MSH5

Summary

MSH5 (mutS homolog 5, HGNC:7328) is a protein-coding gene on chromosome 6p21.33, encoding MutS protein homolog 5 (O43196). Involved in DNA mismatch repair and meiotic recombination processes.

This gene encodes a member of the mutS family of proteins that are involved in DNA mismatch repair and meiotic recombination. This protein is similar to a Saccharomyces cerevisiae protein that participates in segregation fidelity and crossing-over events during meiosis. This protein plays a role in promoting ionizing radiation-induced apoptosis. This protein forms hetero-oligomers with another member of this family, mutS homolog 4. Polymorphisms in this gene have been linked to various human diseases, including IgA deficiency, common variable immunodeficiency, and premature ovarian failure. Alternative splicing results multiple transcript variants. Read-through transcription also exists between this gene and the downstream chromosome 6 open reading frame 26 (C6orf26) gene.

Source: NCBI Gene 4439 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spermatogenic failure 74 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 40
• Clinical variants (ClinVar): 109 total — 4 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 17
• MANE Select transcript: NM_172166

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7328
Approved symbol	MSH5
Name	mutS homolog 5
Location	6p21.33
Locus type	gene with protein product
Status	Approved
Aliases	G7
Ensembl gene	ENSG00000204410
Ensembl biotype	protein_coding
OMIM	603382
Entrez	4439

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 8 protein_coding, 6 retained_intron, 4 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

ENST00000375703, ENST00000375740, ENST00000375750, ENST00000375755, ENST00000395853, ENST00000423982, ENST00000425703, ENST00000429846, ENST00000450148, ENST00000463094, ENST00000463144, ENST00000467319, ENST00000468136, ENST00000468602, ENST00000482280, ENST00000484309, ENST00000494458, ENST00000494646, ENST00000497269, ENST00000650702, ENST00000652715

RefSeq mRNA: 4 — MANE Select: NM_172166 NM_002441, NM_025259, NM_172165, NM_172166

CCDS: CCDS34409, CCDS34410, CCDS4720

Canonical transcript exons

ENST00000375750 — 25 exons

Exon	Start	End
ENSE00001908666	31740005	31740062
ENSE00003466997	31760090	31760216
ENSE00003477757	31759425	31759512
ENSE00003482681	31762112	31762185
ENSE00003486732	31742877	31742957
ENSE00003488368	31740454	31740613
ENSE00003488978	31743108	31743170
ENSE00003494866	31762420	31762676
ENSE00003506083	31747387	31747432
ENSE00003510137	31758548	31758620
ENSE00003542170	31744546	31744581
ENSE00003556089	31760690	31760839
ENSE00003563920	31753301	31753439
ENSE00003584913	31761472	31761615
ENSE00003587615	31759786	31759975
ENSE00003592256	31745237	31745319
ENSE00003595844	31761818	31761955
ENSE00003603994	31758165	31758293
ENSE00003621860	31741163	31741286
ENSE00003640256	31761188	31761262
ENSE00003655541	31759097	31759177
ENSE00003666185	31744190	31744299
ENSE00003667785	31758766	31758875
ENSE00003669409	31753567	31753629
ENSE00003693381	31743904	31744025

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 94.29.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.1934 / max 496.6945, expressed in 1761 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
67041	18.1934	1761

