ARMC2

Summary

ARMC2 (armadillo repeat containing 2, HGNC:23045) is a protein-coding gene on chromosome 6q21, encoding Armadillo repeat-containing protein 2 (Q8NEN0). Required for sperm flagellum axoneme organization and function.

Involved in sperm axoneme assembly. Implicated in spermatogenic failure 38.

Source: NCBI Gene 84071 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spermatogenic failure 38 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 23
• Clinical variants (ClinVar): 214 total — 6 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 9
• MANE Select transcript: NM_032131

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23045
Approved symbol	ARMC2
Name	armadillo repeat containing 2
Location	6q21
Locus type	gene with protein product
Status	Approved
Aliases	DKFZp434P0714, bA787I22.1
Ensembl gene	ENSG00000118690
Ensembl biotype	protein_coding
OMIM	618424
Entrez	84071

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000237512, ENST00000368972, ENST00000392644, ENST00000414610, ENST00000481850, ENST00000896778, ENST00000941042

RefSeq mRNA: 2 — MANE Select: NM_032131 NM_001286609, NM_032131

CCDS: CCDS5069, CCDS69168

Canonical transcript exons

ENST00000392644 — 18 exons

Exon	Start	End
ENSE00000800330	108899694	108899792
ENSE00000800331	108894467	108894543
ENSE00001018230	108904230	108904405
ENSE00001018233	108964980	108965140
ENSE00001018238	108910899	108911001
ENSE00001018240	108936900	108936999
ENSE00001018241	108953033	108953351
ENSE00001018242	108912335	108912558
ENSE00001018245	108928088	108928233
ENSE00001628227	108858199	108858271
ENSE00001913943	108973357	108974476
ENSE00001919836	108848422	108848546
ENSE00003466479	108961572	108961694
ENSE00003526859	108964180	108964312
ENSE00003535287	108854225	108854485
ENSE00003558115	108962014	108962127
ENSE00003623070	108876143	108876350
ENSE00003679116	108868824	108868995

Expression profiles

Bgee: expression breadth ubiquitous, 173 present calls, max score 98.49.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.9034 / max 110.5611, expressed in 1676 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
69210	8.3175	1671
69211	0.5688	268
69212	0.0171	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	98.49	gold quality
right uterine tube	UBERON:0001302	95.87	gold quality
secondary oocyte	CL:0000655	95.77	gold quality
sperm	CL:0000019	95.17	gold quality
bronchial epithelial cell	CL:0002328	92.10	gold quality
bronchus	UBERON:0002185	89.81	gold quality
left testis	UBERON:0004533	87.67	gold quality
right testis	UBERON:0004534	87.53	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.50	gold quality
testis	UBERON:0000473	85.55	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	85.24	gold quality
cortical plate	UBERON:0005343	85.10	gold quality
calcaneal tendon	UBERON:0003701	84.20	gold quality
mucosa of paranasal sinus	UBERON:0005030	83.76	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.08	gold quality
popliteal artery	UBERON:0002250	81.25	gold quality
tibial artery	UBERON:0007610	81.22	gold quality
right hemisphere of cerebellum	UBERON:0014890	81.18	gold quality
adenohypophysis	UBERON:0002196	80.82	gold quality
right coronary artery	UBERON:0001625	80.63	gold quality
ventricular zone	UBERON:0003053	80.41	gold quality
apex of heart	UBERON:0002098	80.11	gold quality
aorta	UBERON:0000947	80.02	gold quality
right atrium auricular region	UBERON:0006631	79.89	gold quality
left coronary artery	UBERON:0001626	79.83	gold quality
cerebellar hemisphere	UBERON:0002245	79.72	gold quality
cerebellar cortex	UBERON:0002129	79.62	gold quality
fallopian tube	UBERON:0003889	79.26	gold quality
pituitary gland	UBERON:0000007	79.20	gold quality
monocyte	CL:0000576	79.19	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.60
E-GEOD-99795	no	18.43

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

48 targeting ARMC2, 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-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
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-5696	99.98	72.36	4487
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-139-5P	99.80	69.50	1399
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-545-5P	99.66	70.18	2308
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-6757-3P	99.63	66.88	1089
HSA-MIR-2053	99.57	69.15	1635
HSA-MIR-3136-3P	99.57	66.59	781
HSA-MIR-7155-3P	99.57	66.48	794
HSA-MIR-3123	99.47	67.15	2693
HSA-MIR-4728-3P	99.47	68.94	981
HSA-MIR-569	99.42	66.32	1009
HSA-MIR-155-5P	99.35	70.16	1509
HSA-MIR-2116-5P	99.32	69.34	1273

Literature-anchored findings (GeneRIF, showing 3)

