IRGC

Summary

IRGC (immunity related GTPase cinema, HGNC:28835) is a protein-coding gene on chromosome 19q13.31, encoding Interferon-inducible GTPase 5 (Q6NXR0). Required for sperm motility and therefore male fertility, via positive regulation of spermatozoa fibrous sheath formation.

Predicted to enable GTP binding activity and GTPase activity. Predicted to be involved in positive regulation of flagellated sperm motility. Located in lipid droplet and sperm mitochondrial sheath.

Source: NCBI Gene 56269 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 75 total
• MANE Select transcript: NM_019612

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28835
Approved symbol	IRGC
Name	immunity related GTPase cinema
Location	19q13.31
Locus type	gene with protein product
Status	Approved
Aliases	Iigp5, CINEMA
Ensembl gene	ENSG00000124449
Ensembl biotype	protein_coding
OMIM	620634
Entrez	56269

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000244314, ENST00000596627

RefSeq mRNA: 1 — MANE Select: NM_019612 NM_019612

CCDS: CCDS12629

Canonical transcript exons

ENST00000244314 — 2 exons

Exon	Start	End
ENSE00000847442	43718493	43720021
ENSE00001410155	43716076	43716142

Expression profiles

Bgee: expression breadth broad, 34 present calls, max score 96.76.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0874 / max 75.3312, expressed in 3 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
176216	0.0336	3
176215	0.0281	3
176217	0.0257	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	96.76	gold quality
right testis	UBERON:0004534	96.66	gold quality
testis	UBERON:0000473	92.96	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.57	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	68.42	gold quality
adult organism	UBERON:0007023	66.65	gold quality
pancreatic ductal cell	CL:0002079	56.14	silver quality
mucosa of sigmoid colon	UBERON:0004993	55.76	gold quality
myocardium	UBERON:0002349	53.55	gold quality
quadriceps femoris	UBERON:0001377	51.36	gold quality
tibialis anterior	UBERON:0001385	51.36	silver quality
colonic mucosa	UBERON:0000317	51.18	gold quality
biceps brachii	UBERON:0001507	50.85	gold quality
vastus lateralis	UBERON:0001379	50.84	gold quality
epithelial cell of pancreas	CL:0000083	50.53	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
hair follicle	UBERON:0002073	49.18	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
thymus	UBERON:0002370	48.90	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
CA1 field of hippocampus	UBERON:0003881	48.50	gold quality
oviduct epithelium	UBERON:0004804	48.42	gold quality
left ventricle myocardium	UBERON:0006566	48.24	gold quality
orbitofrontal cortex	UBERON:0004167	48.20	gold quality
upper arm skin	UBERON:0004263	48.06	gold quality
cervix epithelium	UBERON:0004801	48.04	gold quality
tongue squamous epithelium	UBERON:0006919	47.92	gold quality
mucosa of urinary bladder	UBERON:0001259	47.80	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	1298.83
E-ANND-3	no	0.98

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 1)

• The immunity-related GTPase IRGC mediates interaction between lipid droplets and mitochondria to facilitate sperm motility. (PMID:37195149)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	irgf3	ENSDARG00000062820
danio_rerio	si:ch73-171o20.1	ENSDARG00000062828
danio_rerio	irgf1	ENSDARG00000070774
danio_rerio	irgf2	ENSDARG00000092249
mus_musculus	Irgc	ENSMUSG00000062028
rattus_norvegicus	Irgc	ENSRNOG00000024257

Paralogs (1): IRGM (ENSG00000237693)

Protein

Protein identifiers

Interferon-inducible GTPase 5 — Q6NXR0 (reviewed: Q6NXR0)

Alternative names: Immunity-related GTPase cinema 1

All UniProt accessions (3): J7NNX4, M0R0T1, Q6NXR0

UniProt curated annotations — full annotation on UniProt →

Function. Required for sperm motility and therefore male fertility, via positive regulation of spermatozoa fibrous sheath formation.

Subcellular location. Cell projection. Cilium. Flagellum. Lipid droplet.

Tissue specificity. Abundantly expressed in semen (at protein level).

Miscellaneous. Asthenozoospermic patients show a decrease in IRGC protein abundance in semen samples and a loss of colocalization with the mitochondria which suggests a role for IRGC in sperm motility.

Similarity. Belongs to the TRAFAC class dynamin-like GTPase superfamily. IRG family.

