cessation of ovarian function under the age of 40 years. It is characterized by oligomenorrhea or amenorrhea, in the presence of elevated levels of serum gonadotropins and low estradiol. POF22 is an autosomal recessive form characterized by infertility, and small to atrophic ovaries and no visible ovarian follicles. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The C-terminal 22 AA is required and sufficient for localization to telomeres at the nuclear envelope.

RefSeq proteins (1): NP_653289* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR028168	KASH5_CC	Domain
IPR028170	KASH5	Family
IPR039508	KASH5_EF-hand-like_dom	Domain

Pfam: PF14658, PF14662

UniProt features (14 total): sequence variant 4, region of interest 3, topological domain 2, chain 1, strand 1, transmembrane region 1, coiled-coil region 1, compositionally biased region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6R2I	X-RAY DIFFRACTION	1.54
6WMF	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N6L0-F1	68.92	0.39

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 117 (showing top): GOBP_MEIOTIC_CHROMOSOME_SEGREGATION, GOBP_CHROMOSOME_ORGANIZATION, GOBP_SPINDLE_LOCALIZATION, GOBP_CHROMOSOME_LOCALIZATION, GOBP_OOGENESIS, GOBP_MALE_GAMETE_GENERATION, GOBP_ORGANELLE_FISSION, GOBP_ACTIN_FILAMENT_ORGANIZATION, GOBP_DNA_DAMAGE_RESPONSE, GOBP_ORGANELLE_ASSEMBLY, GOBP_CELLULAR_PROCESS_INVOLVED_IN_REPRODUCTION_IN_MULTICELLULAR_ORGANISM, GOBP_CHROMOSOME_ORGANIZATION_INVOLVED_IN_MEIOTIC_CELL_CYCLE, GOBP_FEMALE_GAMETE_GENERATION, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, GOBP_HOMOLOGOUS_CHROMOSOME_SEGREGATION

GO Biological Process (11): double-strand break repair via homologous recombination (GO:0000724), actin filament organization (GO:0007015), homologous chromosome pairing at meiosis (GO:0007129), spermatogenesis (GO:0007283), telomere localization (GO:0034397), meiotic telomere clustering (GO:0045141), oogenesis (GO:0048477), spindle assembly (GO:0051225), spindle localization (GO:0051653), chromosome localization to nuclear envelope involved in homologous chromosome segregation (GO:0090220), meiotic cell cycle (GO:0051321)

GO Molecular Function (3): identical protein binding (GO:0042802), dynein complex binding (GO:0070840), protein binding (GO:0005515)

GO Cellular Component (9): chromosome, telomeric region (GO:0000781), lateral element (GO:0000800), nuclear outer membrane (GO:0005640), meiotic nuclear membrane microtubule tethering complex (GO:0034993), meiotic spindle pole (GO:0090619), nucleus (GO:0005634), nuclear envelope (GO:0005635), chromosome (GO:0005694), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
homologous chromosome segregation	2
chromosome organization involved in meiotic cell cycle	2
chromosome localization	2
cellular anatomical structure	2
recombinational repair	1
double-strand break repair	1
actin cytoskeleton organization	1
supramolecular fiber organization	1
developmental process involved in reproduction	1
male gamete generation	1
telomere localization	1
chromosome localization to nuclear envelope involved in homologous chromosome segregation	1
germ cell development	1
female gamete generation	1
spindle organization	1
chromosome segregation	1
membraneless organelle assembly	1
cell cycle process	1
organelle localization	1
cell cycle	1
sexual reproduction	1
reproductive process	1
meiotic nuclear division	1
protein binding	1
protein-containing complex binding	1
binding	1
chromosomal region	1
synaptonemal complex	1
nuclear membrane	1
organelle outer membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
microtubule organizing center attachment site	1
nuclear membrane microtubule tethering complex	1
spindle pole	1
meiotic spindle	1
intracellular membrane-bounded organelle	1
nucleus	1
endomembrane system	1
organelle envelope	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