• bi-allelic mutations in ARMC2 cause male infertility in humans and mice by inducing a typical “multiple morphological abnormalities of the flagella” phenotype, indicating that this gene is necessary for sperm flagellum structure and assembly (PMID:30686508)
• A novel stop-gain mutation in ARMC2 is associated with multiple morphological abnormalities of the sperm flagella. (PMID:34493464)
• Identification of novel homozygous asthenoteratospermia-causing ARMC2 mutations associated with multiple morphological abnormalities of the sperm flagella. (PMID:38492154)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	armc2	ENSDARG00000022660
mus_musculus	Armc2	ENSMUSG00000071324
rattus_norvegicus	Armc2	ENSRNOG00000026217
drosophila_melanogaster	CG32668	FBGN0052668

Protein

Protein identifiers

Armadillo repeat-containing protein 2 — Q8NEN0 (reviewed: Q8NEN0)

All UniProt accessions (3): Q8NEN0, A0A0A0MQT2, H0Y4P5

UniProt curated annotations — full annotation on UniProt →

Function. Required for sperm flagellum axoneme organization and function. Involved in axonemal central pair complex assembly and/or stability.

Tissue specificity. Expressed at higher level in testis.

Disease relevance. Spermatogenic failure 38 (SPGF38) [MIM:618433] An autosomal recessive infertility disorder characterized by asthenoteratozoospermia. Spermatozoa exhibit multiple morphologic abnormalities including short, absent, coiled, bent, or irregular-caliber flagella. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8NEN0-1	1	yes
Q8NEN0-2	2

RefSeq proteins (2): NP_001273538, NP_115507* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000225	Armadillo	Repeat
IPR011989	ARM-like	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR038905	ARMC2	Family

UniProt features (26 total): repeat 12, compositionally biased region 5, sequence variant 4, region of interest 2, chain 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NEN0-F1	75.57	0.55

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 114 (showing top): GOBP_MALE_GAMETE_GENERATION, SENGUPTA_NASOPHARYNGEAL_CARCINOMA_DN, WCTCNATGGY_UNKNOWN, GOBP_NUCLEUS_ORGANIZATION, GOBP_CILIUM_ORGANIZATION, GOBP_CILIUM_MOVEMENT, GOBP_CILIUM_OR_FLAGELLUM_DEPENDENT_CELL_MOTILITY, GOBP_ORGANELLE_ASSEMBLY, GOBP_CELLULAR_PROCESS_INVOLVED_IN_REPRODUCTION_IN_MULTICELLULAR_ORGANISM, GOBP_MICROTUBULE_BUNDLE_FORMATION, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, GOBP_MOTILE_CILIUM_ASSEMBLY, GOBP_CELL_PROJECTION_ORGANIZATION, GOBP_AXONEME_ASSEMBLY, DODD_NASOPHARYNGEAL_CARCINOMA_DN

GO Biological Process (7): cell morphogenesis (GO:0000902), nucleus organization (GO:0006997), sperm axoneme assembly (GO:0007288), cilium organization (GO:0044782), spermatogenesis (GO:0007283), cell differentiation (GO:0030154), flagellated sperm motility (GO:0030317)

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

GO Cellular Component (0):

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
organelle organization	2
developmental process involved in reproduction	2
anatomical structure morphogenesis	1
axoneme assembly	1
sperm flagellum assembly	1
plasma membrane bounded cell projection organization	1
male gamete generation	1
cellular developmental process	1
cilium-dependent cell motility	1
cilium movement involved in cell motility	1
sperm motility	1
binding	1

Protein interactions and networks

STRING

604 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ARMC2	CFAP43	Q8NDM7	698
ARMC2	QRICH2	Q9H0J4	687
ARMC2	TTC21A	Q8NDW8	684
ARMC2	CFAP69	A5D8W1	670
ARMC2	SPEF2	Q9C093	653
ARMC2	CFAP251	Q8TBY9	640
ARMC2	DNAH1	Q9P2D7	637
ARMC2	CFAP44	Q96MT7	633
ARMC2	TTC29	Q8NA56	626
ARMC2	CFAP70	Q5T0N1	622
ARMC2	CCDC38	Q502W7	605
ARMC2	FSIP2	Q5CZC0	601
ARMC2	CFAP58	Q5T655	596
ARMC2	SPATA9	Q9BWV2	572
ARMC2	DNAH17	Q9UFH2	572

IntAct

4 interactions, top by confidence:

A	B	Type	Score
ARMC2	NDUFA9	psi-mi:“MI:0915”(physical association)	0.400
PYCARD	MYO1C	psi-mi:“MI:0914”(association)	0.350
IGHG1	PDPK1	psi-mi:“MI:0914”(association)	0.350