RefSeq proteins (1): NP_062558* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007743	Immunity-related_GTPase-like	Family
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR030385	G_IRG_dom	Domain
IPR051515	IRG	Family

Pfam: PF05049

Catalyzed reactions (Rhea), 1 shown:

• GTP + H2O = GDP + phosphate + H(+) (RHEA:19669)

UniProt features (10 total): binding site 4, modified residue 2, chain 1, domain 1, region of interest 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6NXR0-F1	68.67	0.14

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 (4): 62–69; 87–91; 169–171; 216–218

Post-translational modifications (2): 247, 304

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 71 (showing top): GOBP_POSITIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, GOBP_CILIUM_MOVEMENT, GOBP_REGULATION_OF_MICROTUBULE_BASED_MOVEMENT, GOBP_CILIUM_OR_FLAGELLUM_DEPENDENT_CELL_MOTILITY, GOBP_REGULATION_OF_REPRODUCTIVE_PROCESS, MORF_EPHA7, MORF_RAB3A, GOBP_REGULATION_OF_CILIUM_MOVEMENT, MORF_WNT1, MORF_DCC, GOCC_MOTILE_CILIUM, GOCC_SPERM_MIDPIECE, GOCC_CILIUM, GOMF_GTPASE_ACTIVITY

GO Biological Process (1): positive regulation of flagellated sperm motility (GO:1902093)

GO Molecular Function (5): GTPase activity (GO:0003924), GTP binding (GO:0005525), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (7): lipid droplet (GO:0005811), membrane (GO:0016020), sperm flagellum (GO:0036126), sperm mitochondrial sheath (GO:0097226), cilium (GO:0005929), motile cilium (GO:0031514), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
positive regulation of cilium movement	1
flagellated sperm motility	1
regulation of flagellated sperm motility	1
positive regulation of cilium-dependent cell motility	1
positive regulation of reproductive process	1
ribonucleoside triphosphate phosphatase activity	1
guanyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
intracellular membraneless organelle	1
9+2 motile cilium	1
sperm midpiece	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
cilium	1

Protein interactions and networks

STRING

881 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IRGC	DCTN4	Q9UJW0	493
IRGC	ATG16L1	Q676U5	453
IRGC	UVRAG	Q9P2Y5	397
IRGC	ATG5	Q9H1Y0	396
IRGC	MTMR14	Q8NCE2	379
IRGC	WIPI1	Q5MNZ9	372
IRGC	ATG101	Q9BSB4	371
IRGC	ZIC2	O95409	369
IRGC	NBR1	Q14596	368
IRGC	GOPC	Q9HD26	363
IRGC	TSPAN8	P19075	353
IRGC	VDAC1	P21796	353
IRGC	DAPK1	P53355	353
IRGC	WIPI2	Q9Y4P8	353
IRGC	A0A0J9YVX5	A0A0J9YVX5	351

IntAct

13 interactions, top by confidence:

A	B	Type	Score
HNRNPK	IRGC	psi-mi:“MI:0915”(physical association)	0.560
CCNDBP1	IRGC	psi-mi:“MI:0915”(physical association)	0.560
IRGC	RAP1GDS1	psi-mi:“MI:0914”(association)	0.530
MYF6	TBC1D4	psi-mi:“MI:0914”(association)	0.350
IRGC	RPS6KA3	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
IRGC	HNRNPK	psi-mi:“MI:0915”(physical association)	0.000
IRGC	CCNDBP1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (30): METTL7B (Affinity Capture-MS), RPS6KA1 (Affinity Capture-MS), FBXL18 (Affinity Capture-MS), PI4K2A (Affinity Capture-MS), IRGC (Affinity Capture-MS), RHOA (Affinity Capture-MS), SLC26A6 (Affinity Capture-MS), AP3S1 (Affinity Capture-MS), RAP1GDS1 (Affinity Capture-MS), MCU (Affinity Capture-MS), ATP12A (Affinity Capture-MS), OMA1 (Affinity Capture-MS), RPS6KA3 (Affinity Capture-MS), RPS6KA2 (Affinity Capture-MS), HNRNPK (Two-hybrid)

ESM2 similar proteins: A0A140LIF8, A0JN92, A1Z198, A6H603, B1ARD6, B1ARD8, D9I2F9, D9I2G1, D9I2G3, D9I2G4, D9I2H0, E1BPN0, G1SRW8, O02799, P0C7P3, P52630, Q08AF3, Q0GKD5, Q0P3U3, Q149M9, Q1LXZ7, Q1LZ50, Q2LKU9, Q2LKV5, Q2LKW6, Q32KW9, Q5I0J8, Q5NCI0, Q5RCZ8, Q5RFJ8, Q5SY16, Q5U311, Q60766, Q63035, Q68D06, Q6AYC2, Q6AYF9, Q6IEE8, Q6NXR0, Q7Z7L1