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	94.29	gold quality
right testis	UBERON:0004534	94.23	gold quality
left testis	UBERON:0004533	93.70	gold quality
testis	UBERON:0000473	92.30	gold quality
metanephros cortex	UBERON:0010533	91.68	gold quality
bone marrow	UBERON:0002371	90.26	gold quality
ventricular zone	UBERON:0003053	89.99	gold quality
cortex of kidney	UBERON:0001225	89.37	gold quality
sural nerve	UBERON:0015488	89.19	gold quality
bone marrow cell	CL:0002092	88.76	gold quality
lower esophagus mucosa	UBERON:0035834	88.01	gold quality
spleen	UBERON:0002106	87.59	gold quality
prostate gland	UBERON:0002367	87.59	gold quality
granulocyte	CL:0000094	86.94	gold quality
right ovary	UBERON:0002118	86.79	gold quality
colonic epithelium	UBERON:0000397	86.54	gold quality
transverse colon	UBERON:0001157	86.51	gold quality
skin of leg	UBERON:0001511	86.35	gold quality
left ovary	UBERON:0002119	86.30	gold quality
small intestine Peyer’s patch	UBERON:0003454	86.28	gold quality
tibial nerve	UBERON:0001323	86.27	gold quality
zone of skin	UBERON:0000014	86.22	gold quality
skin of abdomen	UBERON:0001416	85.94	gold quality
ovary	UBERON:0000992	85.71	gold quality
ganglionic eminence	UBERON:0004023	85.69	gold quality
small intestine	UBERON:0002108	85.36	gold quality
pituitary gland	UBERON:0000007	85.32	gold quality
body of uterus	UBERON:0009853	84.88	gold quality
esophagus mucosa	UBERON:0002469	84.86	gold quality
kidney	UBERON:0002113	84.59	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.81

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

27 targeting MSH5, 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-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-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-4517	99.76	69.19	1867
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-147B-5P	99.45	70.62	2432
HSA-MIR-6760-5P	98.87	66.73	1515

Literature-anchored findings (GeneRIF, showing 24)

• The different properties associated with these two hMSH5 variants underscore the potential functional diversity of the human hMSH5 gene. (PMID:15907804)
• the GPS2 might function in concert with hMSH4-hMSH5 during the process of homologous recombination. (PMID:16122992)
• A review of the properties and functional roles of MSH5. (PMID:17127347)
• These findings suggest that Msh4/5 heterodimers contribute to class switch recombination. (PMID:17409188)
• occurrence of an unusual TG 3’ splice site in intron 6 (PMID:17672918)
• Dimerization of MSH4 and MSH5 facilitates their nuclear localization suggesting that dimerization may regulate the intracellular trafficking of these proteins. (PMID:17869244)
• Data have identified the interaction region between the individual subunits of hMSH4-hMSH5 that are likely involved in clamp formation and show that each subunit of the heterodimer binds ATP. (PMID:17977839)
• Data show that MSH5 mutations may be one explanation for premature ovarian failure. (PMID:18166824)
• Biochemical identification of the proteins with which it interacted showed that SMCY formed a distinct complex with MSH5, a critical meiosis-regulatory protein in the human testicular germ cell line, NEC8. (PMID:18459961)
• this study implicates a role for hMSH5 in DNA damage response involving c-Abl and p73, and suggests that mutations impairing this process could significantly affect normal cellular responses to anti-cancer treatments. (PMID:19442657)
• There is an association of polymorphism C85T in MSH5 or C2531T in MLH3 with male infertility, specifically azoospermia or severe oligozoospermia, and interaction between these MSH5 and MLH3 polymorphisms increased the risk of developing male infertility (PMID:19808033)
• hMSH5 possesses a CRM1-dependent nuclear export signal and a nuclear localization signal that participates to its nuclear targeting. (PMID:20185565)
• The presence of the MSH5 85F allele marks the subgroup of DRB1*0102 haplotypes carrying susceptibility for selective IgA deficiency. MSH5 polymorphisms per se are not predisposing factors. (PMID:20542071)
• Study has suggested a role for hMSH5 in the processing of cisplatin-induced DSBs, and silencing of hMSH5 may provide a new means to improve the therapeutic efficacy of cisplatin. (PMID:22401567)
• Authors show that MSH5 (MutSHomolog 5) is localized into the mitochondria of germ and somatic cells. (PMID:22917773)
• the roles of hMSH5 variants in the processes of DNA damage response and repair (PMID:24023853)
• our data point to the existence of a functional interplay between hMSH5 and FANCJ in double-strand break repair induced by replication stress. (PMID:26055704)
• Findings indicate that carriers of the MSH5 rs707939 T allele, the MSH2 rs6544991 C allele, the MSH3 rs6151627 and rs6151670 G alleles, and the MSH3 rs7709909 T allele have poor toxicity tolerance to platinum-based chemotherapy in non-small cell lung cancer patients. (PMID:28093084)
• From sanger sequencing of MSH5 in 200 sporadic POI patients, we identified three heterozygous mutations . Considering the heterozygous p.D487Y carrier in the POI pedigree was fertile, the causality of the three heterozygous mutations in POI need more evidence (PMID:28175301)
• Decreased expression of HCP5 in biochemical premature ovarian insufficiency (bPOI) contributed to dysfunctional granulosa cells by regulating MSH5 transcription and DNA damage repair via the interaction with YB1, providing a novel epigenetic mechanism for POI pathogenesis. (PMID:32112110)
• Association of hMSH5 C85T polymorphism with radiation sensitivity of testicular cell lines GC-1, GC-2, TM3, and TM4. (PMID:32306546)
• Bi-allelic variants in DNA mismatch repair proteins MutS Homolog MSH4 and MSH5 cause infertility in both sexes. (PMID:34755185)
• Mutations of MSH5 in nonobstructive azoospermia (NOA) and rescued via in vivo gene editing. (PMID:34980881)
• A Homozygous Loss-of-Function Mutation in MSH5 Abolishes MutSgamma Axial Loading and Causes Meiotic Arrest in NOA-Affected Individuals. (PMID:35742973)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	msh5	ENSDARG00000077479
mus_musculus	Msh5	ENSMUSG00000007035
rattus_norvegicus	Msh5	ENSRNOG00000000857
caenorhabditis_elegans		WBGENE00003421

