HORMAD2

Summary

HORMAD2 (HORMA domain containing 2, HGNC:28383) is a protein-coding gene on chromosome 22q12.2, encoding HORMA domain-containing protein 2 (Q8N7B1). Essential for synapsis surveillance during meiotic prophase via the recruitment of ATR activity.

Predicted to be involved in meiotic cell cycle and meiotic sister chromatid cohesion. Located in centrosome; cytosol; and nucleoplasm.

Source: NCBI Gene 150280 — RefSeq curated summary.

At a glance

• GWAS associations: 36
• Clinical variants (ClinVar): 34 total
• MANE Select transcript: NM_152510

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28383
Approved symbol	HORMAD2
Name	HORMA domain containing 2
Location	22q12.2
Locus type	gene with protein product
Status	Approved
Aliases	MGC26710, CT46.2
Ensembl gene	ENSG00000176635
Ensembl biotype	protein_coding
OMIM	618842
Entrez	150280

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000336726, ENST00000403975, ENST00000450612, ENST00000491605, ENST00000862797, ENST00000862798

RefSeq mRNA: 3 — MANE Select: NM_152510 NM_001329457, NM_001329458, NM_152510

CCDS: CCDS46683

Canonical transcript exons

ENST00000336726 — 11 exons

Exon	Start	End
ENSE00001216086	30121964	30122214
ENSE00001216149	30093916	30094003
ENSE00001313273	30080464	30080491
ENSE00001342290	30176063	30177075
ENSE00001560303	30104401	30104437
ENSE00003476447	30103437	30103500
ENSE00003501240	30121632	30121789
ENSE00003545337	30112496	30112522
ENSE00003666975	30111796	30111816
ENSE00003675758	30118980	30119047
ENSE00003676611	30098852	30098993

Expression profiles

Bgee: expression breadth broad, 66 present calls, max score 87.78.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0224 / max 12.6304, expressed in 5 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
191638	0.0224	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	87.78	gold quality
left testis	UBERON:0004533	87.38	gold quality
testis	UBERON:0000473	85.04	gold quality
sperm	CL:0000019	84.99	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.41	gold quality
epithelial cell of pancreas	CL:0000083	72.37	gold quality
pigmented layer of retina	UBERON:0001782	71.90	gold quality
ileal mucosa	UBERON:0000331	68.78	silver quality
tibialis anterior	UBERON:0001385	66.95	silver quality
adult organism	UBERON:0007023	65.83	gold quality
right lobe of liver	UBERON:0001114	61.86	gold quality
liver	UBERON:0002107	57.50	gold quality
pancreatic ductal cell	CL:0002079	56.44	silver quality
deltoid	UBERON:0001476	55.33	gold 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
upper arm skin	UBERON:0004263	53.52	gold quality
myocardium	UBERON:0002349	50.25	gold quality
caudate nucleus	UBERON:0001873	49.30	gold quality
ventricular zone	UBERON:0003053	48.58	gold quality
ganglionic eminence	UBERON:0004023	48.48	gold quality
nasal cavity epithelium	UBERON:0005384	47.54	gold quality
quadriceps femoris	UBERON:0001377	47.51	gold quality
putamen	UBERON:0001874	47.02	gold quality
cardia of stomach	UBERON:0001162	46.66	gold quality
nucleus accumbens	UBERON:0001882	46.25	gold quality
vastus lateralis	UBERON:0001379	45.47	gold quality
substantia nigra	UBERON:0002038	45.44	gold quality
layer of synovial tissue	UBERON:0007616	45.31	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.25

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

36 targeting HORMAD2, 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-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-4666B	99.64	68.69	1282
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-888-3P	99.53	69.77	1057
HSA-MIR-216A-5P	99.50	68.02	1288
HSA-MIR-657	99.48	66.02	848
HSA-MIR-32-3P	99.36	68.20	2517
HSA-MIR-133A-3P	99.27	71.53	1270
HSA-MIR-133B	99.27	71.53	1270
HSA-MIR-1228-3P	99.00	66.53	857
HSA-MIR-12135	98.99	70.26	1814
HSA-MIR-491-3P	98.88	68.86	1224
HSA-MIR-3124-3P	98.87	68.95	2123
HSA-MIR-3074-5P	98.82	66.56	1414
HSA-MIR-655-5P	98.74	65.93	888

Literature-anchored findings (GeneRIF, showing 7)

