TMOD4

Summary

TMOD4 (tropomodulin 4, HGNC:11874) is a protein-coding gene on chromosome 1q21.3, encoding Tropomodulin-4 (Q9NZQ9). Blocks the elongation and depolymerization of the actin filaments at the pointed end.

Predicted to enable tropomyosin binding activity. Predicted to be involved in actin filament organization; muscle contraction; and myofibril assembly. Located in striated muscle thin filament.

Source: NCBI Gene 29765 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 61 total
• MANE Select transcript: NM_013353

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11874
Approved symbol	TMOD4
Name	tropomodulin 4
Location	1q21.3
Locus type	gene with protein product
Status	Approved
Aliases	Sk-Tmod
Ensembl gene	ENSG00000163157
Ensembl biotype	protein_coding
OMIM	605834
Entrez	29765

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 10 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000295314, ENST00000441701, ENST00000463543, ENST00000466891, ENST00000488488, ENST00000601585, ENST00000945625, ENST00000945626, ENST00000945627, ENST00000945628, ENST00000945629, ENST00000945630, ENST00000945631

RefSeq mRNA: 1 — MANE Select: NM_013353 NM_013353

CCDS: CCDS988

Canonical transcript exons

ENST00000295314 — 10 exons

Exon	Start	End
ENSE00001592965	151174391	151174547
ENSE00001824229	151175924	151175981
ENSE00003231271	151174753	151174917
ENSE00003508053	151169987	151170103
ENSE00003508763	151171633	151171763
ENSE00003515372	151172268	151172357
ENSE00003526441	151173499	151173615
ENSE00003627787	151170519	151170663
ENSE00003650418	151171433	151171540
ENSE00003687002	151170920	151171063

Expression profiles

Bgee: expression breadth ubiquitous, 176 present calls, max score 99.51.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.4866 / max 578.8173, expressed in 39 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
14413	1.2652	36
14414	0.2214	26

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
vastus lateralis	UBERON:0001379	99.51	gold quality
quadriceps femoris	UBERON:0001377	99.50	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.41	gold quality
tibialis anterior	UBERON:0001385	99.28	gold quality
skeletal muscle tissue	UBERON:0001134	99.26	gold quality
biceps brachii	UBERON:0001507	99.25	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.25	gold quality
gastrocnemius	UBERON:0001388	99.23	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.15	gold quality
deltoid	UBERON:0001476	99.09	gold quality
muscle organ	UBERON:0001630	98.26	gold quality
skeletal muscle organ	UBERON:0014892	98.26	gold quality
muscle of leg	UBERON:0001383	97.97	gold quality
body of tongue	UBERON:0011876	97.05	gold quality
muscle tissue	UBERON:0002385	94.22	gold quality
tongue	UBERON:0001723	88.22	gold quality
granulocyte	CL:0000094	84.13	gold quality
mucosa of stomach	UBERON:0001199	80.56	gold quality
mucosa of transverse colon	UBERON:0004991	76.98	gold quality
right uterine tube	UBERON:0001302	76.48	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	75.96	gold quality
monocyte	CL:0000576	75.91	gold quality
lower esophagus muscularis layer	UBERON:0035833	75.70	gold quality
lower esophagus	UBERON:0013473	75.64	gold quality
superior surface of tongue	UBERON:0007371	75.52	gold quality
leukocyte	CL:0000738	75.44	gold quality
spleen	UBERON:0002106	75.37	gold quality
minor salivary gland	UBERON:0001830	74.68	gold quality
small intestine Peyer’s patch	UBERON:0003454	74.59	gold quality
vermiform appendix	UBERON:0001154	73.79	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.48

Regulation

Is transcription factor: no

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmod4	ENSDARG00000020890
mus_musculus	Tmod4	ENSMUSG00000005628
rattus_norvegicus	Tmod4	ENSRNOG00000021088
drosophila_melanogaster	tmod	FBGN0082582
caenorhabditis_elegans	unc-94	WBGENE00006823

Paralogs (6): TMOD2 (ENSG00000128872), TMOD1 (ENSG00000136842), TMOD3 (ENSG00000138594), LMOD3 (ENSG00000163380), LMOD1 (ENSG00000163431), LMOD2 (ENSG00000170807)

Protein

Protein identifiers

Tropomodulin-4 — Q9NZQ9 (reviewed: Q9NZQ9)

Alternative names: Skeletal muscle tropomodulin

All UniProt accessions (4): Q9NZQ9, K7EQW4, K7ES04, Q5JR82

UniProt curated annotations — full annotation on UniProt →

Function. Blocks the elongation and depolymerization of the actin filaments at the pointed end. The Tmod/TM complex contributes to the formation of the short actin protofilament, which in turn defines the geometry of the membrane skeleton.

Subunit / interactions. Binds to the N-terminus of tropomyosin and to actin.

Subcellular location. Cytoplasm. Cytoskeleton.