Paralogs (4): MSH4 (ENSG00000057468), MSH2 (ENSG00000095002), MSH3 (ENSG00000113318), MSH6 (ENSG00000116062)

Protein

Protein identifiers

MutS protein homolog 5 — O43196 (reviewed: O43196)

All UniProt accessions (10): A0A024RCM1, A0A494C0L0, A2ABE9, A2ABF1, O43196, H0YDS7, H7C2J4, H7C572, H7C5D6, Q5SSR2

UniProt curated annotations — full annotation on UniProt →

Function. Involved in DNA mismatch repair and meiotic recombination processes. Facilitates crossovers between homologs during meiosis.

Subunit / interactions. Heterooligomer of MSH4 and MSH5. Interacts with HJURP. Interacts with REDIC1.

Tissue specificity. Widely expressed, with high levels in testis and ovary, including granulosa cells. Also expressed in fetal ovary and adrenal gland.

Disease relevance. Premature ovarian failure 13 (POF13) [MIM:617442] 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. The disease is caused by variants affecting the gene represented in this entry. Spermatogenic failure 74 (SPGF74) [MIM:619937] An autosomal recessive male infertility disorder characterized by non-obstructive azoospermia due to complete meiotic arrest at the spermatocyte zygotene or pachytene stage. Some men exhibit reduced testicular volume and/or reduced testosterone level. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the DNA mismatch repair MutS family.

Isoforms (4)

UniProt ID	Names	Canonical?
O43196-1	1	yes
O43196-2	2
O43196-3	3
O43196-4	4

RefSeq proteins (4): NP_002432, NP_079535, NP_751897, NP_751898* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000432	DNA_mismatch_repair_MutS_C	Domain
IPR007696	DNA_mismatch_repair_MutS_core	Domain
IPR007861	DNA_mismatch_repair_MutS_clamp	Domain
IPR011184	DNA_mismatch_repair_Msh2	Family
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR036187	DNA_mismatch_repair_MutS_sf	Homologous_superfamily
IPR045076	MutS	Family

Pfam: PF00488, PF05190, PF05192

UniProt features (18 total): sequence variant 11, splice variant 3, chain 1, region of interest 1, sequence conflict 1, binding site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43196-F1	82.36	0.36

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 (1): 592–599

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-912446	Meiotic recombination
R-HSA-1474165	Reproduction
R-HSA-1500620	Meiosis
R-HSA-1640170	Cell Cycle