• HORMAD2 is predominantly expressed in human testis and weakly expressed in liver. HORMAD2 is ectopically expressed in nearly 10% of lung cancer samples from Chinese Han individuals. (PMID:22893617)
• These findings indicate that polymorphisms at the CT gene HORMAD2 might be involved in the prognosis of advanced non-small-cell lung cancer in Han Chinese. (PMID:24797335)
• Hormad1 and Hormad2 might not be the susceptible genes for the non-obstructive azoospermia in our study population. However, rs718772 of Hormad2 variant might be associated with testis development in NOA patients. (PMID:24803422)
• The variant rs2412971, intronic in HORMAD2 at chromosome 22q12.2, was robustly associated with tonsillectomy. (PMID:27941131)
• Hypermethylation of HORMAD2 could induce thyroid carcinoma progression, while hypomethylation of HORMAD2 retards cell growth and mobility and facilitates apoptosis through increasing its mRNA expression. (PMID:30039914)
• Identification of susceptibility locus shared by IgA nephropathy and inflammatory bowel disease in a Chinese Han population. (PMID:31857673)
• A homozygous stop codon in HORMAD2 in a patient with recurrent digynic triploid miscarriage. (PMID:38400599)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
mus_musculus	Hormad2	ENSMUSG00000020419
rattus_norvegicus	Hormad2	ENSRNOG00000037865
caenorhabditis_elegans		WBGENE00001862
caenorhabditis_elegans		WBGENE00002032
caenorhabditis_elegans		WBGENE00002033

Paralogs (1): HORMAD1 (ENSG00000143452)

Protein

Protein identifiers

HORMA domain-containing protein 2 — Q8N7B1 (reviewed: Q8N7B1)

All UniProt accessions (2): Q8N7B1, F8WES9

UniProt curated annotations — full annotation on UniProt →

Function. Essential for synapsis surveillance during meiotic prophase via the recruitment of ATR activity. Plays a key role in the male mid-pachytene checkpoint and the female meiotic prophase checkpoint: required for efficient build-up of ATR activity on unsynapsed chromosome regions, a process believed to form the basis of meiotic silencing of unsynapsed chromatin (MSUC) and meiotic prophase quality control in both sexes. Required for the DNA double-strand break-independent, BRCA1-dependent activation of ATR on the sex chromosomes that is essential for normal sex body formation.

Subunit / interactions. Interacts with HORMAD1.

Subcellular location. Nucleus. Chromosome.

Tissue specificity. Highly expressed in testis (at protein level). Expressed in lung adenocarcinoma and squamous cell carcinoma (at protein level). Expressed at lower levels in the liver, brain and kidney.

Post-translational modifications. Phosphorylated in a SPO11-dependent manner.

RefSeq proteins (3): NP_001316386, NP_001316387, NP_689723* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003511	HORMA_dom	Domain
IPR036570	HORMA_dom_sf	Homologous_superfamily
IPR051294	HORMA_MeioticProgression	Family

Pfam: PF02301

UniProt features (5 total): sequence variant 2, chain 1, domain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N7B1-F1	72.61	0.40

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 74 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, GOBP_MEIOTIC_CHROMOSOME_SEGREGATION, GOBP_CHROMOSOME_ORGANIZATION, GOBP_NEGATIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_REGULATION_OF_NUCLEAR_DIVISION, GOBP_REGULATION_OF_MEIOTIC_NUCLEAR_DIVISION, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_NEGATIVE_REGULATION_OF_MEIOTIC_NUCLEAR_DIVISION, GOBP_REGULATION_OF_MEIOTIC_CELL_CYCLE, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_SYNAPTONEMAL_COMPLEX_ORGANIZATION, GOBP_NEGATIVE_REGULATION_OF_MEIOTIC_CELL_CYCLE, GOBP_ORGANELLE_FISSION, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE_PROCESS, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE

GO Biological Process (2): meiotic sister chromatid cohesion (GO:0051177), meiotic cell cycle (GO:0051321)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (6): synaptonemal complex (GO:0000795), nucleus (GO:0005634), nucleoplasm (GO:0005654), chromosome (GO:0005694), centrosome (GO:0005813), cytosol (GO:0005829)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
sister chromatid cohesion	1
cell cycle	1
sexual reproduction	1
reproductive process	1
meiotic nuclear division	1
binding	1
synaptonemal structure	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular membraneless organelle	1
centriole	1
microtubule organizing center	1
cytoplasm	1

Protein interactions and networks

STRING

1111 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HORMAD2	SYCP3	Q8IZU3	979
HORMAD2	MSH4	O15457	929
HORMAD2	SPO11	Q9Y5K1	815
HORMAD2	REC8	O95072	782
HORMAD2	MSH5	O43196	777
HORMAD2	SYCP1	Q15431	763
HORMAD2	SYCE1	Q8N0S2	723
HORMAD2	SMC3	Q9UQE7	709
HORMAD2	SYCE2	Q6PIF2	707
HORMAD2	STAG3	Q9UJ98	691
HORMAD2	SYCP2	Q9BX26	689
HORMAD2	TRIP13	Q15645	688
HORMAD2	TERB1	Q8NA31	674
HORMAD2	TEX11	Q8IYF3	663
HORMAD2	MAD2L2	Q9UI95	658