Tissue specificity. Highly expressed in skeletal muscle.

Similarity. Belongs to the tropomodulin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NZQ9-1	1	yes
Q9NZQ9-2	2

RefSeq proteins (1): NP_037485* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004934	TMOD	Family
IPR032675	LRR_dom_sf	Homologous_superfamily

Pfam: PF03250

UniProt features (6 total): sequence conflict 2, chain 1, region of interest 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NZQ9-F1	86.28	0.51

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-390522	Striated Muscle Contraction

MSigDB gene sets: 118 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, SP3_Q3, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, AP4_Q6, GOBP_NEGATIVE_REGULATION_OF_ACTIN_FILAMENT_DEPOLYMERIZATION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, CAGCTG_AP4_Q5, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_REGULATION_OF_ACTIN_FILAMENT_BASED_PROCESS, EVI1_05, GOBP_REGULATION_OF_ANATOMICAL_STRUCTURE_SIZE

GO Biological Process (4): muscle contraction (GO:0006936), actin filament organization (GO:0007015), myofibril assembly (GO:0030239), pointed-end actin filament capping (GO:0051694)

GO Molecular Function (3): actin binding (GO:0003779), tropomyosin binding (GO:0005523), protein binding (GO:0005515)

GO Cellular Component (4): cytoskeleton (GO:0005856), striated muscle thin filament (GO:0005865), myofibril (GO:0030016), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Muscle contraction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
supramolecular fiber organization	2
cytoskeletal protein binding	2
muscle system process	1
actin cytoskeleton organization	1
cellular component assembly involved in morphogenesis	1
actomyosin structure organization	1
striated muscle cell development	1
membraneless organelle assembly	1
actin filament capping	1
binding	1
intracellular membraneless organelle	1
actin cytoskeleton	1
sarcomere	1
myofilament	1
contractile muscle fiber	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1084 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMOD4	CARMIL1	Q5VZK9	972
TMOD4	ADD1	P35611	970
TMOD4	CAPZA3	Q96KX2	963
TMOD4	ADD2	P35612	953
TMOD4	ADD3	Q9UEY8	947
TMOD4	NEB	P20929	931
TMOD4	CARMIL2	Q6F5E8	899
TMOD4	CAPZA2	P47755	888
TMOD4	CAPZA1	P52907	885
TMOD4	DMTN	Q08495	883
TMOD4	EPB41	P11171	820
TMOD4	MYPN	Q86TC9	810
TMOD4	SCIN	Q9Y6U3	767
TMOD4	GSN	P06396	750
TMOD4	TWF2	Q6IBS0	733

IntAct

12 interactions, top by confidence:

A	B	Type	Score
TXN2	TMOD4	psi-mi:“MI:0915”(physical association)	0.560
TMOD4	PCNA	psi-mi:“MI:0915”(physical association)	0.370
IDH1	TMOD4	psi-mi:“MI:0915”(physical association)	0.370
TMOD4	MYO9A	psi-mi:“MI:0914”(association)	0.350
TMOD4	FECH	psi-mi:“MI:0914”(association)	0.350
CDC37L1	EL52	psi-mi:“MI:0914”(association)	0.350
HSP90AB1	EL52	psi-mi:“MI:0914”(association)	0.350
TTC4	EL52	psi-mi:“MI:0914”(association)	0.350
TXN2	TMOD4	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (47): LRRFIP1 (Affinity Capture-MS), MTFR2 (Affinity Capture-MS), FECH (Affinity Capture-MS), LRRFIP2 (Affinity Capture-MS), FLII (Affinity Capture-MS), MYO5A (Affinity Capture-MS), ALAS1 (Affinity Capture-MS), CSRP2BP (Affinity Capture-MS), GIT1 (Affinity Capture-MS), NELFA (Affinity Capture-MS), HSP90AA4P (Affinity Capture-MS), MYO5C (Affinity Capture-MS), GIT2 (Affinity Capture-MS), ACAD11 (Affinity Capture-MS), MYO9A (Affinity Capture-MS)

ESM2 similar proteins: A0JNC0, A1A5Q0, A2VE39, A4IHS2, D2HRF1, E1BTG2, O08808, O14730, O35226, O60870, O95801, P28289, P42898, P49813, P70566, P70567, Q0VC48, Q13576, Q1JQD4, Q1RMT7, Q2M146, Q3UQ44, Q58DA0, Q5BLF0, Q5EA11, Q5I598, Q5R981, Q5U2Z5, Q60HE5, Q6GNS3, Q6P2Z6, Q6P5Q4, Q6TH47, Q7T0W1, Q7ZXX9, Q803R5, Q8K339, Q8N1G2, Q8R3H9, Q8R424