MSigDB gene sets: 192 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_UP, GOBP_MEIOTIC_CHROMOSOME_SEGREGATION, REACTOME_MEIOTIC_RECOMBINATION, GOBP_CHROMOSOME_ORGANIZATION, E2F4DP1_01, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, HNF1_Q6, KAUFFMANN_DNA_REPAIR_GENES, TTGCWCAAY_CEBPB_02, RODRIGUES_NTN1_TARGETS_DN, PATIL_LIVER_CANCER, PUJANA_CHEK2_PCC_NETWORK, E2F1DP1_01, E2F1DP2_01, GOBP_ORGANELLE_FISSION

GO Biological Process (6): mismatch repair (GO:0006298), chiasma assembly (GO:0051026), DNA repair (GO:0006281), DNA damage response (GO:0006974), meiosis I (GO:0007127), meiotic cell cycle (GO:0051321)

GO Molecular Function (7): double-stranded DNA binding (GO:0003690), ATP binding (GO:0005524), mismatched DNA binding (GO:0030983), ATP-dependent DNA damage sensor activity (GO:0140664), nucleotide binding (GO:0000166), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (1): nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Meiosis	1
Reproduction	1
Cell Cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
meiotic nuclear division	2
DNA repair	1
homologous chromosome pairing at meiosis	1
reciprocal meiotic recombination	1
cellular component assembly	1
meiotic cell cycle process	1
DNA metabolic process	1
DNA damage response	1
cellular response to stress	1
meiotic telophase I	1
meiosis I cell cycle process	1
cell cycle	1
sexual reproduction	1
reproductive process	1
DNA binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
double-stranded DNA binding	1
ATP-dependent activity, acting on DNA	1
DNA damage sensor activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
nucleic acid binding	1
binding	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1502 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MSH5	MSH4	O15457	993
MSH5	HFM1	A2PYH4	953
MSH5	HJURP	Q8NCD3	930
MSH5	MLH3	P49751	913
MSH5	PMS2	P54278	871
MSH5	SPO11	Q9Y5K1	845
MSH5	MLH1	P40692	824
MSH5	RAD51	Q06609	817
MSH5	C1orf146	Q5VVC0	808
MSH5	MND1	Q9BWT6	798
MSH5	PMS1	P54277	794
MSH5	HORMAD2	Q8N7B1	777
MSH5	HORMAD1	Q86X24	770
MSH5	RNF212	Q495C1	754
MSH5	CNTD1	Q8N815	750

IntAct

24 interactions, top by confidence:

A	B	Type	Score
MSH5	ABL1	psi-mi:“MI:0915”(physical association)	0.820
ABL1	MSH5	psi-mi:“MI:0915”(physical association)	0.820
MSH5	MSH4	psi-mi:“MI:0915”(physical association)	0.630
MSH4	MSH5	psi-mi:“MI:0915”(physical association)	0.630
XRCC5	BACC1	psi-mi:“MI:0914”(association)	0.350
Tecpr2	PUF60	psi-mi:“MI:0914”(association)	0.350
Brca1	SMCHD1	psi-mi:“MI:0914”(association)	0.350
SGTB	ARHGAP32	psi-mi:“MI:0914”(association)	0.350
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
MSH5	GET1	psi-mi:“MI:0914”(association)	0.350
EDEM1	MSH5	psi-mi:“MI:0914”(association)	0.350
LRRK2	SF3B1	psi-mi:“MI:0914”(association)	0.350

BioGRID (46): ABL1 (Affinity Capture-Western), MSH5 (Affinity Capture-Western), ABL1 (Reconstituted Complex), ABL1 (Two-hybrid), MSH5 (Biochemical Activity), MSH5 (Reconstituted Complex), MSH5 (Affinity Capture-Western), MSH5 (Two-hybrid), ABL1 (Affinity Capture-Western), MSH5 (Affinity Capture-MS), MSH5 (Affinity Capture-MS), MSH5 (Affinity Capture-MS), MSH5 (Affinity Capture-MS), MSH5 (Affinity Capture-MS), FANCA (Affinity Capture-Luminescence)