776 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KASH5	SUN1	O94901	995
KASH5	SUN2	Q9UH99	963
KASH5	DKKL1	Q9UK85	915
KASH5	SYNE4	Q8N205	878
KASH5	TERB1	Q8NA31	875
KASH5	H0YEC1	H0YEC1	850
KASH5	TERB2	Q8NHR7	839
KASH5	IRAG2	Q12912	696
KASH5	SYNE3	Q6ZMZ3	665
KASH5	SYNE1	Q8NF91	665
KASH5	SYNE2	Q8WXH0	647
KASH5	PLEC	Q15149	642
KASH5	SUN3	Q8TAQ9	625
KASH5	SUN5	Q8TC36	596
KASH5	DMC1	Q14565	575

IntAct

579 interactions, top by confidence:

A	B	Type	Score
KASH5	LHFPL5	psi-mi:“MI:0915”(physical association)	0.810
KASH5	SLC30A2	psi-mi:“MI:0915”(physical association)	0.810
LHFPL5	KASH5	psi-mi:“MI:0915”(physical association)	0.810
SLC30A2	KASH5	psi-mi:“MI:0915”(physical association)	0.810
KASH5	SGTA	psi-mi:“MI:0915”(physical association)	0.790
RIPPLY2	KASH5	psi-mi:“MI:0915”(physical association)	0.790
KASH5	BCL2L2	psi-mi:“MI:0915”(physical association)	0.790
SGTA	KASH5	psi-mi:“MI:0915”(physical association)	0.790
KASH5	RIPPLY2	psi-mi:“MI:0915”(physical association)	0.790
GPR25	KASH5	psi-mi:“MI:0915”(physical association)	0.720
GOSR2	KASH5	psi-mi:“MI:0915”(physical association)	0.720
KASH5	MTX2	psi-mi:“MI:0915”(physical association)	0.720
KASH5	CRABP2	psi-mi:“MI:0915”(physical association)	0.720
NSG1	KASH5	psi-mi:“MI:0915”(physical association)	0.720
KASH5	GALNT2	psi-mi:“MI:0915”(physical association)	0.720
KASH5	STX5	psi-mi:“MI:0915”(physical association)	0.720
KASH5	GPATCH4	psi-mi:“MI:0915”(physical association)	0.720
KASH5	PPP1R18	psi-mi:“MI:0915”(physical association)	0.720
CDC73	KASH5	psi-mi:“MI:0915”(physical association)	0.720
KASH5	JAGN1	psi-mi:“MI:0915”(physical association)	0.720
KASH5	SERP2	psi-mi:“MI:0915”(physical association)	0.720
FATE1	KASH5	psi-mi:“MI:0915”(physical association)	0.720
SLC41A2	KASH5	psi-mi:“MI:0915”(physical association)	0.720
CYBC1	KASH5	psi-mi:“MI:0915”(physical association)	0.720
SENP2	KASH5	psi-mi:“MI:0915”(physical association)	0.720

BioGRID (192): CCDC155 (Two-hybrid), CCDC155 (Two-hybrid), CCDC155 (Two-hybrid), CCDC155 (Two-hybrid), CCDC155 (Two-hybrid), CCDC155 (Two-hybrid), CCDC155 (Two-hybrid), CCDC155 (Two-hybrid), CCDC155 (Two-hybrid), CCDC155 (Two-hybrid), CCDC155 (Two-hybrid), CCDC155 (Two-hybrid), CCDC155 (Two-hybrid), CCDC155 (Two-hybrid), CCDC155 (Two-hybrid)

ESM2 similar proteins: A0A5F4BST2, A5PJC7, A8MWV9, D3ZZP4, O14836, P0CAN6, P11911, P11912, P14753, Q01114, Q07303, Q13113, Q2KI80, Q2KL21, Q3TS39, Q3URD2, Q4V9L6, Q5F267, Q5FVJ4, Q5FVQ7, Q5RA41, Q5T1S8, Q6P9G4, Q6UWJ8, Q6UX34, Q80VJ8, Q810F0, Q86XR5, Q8BRJ3, Q8BX43, Q8K064, Q8K5A9, Q8N112, Q8N4K4, Q8N6L0, Q8NBR0, Q8NC24, Q8QZT4, Q8R138, Q923S2