Diamond homologs: A0A140LIF8, A1A4Y4, Q0GUM3, Q32KW9, Q3T9E4, Q60766, Q62293, Q6AYC2, Q6AYF9, Q6NXR0, Q9DCE9, Q9QZ85, Q8C262, Q8VIM9, Q8WZA9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	69
Likely benign	4
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

189 predictions. Top by Δscore:

Variant	Effect	Δscore
19:43716086:G:T	donor_gain	0.9900
19:43718488:TGCA:T	acceptor_loss	0.9700
19:43718489:GCAG:G	acceptor_loss	0.9700
19:43718490:CAGGC:C	acceptor_loss	0.9700
19:43718491:A:AT	acceptor_loss	0.9700
19:43716086:G:GT	donor_gain	0.9600
19:43718491:A:AG	acceptor_gain	0.9500
19:43718492:G:GG	acceptor_gain	0.9500
19:43718492:GGC:G	acceptor_gain	0.9300
19:43718488:T:TA	acceptor_gain	0.9100
19:43716077:GC:G	donor_gain	0.9000
19:43716108:A:T	donor_gain	0.9000
19:43716140:CAG:C	donor_loss	0.9000
19:43716141:AGGTG:A	donor_loss	0.9000
19:43716142:GG:G	donor_loss	0.9000
19:43716143:GTGA:G	donor_loss	0.9000
19:43716144:T:G	donor_loss	0.9000
19:43716145:GAG:G	donor_loss	0.9000
19:43716078:C:G	donor_gain	0.8700
19:43716867:TGAG:T	acceptor_gain	0.8700
19:43718491:AGGC:A	acceptor_gain	0.8700
19:43718492:GGCG:G	acceptor_gain	0.8700
19:43716146:AGTCC:A	donor_loss	0.8400
19:43718491:AG:A	acceptor_gain	0.8100
19:43718492:GG:G	acceptor_gain	0.8100
19:43718492:GGCGC:G	acceptor_gain	0.8000
19:43716868:G:GC	acceptor_gain	0.7900
19:43716147:G:C	donor_loss	0.7700
19:43716139:GCAG:G	donor_gain	0.7500
19:43718669:CCAGG:C	acceptor_gain	0.7500

AlphaMissense

2959 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:43719195:T:C	F213L	0.990
19:43719197:C:A	F213L	0.990
19:43719197:C:G	F213L	0.990
19:43719741:G:C	D395H	0.989
19:43719744:G:C	A396P	0.978
19:43718759:G:C	K67N	0.977
19:43718759:G:T	K67N	0.977
19:43719111:T:C	F185L	0.977
19:43719113:C:A	F185L	0.977
19:43719113:C:G	F185L	0.977
19:43719735:G:C	A393P	0.975
19:43719743:C:A	D395E	0.975
19:43719743:C:G	D395E	0.975
19:43718774:T:A	N72K	0.974
19:43718774:T:G	N72K	0.974
19:43719471:T:C	F305L	0.973
19:43719473:T:A	F305L	0.973
19:43719473:T:G	F305L	0.973
19:43719196:T:C	F213S	0.972
19:43718758:A:T	K67M	0.971
19:43718758:A:C	K67T	0.970
19:43719231:T:C	F225L	0.967
19:43719233:T:A	F225L	0.967
19:43719233:T:G	F225L	0.967
19:43719751:G:C	R398P	0.966
19:43719061:C:T	T168I	0.962
19:43719065:G:C	K169N	0.962
19:43719065:G:T	K169N	0.962
19:43719205:C:T	S216F	0.962
19:43719690:T:C	F378L	0.961

dbSNP variants (sampled 300 via entrez): RS1000120461 (19:43716757 G>A), RS1000267095 (19:43718272 G>A,T), RS1000514890 (19:43717048 G>A), RS1001115186 (19:43715759 G>A), RS1001768317 (19:43718837 G>A), RS1001778092 (19:43718316 C>A), RS1001802311 (19:43717996 G>A), RS1002220756 (19:43718604 A>T), RS1003056497 (19:43715150 C>T), RS1003443833 (19:43719375 G>A), RS1004003189 (19:43714243 G>A), RS1004687561 (19:43715001 G>A), RS1005136620 (19:43717769 A>T), RS1005822519 (19:43717582 G>A), RS1006410843 (19:43716487 G>A)

Disease associations

OMIM: gene MIM:620634 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

9 total (human), top 9 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	decreases methylation	1
licochalcone B	increases expression	1
theaflavin-3,3’-digallate	affects expression	1
Benzo(a)pyrene	increases methylation	1
Methapyrilene	decreases methylation	1
Rotenone	increases expression	1
Testosterone	increases expression	1
Tobacco Smoke Pollution	increases expression	1

Clinical trials (associated diseases)

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