ESM2 similar proteins: A1DCB2, A2R1F6, A5PF48, B0YCF6, D3ZG52, D3ZVK1, E1BMP7, F4IFF3, F4JEP5, F4JP48, I0IUP3, O15457, O23617, O24617, O43196, O74773, O80738, O94065, O95573, P13705, P20585, P25847, P40965, P43248, P51530, Q0CPP9, Q0UXL8, Q0WUI9, Q1DQ73, Q1EG27, Q2UT70, Q4WGB7, Q5B6T1, Q5R668, Q5ZKG3, Q5ZPI9, Q63151, Q6DNF4, Q6MG62, Q6ZD95

Diamond homologs: A0AHX3, A1CDD4, A1DCB2, A2R1F6, A3CKV4, A3LU10, A3PNR5, A4R0R0, A4VJN9, A4XK62, A5D0W6, A5DEV6, A5DYV8, A5ICW2, A5IS30, A5N245, A6R7S1, A6RPB6, A6TNX0, A6U0W1, A6ZTR3, A7EC69, A7TTQ1, A7X169, A7Z7E7, A8AUW9, A8MHU4, A8YTJ4, B0S1P2, B0YCF6, B1MXB4, B3WC74, B4U143, B8D298, B8DI00, B9DPU2, B9DVK7, B9E5U7, B9MK78, C0MAV6

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MSH5	“form complex”	“MutSgamma meiotic recombination complex”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	4
Uncertain significance	82
Likely benign	10
Benign	8

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
1328951	NM_172166.4(MSH5):c.537+1G>A	Pathogenic
417969	NM_172166.4(MSH5):c.1459G>T (p.Asp487Tyr)	Pathogenic
992890	NM_172166.4(MSH5):c.75dup (p.Ser26fs)	Pathogenic
992891	NM_172166.4(MSH5):c.1857del (p.Ala620fs)	Pathogenic
1077005	NM_172166.4(MSH5):c.964C>T (p.Arg322Cys)	Likely pathogenic
1255996	NM_172166.4(MSH5):c.826C>T (p.Arg276Cys)	Likely pathogenic
2632077	NM_172166.4(MSH5):c.2071C>T (p.Arg691Ter)	Likely pathogenic
4849309	NM_172166.4(MSH5):c.1531C>T (p.Gln511Ter)	Likely pathogenic

SpliceAI

4443 predictions. Top by Δscore:

Variant	Effect	Δscore
6:31740113:GAAGA:G	donor_gain	1.0000
6:31740117:A:G	donor_gain	1.0000
6:31740584:G:GT	donor_gain	1.0000
6:31740624:G:GT	donor_gain	1.0000
6:31740643:A:T	donor_gain	1.0000
6:31740654:G:T	donor_gain	1.0000
6:31741153:T:A	acceptor_gain	1.0000
6:31741153:T:TA	acceptor_gain	1.0000
6:31741156:T:A	acceptor_gain	1.0000
6:31742873:CAAGT:C	acceptor_loss	1.0000
6:31742874:A:AG	acceptor_gain	1.0000
6:31742875:A:AG	acceptor_gain	1.0000
6:31742875:AGTTC:A	acceptor_loss	1.0000
6:31742876:G:A	acceptor_loss	1.0000
6:31742876:G:GG	acceptor_gain	1.0000
6:31742876:GTTCT:G	acceptor_gain	1.0000
6:31742953:GCTTG:G	donor_gain	1.0000
6:31742957:GGT:G	donor_loss	1.0000
6:31742957:GGTA:G	donor_loss	1.0000
6:31742958:G:GA	donor_loss	1.0000
6:31742958:G:GG	donor_gain	1.0000
6:31742959:TAA:T	donor_loss	1.0000
6:31744026:G:GG	donor_gain	1.0000
6:31744280:GGCTT:G	donor_gain	1.0000
6:31744281:GCTT:G	donor_gain	1.0000
6:31744297:GTT:G	donor_gain	1.0000
6:31744300:G:GG	donor_gain	1.0000
6:31753436:GCCT:G	donor_gain	1.0000
6:31753440:G:GG	donor_gain	1.0000
6:31758164:GACT:G	acceptor_gain	1.0000