IntAct

10 interactions, top by confidence:

A	B	Type	Score
NSD2	HORMAD2	psi-mi:“MI:0915”(physical association)	0.560
STUB1	DNAJC13	psi-mi:“MI:0914”(association)	0.530
COPE	COPB2	psi-mi:“MI:0914”(association)	0.530
HORMAD2	PDLIM1	psi-mi:“MI:0915”(physical association)	0.500
TADA2A	IGLL5	psi-mi:“MI:0914”(association)	0.350
HORMAD2	WASH3P	psi-mi:“MI:0914”(association)	0.350
HORMAD2	NSD2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (31): HORMAD2 (Affinity Capture-MS), HORMAD2 (Two-hybrid), HORMAD2 (Reconstituted Complex), HORMAD2 (Protein-peptide), HORMAD2 (Synthetic Lethality), HORMAD2 (Two-hybrid), NRN1 (Affinity Capture-MS), TRIM24 (Affinity Capture-MS), CCDC53 (Affinity Capture-MS), KIAA1033 (Affinity Capture-MS), MCM9 (Affinity Capture-MS), HIST2H2AC (Affinity Capture-MS), WASH3P (Affinity Capture-MS), KDM2A (Affinity Capture-MS), GAP43 (Affinity Capture-MS)

ESM2 similar proteins: A0A571BF63, A2BF66, A6QQY4, B0UYH6, D3ZWE7, E2QXH7, F6RRD7, O60566, O88665, P23611, P38531, Q05B18, Q08DB0, Q0P4I1, Q28IH8, Q2KIY6, Q3B7T8, Q3U1T9, Q3UB74, Q3YBR2, Q4R8B9, Q5HZK1, Q5I0E6, Q5JTW2, Q5M7C8, Q5PQK8, Q5PQQ9, Q5R789, Q5RA37, Q5SQP1, Q5XIZ9, Q66IH2, Q6IQY5, Q6NZY4, Q7T0S7, Q7Z3E5, Q86VD1, Q86X24, Q8BMD7, Q8C5W4

Diamond homologs: A2BF66, A6QQY4, D3ZWE7, E2IUK4, E2QXH7, E2RSQ2, F4HRV8, Q2KIY6, Q4R8B9, Q5M7C8, Q5SQP1, Q76CY8, Q86X24, Q8N7B1, Q9D5T7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	27
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1702 predictions. Top by Δscore:

Variant	Effect	Δscore
22:30093995:GCTTC:G	donor_gain	1.0000
22:30121630:A:AG	acceptor_gain	1.0000
22:30121631:G:GT	acceptor_gain	1.0000
22:30121631:GTC:G	acceptor_gain	1.0000
22:30121959:C:CA	acceptor_gain	1.0000
22:30121959:CGCA:C	acceptor_loss	1.0000
22:30121961:CAG:C	acceptor_loss	1.0000
22:30121962:A:AG	acceptor_gain	1.0000
22:30121962:AGT:A	acceptor_gain	1.0000
22:30121963:G:GA	acceptor_gain	1.0000
22:30121963:GT:G	acceptor_gain	1.0000
22:30121963:GTG:G	acceptor_gain	1.0000
22:30122194:G:GT	donor_gain	1.0000
22:30122211:CCAT:C	donor_gain	1.0000
22:30122215:G:GG	donor_gain	1.0000
22:30099000:T:G	donor_gain	0.9900
22:30101403:G:GT	donor_gain	0.9900
22:30111817:G:GG	donor_gain	0.9900
22:30118968:T:A	acceptor_gain	0.9900
22:30121628:GTAGT:G	acceptor_loss	0.9900
22:30121629:TAG:T	acceptor_gain	0.9900
22:30121629:TAGT:T	acceptor_loss	0.9900
22:30121631:GT:G	acceptor_gain	0.9900
22:30121631:GTCA:G	acceptor_gain	0.9900
22:30121631:GTCAT:G	acceptor_gain	0.9900
22:30121788:AG:A	donor_loss	0.9900
22:30121789:GG:G	donor_loss	0.9900
22:30121790:G:A	donor_loss	0.9900
22:30121791:TAG:T	donor_loss	0.9900
22:30121955:A:AG	acceptor_gain	0.9900