BioGRID (6): ARMC2 (Affinity Capture-MS), ARMC2 (Affinity Capture-RNA), ARMC2 (Affinity Capture-MS), ARMC2 (Proximity Label-MS), HSPA1A (Cross-Linking-MS (XL-MS)), TRMT1 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A5F9C6I2, A1L3F5, B0I564, B1AY13, D3ZXK7, F8VPU6, O15259, O15327, O17482, O95876, P21359, P49021, P50851, P97526, Q04690, Q2HJ90, Q3B7T1, Q4KM95, Q4QQM5, Q4R4D7, Q5R9R1, Q5RA60, Q5U1Z0, Q5XPI3, Q5XPI4, Q62717, Q6GLR7, Q6GQV7, Q6P4S8, Q6VNB8, Q7TMY8, Q7Z494, Q7Z6Z7, Q86UW7, Q8BYR5, Q8IY22, Q8IZQ1, Q8N201, Q8NAN2, Q8NEN0

Diamond homologs: P0C6R2, Q3URY6, Q8NEN0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	1
Uncertain significance	150
Likely benign	14
Benign	8

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
3389825	NM_032131.6(ARMC2):c.279dup (p.Pro94fs)	Pathogenic
617790	NM_032131.6(ARMC2):c.1023+1G>A	Pathogenic
627628	NM_032131.6(ARMC2):c.2279T>A (p.Ile760Asn)	Pathogenic
627629	NM_032131.6(ARMC2):c.2353_2354del (p.Leu785fs)	Pathogenic
627630	NM_032131.6(ARMC2):c.1284_1288del (p.Lys428fs)	Pathogenic
627631	NM_032131.6(ARMC2):c.421C>T (p.Gln141Ter)	Pathogenic
3239656	NM_032131.6(ARMC2):c.2227A>G (p.Asn743Asp)	Likely pathogenic

SpliceAI

4103 predictions. Top by Δscore:

Variant	Effect	Δscore
6:108868912:GA:G	donor_gain	1.0000
6:108868914:G:GG	donor_gain	1.0000
6:108876141:A:AG	acceptor_gain	1.0000
6:108876142:G:GA	acceptor_gain	1.0000
6:108876142:GC:G	acceptor_gain	1.0000
6:108876346:GGAGG:G	donor_gain	1.0000
6:108876347:GAGG:G	donor_gain	1.0000
6:108876347:GAGGG:G	donor_gain	1.0000
6:108876348:AGGG:A	donor_loss	1.0000
6:108876349:GG:G	donor_gain	1.0000
6:108876350:GG:G	donor_gain	1.0000
6:108876351:GTCA:G	donor_loss	1.0000
6:108899761:G:GT	donor_gain	1.0000
6:108899762:A:T	donor_gain	1.0000
6:108904403:GCA:G	donor_gain	1.0000
6:108904406:G:GG	donor_gain	1.0000
6:108927308:G:GT	donor_gain	1.0000
6:108936886:T:TA	acceptor_gain	1.0000
6:108961679:C:G	donor_gain	1.0000
6:108961691:GAAT:G	donor_gain	1.0000
6:108961695:G:GG	donor_gain	1.0000
6:108961998:T:TA	acceptor_gain	1.0000
6:108962007:A:G	acceptor_gain	1.0000
6:108962012:A:AG	acceptor_gain	1.0000
6:108962012:AGT:A	acceptor_gain	1.0000
6:108962013:G:GA	acceptor_gain	1.0000
6:108962013:GTG:G	acceptor_gain	1.0000
6:108962124:AATGG:A	donor_loss	1.0000
6:108962125:ATG:A	donor_gain	1.0000
6:108962125:ATGGT:A	donor_loss	1.0000

AlphaMissense

5701 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:108962061:G:C	A696P	0.992
6:108962083:T:C	L703P	0.990
6:108973453:T:C	L848P	0.989
6:108953070:T:C	L545P	0.988
6:108953054:T:C	F540L	0.987
6:108953056:T:A	F540L	0.987
6:108953056:T:G	F540L	0.987
6:108964258:T:C	L744P	0.987
6:108965038:T:C	C782R	0.987
6:108962068:G:C	R698P	0.986
6:108965017:T:A	W775R	0.984
6:108965017:T:C	W775R	0.984
6:108961633:T:A	N659K	0.983
6:108961633:T:G	N659K	0.983
6:108973431:T:C	F841L	0.983
6:108973433:C:A	F841L	0.983
6:108973433:C:G	F841L	0.983
6:108953262:G:C	R609P	0.981
6:108973432:T:C	F841S	0.981
6:108928105:A:C	R456S	0.979
6:108928105:A:T	R456S	0.979
6:108953254:G:C	K606N	0.979
6:108953254:G:T	K606N	0.979
6:108962081:T:A	N702K	0.977
6:108962081:T:G	N702K	0.977
6:108964237:C:A	A737D	0.977
6:108965040:T:G	C782W	0.977
6:108964249:T:C	L741P	0.975
6:108928104:G:C	R456T	0.974
6:108961630:C:A	N658K	0.974