Diamond homologs: Q2T9R2, Q5RHB5, Q80VJ8, Q8N6L0, Q12912, Q60664, Q9N1F0, Q9WUX5, Q9Y6F6

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
KASH5	“form complex”	“LINC complex”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	1
Uncertain significance	88
Likely benign	11
Benign	0

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
1328949	NM_144688.5(KASH5):c.1146+5G>A	Pathogenic
2626771	NM_144688.5(KASH5):c.1604T>A (p.Leu535Gln)	Pathogenic
2626772	NM_144688.5(KASH5):c.590T>C (p.Leu197Pro)	Pathogenic
2626773	NM_144688.5(KASH5):c.981_982del (p.Arg327fs)	Pathogenic
2626774	NM_144688.5(KASH5):c.-95-2_798+248del	Pathogenic
2626776	NM_144688.5(KASH5):c.1271_1274del (p.Arg424fs)	Pathogenic
1232307	NM_144688.5(KASH5):c.747G>A (p.Ala249=)	Likely pathogenic

SpliceAI

3562 predictions. Top by Δscore:

Variant	Effect	Δscore
19:49395290:TGG:T	donor_gain	1.0000
19:49395291:GG:G	donor_gain	1.0000
19:49395291:GGG:G	donor_gain	1.0000
19:49395291:GGGT:G	donor_loss	1.0000
19:49395292:GG:G	donor_gain	1.0000
19:49395293:G:GG	donor_gain	1.0000
19:49395294:T:A	donor_loss	1.0000
19:49397649:A:AG	acceptor_gain	1.0000
19:49397650:G:GG	acceptor_gain	1.0000
19:49397715:GCT:G	donor_gain	1.0000
19:49397718:G:GG	donor_gain	1.0000
19:49397973:T:TA	acceptor_gain	1.0000
19:49397980:A:AG	acceptor_gain	1.0000
19:49397980:AG:A	acceptor_loss	1.0000
19:49397981:G:GA	acceptor_gain	1.0000
19:49397981:GA:G	acceptor_gain	1.0000
19:49397981:GAC:G	acceptor_gain	1.0000
19:49397981:GACA:G	acceptor_gain	1.0000
19:49397981:GACAA:G	acceptor_gain	1.0000
19:49398083:C:G	donor_gain	1.0000
19:49398088:G:GT	donor_gain	1.0000
19:49398126:GC:G	donor_gain	1.0000
19:49398128:G:GG	donor_gain	1.0000
19:49399139:GGCG:G	donor_gain	1.0000
19:49399140:GCGG:G	donor_gain	1.0000
19:49399160:G:T	donor_gain	1.0000
19:49399164:G:GT	donor_gain	1.0000
19:49399165:A:T	donor_gain	1.0000
19:49399444:T:TA	acceptor_gain	1.0000
19:49406884:A:AG	acceptor_gain	1.0000

AlphaMissense

3600 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:49394553:T:C	F41L	0.993
19:49394555:C:A	F41L	0.993
19:49394555:C:G	F41L	0.993
19:49395246:T:C	F97L	0.987
19:49395248:C:A	F97L	0.987
19:49395248:C:G	F97L	0.987
19:49394554:T:G	F41C	0.984
19:49395247:T:C	F97S	0.978
19:49395267:T:A	W104R	0.977
19:49395267:T:C	W104R	0.977
19:49395187:T:C	L77S	0.975
19:49395269:G:C	W104C	0.975
19:49395269:G:T	W104C	0.975
19:49394554:T:C	F41S	0.973
19:49408971:T:C	L333P	0.973
19:49399078:T:C	L228P	0.971
19:49406896:T:C	L270P	0.963
19:49398125:T:C	L204P	0.959
19:49395139:T:C	L61P	0.958
19:49395247:T:G	F97C	0.958
19:49398137:T:C	L208P	0.956
19:49394559:G:C	A43P	0.953
19:49399497:T:C	L263P	0.951
19:49407247:T:C	L295P	0.946
19:49398020:T:C	L169P	0.945
19:49399089:G:C	A232P	0.944
19:49395260:G:A	M101I	0.943
19:49395260:G:C	M101I	0.943
19:49395260:G:T	M101I	0.943
19:49407241:G:C	R293P	0.943