AlphaMissense

5451 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:31745310:A:C	S253R	0.999
6:31745312:C:A	S253R	0.999
6:31745312:C:G	S253R	0.999
6:31753612:T:A	W333R	0.999
6:31753612:T:C	W333R	0.999
6:31759103:T:C	F445L	0.999
6:31759105:C:A	F445L	0.999
6:31759105:C:G	F445L	0.999
6:31759107:T:C	L446P	0.999
6:31759425:T:C	F470L	0.999
6:31759427:T:A	F470L	0.999
6:31759427:T:G	F470L	0.999
6:31759449:T:G	Y478D	0.999
6:31760832:T:C	L652P	0.999
6:31745242:T:C	L230P	0.998
6:31747403:C:G	C261W	0.998
6:31759101:G:A	G444D	0.998
6:31759455:A:C	S480R	0.998
6:31759457:T:A	S480R	0.998
6:31759457:T:G	S480R	0.998
6:31760092:A:G	H563R	0.998
6:31760199:A:C	S599R	0.998
6:31760201:C:A	S599R	0.998
6:31760201:C:G	S599R	0.998
6:31760723:A:C	S616R	0.998
6:31760725:C:A	S616R	0.998
6:31760725:C:G	S616R	0.998
6:31760819:T:C	F648L	0.998
6:31760821:C:A	F648L	0.998
6:31760821:C:G	F648L	0.998

dbSNP variants (sampled 300 via entrez): RS1000273001 (6:31753093 A>G), RS1000398315 (6:31738730 CT>C), RS1000439216 (6:31740156 G>A), RS1000871989 (6:31739268 C>CT), RS1000872130 (6:31739921 G>C), RS1000936078 (6:31745070 C>A), RS1000968455 (6:31744815 C>A), RS1001102639 (6:31744679 G>T), RS1001548879 (6:31754828 T>A,C), RS1001561816 (6:31738107 C>A), RS1001610907 (6:31748110 C>G,T), RS1001633527 (6:31738468 G>A), RS1001644972 (6:31747720 G>A,C,T), RS1001668923 (6:31761838 T>C), RS1001765152 (6:31745179 A>G)

Disease associations

OMIM: gene MIM:603382 | disease phenotypes: MIM:619937, MIM:617442

GenCC curated gene-disease

Disease	Classification	Inheritance
spermatogenic failure 74	Strong	Autosomal recessive
premature ovarian failure 13	Moderate	Autosomal recessive

Mondo (3): spermatogenic failure 74 (MONDO:0030972), premature ovarian failure 13 (MONDO:0044317), azoospermia (MONDO:0100459)

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

HPO phenotypes

17 total (17 of 17 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000013	Hypoplasia of the uterus
HP:0000027	Azoospermia
HP:0000118	Phenotypic abnormality
HP:0000141	Amenorrhea
HP:0000837	Increased circulating gonadotropin level
HP:0000876	Oligomenorrhea
HP:0003251	Male infertility
HP:0003621	Juvenile onset
HP:0008222	Female infertility
HP:0008232	Elevated circulating follicle stimulating hormone level
HP:0008669	Abnormal spermatogenesis
HP:0008734	Decreased testicular size
HP:0011462	Young adult onset
HP:0011961	Non-obstructive azoospermia
HP:0011962	Obstructive azoospermia
HP:0031038	Spermatogenesis maturation arrest

GWAS associations

40 associations (top):