dbSNP variants (sampled 300 via entrez): RS1000024959 (6:109020925 A>C), RS1000068839 (6:108975510 G>A), RS1000071607 (6:108861636 T>C), RS1000081975 (6:108968352 G>A), RS1000110782 (6:108976786 C>A,T), RS1000124550 (6:108944576 T>G), RS1000128173 (6:108881226 TTCTG>T), RS1000155533 (6:108944370 G>A), RS1000166344 (6:109042762 T>TG), RS1000166896 (6:109051822 A>G), RS1000175888 (6:108898335 C>A,G), RS1000187877 (6:108927205 A>G), RS1000193312 (6:109037435 C>A,T), RS1000195310 (6:108849921 A>C,G), RS1000200575 (6:108988456 A>G)

Disease associations

OMIM: gene MIM:618424 | disease phenotypes: MIM:618433

GenCC curated gene-disease

Disease	Classification	Inheritance
spermatogenic failure 38	Strong	Autosomal recessive
non-syndromic male infertility due to sperm motility disorder	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
spermatogenic failure 38	Definitive	AR

Mondo (3): spermatogenic failure 38 (MONDO:0032748), male infertility with teratozoospermia due to single gene mutation (MONDO:0018394), (MONDO:0017173)

Orphanet (1): Male infertility with teratozoospermia due to single gene mutation (Orphanet:399808)

HPO phenotypes

9 total (9 of 9 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000798	Oligozoospermia
HP:0003251	Male infertility
HP:0012207	Reduced sperm motility
HP:0012258	Abnormal axonemal organization of respiratory motile cilia
HP:0012865	Abnormal sperm head morphology
HP:0032558	Absent sperm flagella
HP:0032560	Coiled sperm flagella
HP:0032562	Tapered sperm head

GWAS associations

23 associations (top):

Study	Trait	p-value
GCST001248_13	Pulmonary function	8.000000e-09
GCST001251_16	Pulmonary function	5.000000e-06
GCST001784_4	Pulmonary function (smoking interaction)	2.000000e-07
GCST001942_10	Prostate cancer	8.000000e-09
GCST004147_26	Chronic obstructive pulmonary disease	8.000000e-10
GCST004185_46	Lung function (FEV1/FVC)	6.000000e-11
GCST006810_24	Self-reported risk-taking behaviour	4.000000e-08
GCST007325_270	General risk tolerance (MTAG)	1.000000e-13
GCST007430_77	Peak expiratory flow	3.000000e-14
GCST007431_144	Lung function (FEV1/FVC)	4.000000e-48
GCST007432_173	FEV1	2.000000e-26
GCST007465_6	Phoneme awareness	2.000000e-06
GCST007692_58	Chronic obstructive pulmonary disease	3.000000e-15
GCST008362_158	Birth weight	2.000000e-11
GCST008363_51	Offspring birth weight	2.000000e-09
GCST010173_179	Triglyceride levels	1.000000e-08
GCST010244_150	Triglyceride levels	1.000000e-11
GCST90002392_688	Mean corpuscular volume	3.000000e-31
GCST90002396_332	Mean reticulocyte volume	3.000000e-24
GCST90002397_472	Mean spheric corpuscular volume	6.000000e-31
GCST90016669_11	Pancreas volume	2.000000e-08
GCST90020025_1080	Waist-to-hip ratio adjusted for BMI	1.000000e-09
GCST90020027_1105	Waist-hip index	1.000000e-09

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0003892	pulmonary function measurement
EFO:0004713	FEV/FVC ratio
EFO:0004314	forced expiratory volume
EFO:0008579	risk-taking behaviour
EFO:0009718	peak expiratory flow
EFO:0005301	reading and spelling ability
EFO:0004344	birth weight
EFO:0005939	parental genotype effect measurement
EFO:0004530	triglyceride measurement
EFO:0010701	mean reticulocyte volume
EFO:0007788	BMI-adjusted waist-hip ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

12 total (human), top 12 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, affects methylation, decreases expression	3
aristolochic acid I	decreases expression	1
sodium arsenite	affects methylation	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
Sunitinib	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	decreases expression	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	decreases expression	1
Acrylamide	decreases expression	1

Clinical trials (associated diseases)

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