dbSNP variants (sampled 300 via entrez): RS1000068216 (19:49396005 G>A,T), RS1000265311 (19:49418129 C>A,T), RS1000318023 (19:49418344 G>A,C), RS1000409938 (19:49396533 C>G,T), RS1000426032 (19:49402479 G>A), RS1000535050 (19:49400835 A>G), RS1000642101 (19:49406600 C>G,T), RS1000660904 (19:49417771 G>A), RS1000754088 (19:49412603 G>A), RS1000759849 (19:49396261 T>C,G), RS1000874160 (19:49400995 T>C), RS1000938807 (19:49388598 A>G), RS1001066554 (19:49406083 G>A,T), RS1001073015 (19:49394850 C>G,T), RS1001186591 (19:49389711 C>T)

Disease associations

OMIM: gene MIM:618125 | disease phenotypes: MIM:620548, MIM:620547

GenCC curated gene-disease

Mondo (3): premature ovarian failure 22 (MONDO:0957822), azoospermia (MONDO:0100459), spermatogenic failure 88 (MONDO:0957821)

Orphanet (1): Rare genetic premature ovarian failure (Orphanet:485382)

HPO phenotypes

11 total (11 of 11 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000869	Secondary amenorrhea
HP:0003251	Male infertility
HP:0008209	Premature ovarian insufficiency
HP:0008222	Female infertility
HP:0008232	Elevated circulating follicle stimulating hormone level
HP:0011462	Young adult onset
HP:0011961	Non-obstructive azoospermia
HP:0025708	Early young adult onset
HP:0031039	Spermatocyte maturation arrest
HP:0031103	Decreased circulating antimullerian hormone circulation

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D053713	Azoospermia	C12.100.500.430.380; C12.100.750.700.380; C12.200.294.430.380

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

4 total (human), top 4 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
ethyl-p-hydroxybenzoate	decreases expression	1
Acetaminophen	decreases expression	1
Valproic Acid	increases methylation	1
1-Methyl-4-phenylpyridinium	increases expression	1

Clinical trials (associated diseases)

27 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
NCT02275169	PHASE3	UNKNOWN	FSH Treatment for Non-obstructive Azoospermic Patients
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
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
NCT05628987	Not specified	RECRUITING	The Association of Gut Microbiota and Spermatogenic Dysfunction
NCT05866484	Not specified	COMPLETED	Testicular Sperm Aspiration (TESA) vs. Microfluidic Sperm Separation (MSS)
NCT06524258	Not specified	COMPLETED	Testicular Elastography for Microscopic Testicular Sperm Extraction
NCT06841328	Not specified	RECRUITING	Fertility Enhancement Through Regenerative Treatment in Ovaries and Testes
NCT06941922	Not specified	RECRUITING	Testicular Evaluation of Azoospermia Using Micro-Ultrasound
NCT07074015	Not specified	RECRUITING	IntelliWell: An AI-Assisted Imaging Platform for Detection and Location of Ultra-Rare Testicular Sperm in Surgical Specimens
NCT07357701	Not specified	RECRUITING	Identifying Genome Variants in Non-Obstructive Azoospermia (NOA) or Primary Ovarian Insufficiency (POI)
NCT07542626	Not specified	RECRUITING	Fertility Restoration With Autografting of Cryopreserved Immature Testicular Tissue