Study	Trait	p-value
GCST000257_1	Lung cancer	5.000000e-10
GCST002453_3	Ulcerative colitis	5.000000e-14
GCST002884_5	Cutaneous lupus erythematosus	3.000000e-14
GCST003103_6	Systemic lupus erythematosus	8.000000e-08
GCST003450_2	Clozapine-induced agranulocytosis/granulocytopenia in treatment-resistant schizophrenia	3.000000e-09
GCST004131_25	Inflammatory bowel disease	2.000000e-31
GCST004133_79	Ulcerative colitis	5.000000e-65
GCST004521_114	Autism spectrum disorder or schizophrenia	3.000000e-17
GCST004521_117	Autism spectrum disorder or schizophrenia	3.000000e-15
GCST004521_126	Autism spectrum disorder or schizophrenia	2.000000e-10
GCST004521_154	Autism spectrum disorder or schizophrenia	3.000000e-08
GCST004521_17	Autism spectrum disorder or schizophrenia	2.000000e-12
GCST004521_209	Autism spectrum disorder or schizophrenia	5.000000e-16
GCST004521_211	Autism spectrum disorder or schizophrenia	5.000000e-15
GCST004521_213	Autism spectrum disorder or schizophrenia	5.000000e-13
GCST004521_224	Autism spectrum disorder or schizophrenia	5.000000e-10
GCST004521_227	Autism spectrum disorder or schizophrenia	4.000000e-12
GCST004521_265	Autism spectrum disorder or schizophrenia	7.000000e-14
GCST004521_281	Autism spectrum disorder or schizophrenia	5.000000e-09
GCST004521_296	Autism spectrum disorder or schizophrenia	6.000000e-18
GCST004521_45	Autism spectrum disorder or schizophrenia	2.000000e-16
GCST004521_70	Autism spectrum disorder or schizophrenia	8.000000e-20
GCST004521_81	Autism spectrum disorder or schizophrenia	1.000000e-14
GCST005312_21	Menopause (age at onset)	8.000000e-10
GCST005312_22	Menopause (age at onset)	7.000000e-15
GCST006228_4	Systolic blood pressure	6.000000e-08
GCST006230_2	Pulse pressure	3.000000e-09
GCST006575_37	Takayasu arteritis	8.000000e-08
GCST006575_46	Takayasu arteritis	5.000000e-06
GCST006988_137	Blond vs. brown/black hair color	3.000000e-08

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004704	age at menopause
EFO:0006335	systolic blood pressure
EFO:0005763	pulse pressure measurement
EFO:0003924	hair color
EFO:0009938	Anilide use measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0007789	BMI-adjusted waist circumference

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)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs3115672	Toxicity	3	carboplatin;gemcitabine	Non-Small Cell Lung Carcinoma;Thrombocytopenia

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3115672	MSH5	3	2.50	1	carboplatin;gemcitabine

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression	3
Tobacco Smoke Pollution	decreases expression, affects expression	3
Benzo(a)pyrene	affects methylation, decreases expression	2
GSK-J4	decreases expression	1
apocarotenal	increases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	decreases expression, increases activity, affects binding	1
beta-lapachone	decreases expression	1
CGP 52608	increases reaction, affects binding	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	increases expression, affects cotreatment	1
jinfukang	increases expression	1
Sunitinib	decreases expression	1
Arsenic	affects methylation	1
Calcitriol	affects cotreatment, decreases expression	1
Quercetin	increases expression	1
Rotenone	increases expression	1
Selenium	decreases expression	1
Testosterone	affects cotreatment, decreases expression	1
Tetrachlorodibenzodioxin	affects cotreatment, increases expression	1
Thiram	decreases expression	1
Urethane	decreases expression	1
Valproic Acid	affects expression	1
Vitamin E	decreases expression	1
Gold Compounds	increases expression	1
beta Carotene	increases expression	1
Okadaic Acid	decreases expression	1
Copper Sulfate	increases expression	1
Acrylamide	decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1XM	Abcam HeLa MSH5 KO	Cancer cell line	Female
CVCL_SY99	HAP1 MSH5 (-) 1	Cancer cell line	Male
CVCL_SZ00	HAP1 MSH5 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

28 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
NCT04009473	PHASE1/PHASE2	UNKNOWN	Stem Cell Therapy and Growth Factor Ovarian in Vitro Activation
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