Diamond homologs: A0A0G2K0D3, A0JNC0, A1A5Q0, E1BTG2, E7F7X0, E9QA62, O01479, P28289, P29536, P49813, P70566, P70567, Q0VAK6, Q0VC48, Q3UHZ5, Q6P5Q4, Q8BVA4, Q9JHJ0, Q9JKK7, Q9JLH8, Q9NYL9, Q9NZQ9, Q9NZR1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	55
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1464 predictions. Top by Δscore:

Variant	Effect	Δscore
1:151170517:A:AC	donor_gain	1.0000
1:151170518:C:CC	donor_gain	1.0000
1:151170662:CG:C	acceptor_gain	1.0000
1:151170664:C:CC	acceptor_gain	1.0000
1:151172263:CTCA:C	donor_gain	1.0000
1:151172266:A:AC	donor_gain	1.0000
1:151172267:C:CA	donor_gain	1.0000
1:151172267:CTG:C	donor_gain	1.0000
1:151173494:CCCA:C	donor_loss	1.0000
1:151173616:C:CC	acceptor_gain	1.0000
1:151174389:AC:A	donor_gain	1.0000
1:151174390:CC:C	donor_gain	1.0000
1:151174390:CCCTT:C	donor_gain	1.0000
1:151174927:A:C	acceptor_gain	1.0000
1:151170104:C:CG	acceptor_loss	0.9900
1:151170105:T:G	acceptor_loss	0.9900
1:151170510:GTTAC:G	donor_loss	0.9900
1:151170511:TTACT:T	donor_loss	0.9900
1:151170512:TACT:T	donor_loss	0.9900
1:151170513:AC:A	donor_loss	0.9900
1:151170514:C:CA	donor_loss	0.9900
1:151170515:T:TG	donor_loss	0.9900
1:151170516:CA:C	donor_loss	0.9900
1:151170517:ACGTA:A	donor_loss	0.9900
1:151170518:C:A	donor_loss	0.9900
1:151170518:CG:C	donor_gain	0.9900
1:151170518:CGT:C	donor_gain	0.9900
1:151170518:CGTA:C	donor_gain	0.9900
1:151170659:TGGCG:T	acceptor_gain	0.9900
1:151170660:GGCG:G	acceptor_gain	0.9900

AlphaMissense

2291 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:151171004:G:C	N262K	0.999
1:151171004:G:T	N262K	0.999
1:151171009:A:G	S261P	0.998
1:151170577:A:C	F319L	0.997
1:151170577:A:T	F319L	0.997
1:151170578:A:G	F319S	0.997
1:151170579:A:G	F319L	0.997
1:151170936:A:G	L285P	0.997
1:151171005:T:A	N262I	0.997
1:151171008:G:A	S261F	0.997
1:151171020:A:G	L257P	0.997
1:151171642:A:C	N203K	0.997
1:151171642:A:T	N203K	0.997
1:151170543:C:G	A331P	0.996
1:151170552:C:G	A328P	0.996
1:151171006:T:A	N262Y	0.996
1:151171011:T:A	E260V	0.996
1:151171016:G:C	N258K	0.996
1:151171016:G:T	N258K	0.996
1:151171437:G:T	A241D	0.996
1:151170627:C:G	A303P	0.995
1:151170637:C:A	E299D	0.995
1:151170637:C:G	E299D	0.995
1:151170920:C:A	Q290H	0.995
1:151170920:C:G	Q290H	0.995
1:151171047:A:G	L248S	0.995
1:151171451:A:C	S236R	0.995
1:151171451:A:T	S236R	0.995
1:151171453:T:G	S236R	0.995
1:151171639:A:C	N204K	0.995

dbSNP variants (sampled 300 via entrez): RS1000141052 (1:151175756 G>A,C), RS1000857135 (1:151172158 T>C,G), RS1001034876 (1:151177837 T>C), RS1001373081 (1:151171734 C>G), RS1001465731 (1:151170622 G>A,T), RS1001819853 (1:151176821 T>C), RS1002218154 (1:151176962 A>G), RS1002322921 (1:151176329 T>A), RS1002355092 (1:151172556 G>A), RS1002468238 (1:151172282 G>A), RS1002942544 (1:151177905 A>G), RS1003376367 (1:151173797 G>A), RS1003473429 (1:151173412 T>C), RS1003834085 (1:151172852 C>T), RS1004882199 (1:151173923 A>T)

Disease associations

OMIM: gene MIM:605834 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST009879_5	Coronary artery disease	1.000000e-28
GCST010476_5	Myocardial infarction	9.000000e-25
GCST010477_8	Hypertension	5.000000e-07
GCST010478_8	Chronic kidney disease	1.000000e-07
GCST010836_6	Ischemic stroke	9.000000e-09

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

7 total (human), top 7 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression	1
CGP 52608	affects binding, increases reaction	1
Aspirin	increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Silicon Dioxide	increases expression	1
Testosterone	increases expression	1
Aflatoxin B1	increases methylation	1

Clinical trials (associated diseases)

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