AlphaMissense

2071 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:30121993:T:C	F200L	0.996
22:30121995:T:A	F200L	0.996
22:30121995:T:G	F200L	0.996
22:30098950:G:C	R50S	0.991
22:30098950:G:T	R50S	0.991
22:30121994:T:C	F200S	0.991
22:30119002:T:C	F122S	0.990
22:30098949:G:C	R50T	0.987
22:30098949:G:T	R50M	0.987
22:30104411:T:C	C90R	0.987
22:30118995:T:G	Y120D	0.987
22:30098930:T:C	S44P	0.985
22:30119008:T:C	F124S	0.984
22:30103499:T:A	W86R	0.983
22:30103499:T:C	W86R	0.983
22:30104420:G:C	A93P	0.983
22:30098913:T:C	L38P	0.982
22:30104413:T:G	C90W	0.982
22:30098942:T:G	Y48D	0.980
22:30098958:T:C	F53S	0.979
22:30111797:T:C	L99P	0.978
22:30111806:C:A	A102E	0.978
22:30111812:T:C	L104P	0.978
22:30111805:G:C	A102P	0.977
22:30103455:T:A	L71H	0.976
22:30121772:T:C	L184P	0.976
22:30098924:T:C	S42P	0.974
22:30098946:T:C	L49P	0.974
22:30121706:G:C	R162P	0.974
22:30121994:T:G	F200C	0.971

dbSNP variants (sampled 300 via entrez): RS1000010554 (22:30095752 A>G), RS1000035383 (22:30137073 T>C), RS1000044166 (22:30186631 G>A), RS1000090365 (22:30136810 TC>T), RS1000094448 (22:30157789 G>A), RS1000113127 (22:30168997 G>C), RS1000146106 (22:30126469 G>A), RS1000224693 (22:30178918 C>T), RS1000271980 (22:30168571 A>G), RS1000301442 (22:30112130 T>G), RS1000308612 (22:30115109 G>A,C), RS1000330982 (22:30206622 C>T), RS1000339322 (22:30164126 A>C), RS1000368475 (22:30082298 G>A), RS1000383793 (22:30130445 T>C)

Disease associations

OMIM: gene MIM:618842 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

36 associations (top):

Study	Trait	p-value
GCST000531_1	Inflammatory bowel disease (early onset)	2.000000e-09
GCST001009_3	Nephropathy	2.000000e-09
GCST002655_12	IgA nephropathy	5.000000e-12
GCST002655_16	IgA nephropathy	6.000000e-11
GCST002763_17	Optic disc area	1.000000e-06
GCST002763_9	Optic disc area	3.000000e-08
GCST002943_9	IgA nephropathy	3.000000e-09
GCST003974_1	Tonsillectomy	1.000000e-09
GCST004131_67	Inflammatory bowel disease	4.000000e-08
GCST004132_86	Crohn’s disease	8.000000e-07
GCST004627_116	Lymphocyte count	3.000000e-21
GCST004630_37	Mean corpuscular hemoglobin	5.000000e-15
GCST004632_81	Lymphocyte percentage of white cells	1.000000e-13
GCST004633_17	Neutrophil percentage of white cells	7.000000e-10
GCST005575_5	Moyamoya disease	8.000000e-12
GCST005851_15	Delirium	1.000000e-06
GCST005987_7	Albumin-globulin ratio	2.000000e-10
GCST005990_27	Non-albumin protein levels	3.000000e-10
GCST006014_30	Creatine kinase levels	1.000000e-08
GCST006867_88	Type 2 diabetes	9.000000e-09
GCST007932_5	Medication use (thyroid preparations)	3.000000e-14
GCST009144_10	Disease progression in age-related macular degeneration (adjusted for baseline)	7.000000e-06
GCST009404_5	Optic cup area	5.000000e-09
GCST009412_17	Vertical cup-disc ratio	2.000000e-09
GCST009723_36	Vertical cup-disc ratio (adjusted for vertical disc diameter)	9.000000e-14
GCST009724_105	Vertical cup-disc ratio (multi-trait analysis)	8.000000e-19
GCST009875_14	Type 1 diabetes	2.000000e-11
GCST010571_78	Autoimmune thyroid disease	7.000000e-15
GCST011781_9	IgA nephropathy	6.000000e-13
GCST012073_22	Behcet’s disease	2.000000e-06

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0007924	tonsillectomy risk measurement
EFO:0004587	lymphocyte count
EFO:0004527	mean corpuscular hemoglobin
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0007990	neutrophil percentage of leukocytes
EFO:0005128	albumin:globulin ratio measurement
EFO:0004534	creatine kinase measurement
EFO:0009933	Thyroid preparation use measurement
EFO:0008336	disease progression measurement
EFO:0006939	cup-to-disc ratio measurement
EFO:0004980	appendicular lean mass

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

6 total (human), top 6 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation, increases methylation	2
abrine	increases expression	1
theaflavin-3,3’-digallate	affects expression	1
Smoke	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

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