TMOD2

Summary

TMOD2 (tropomodulin 2, HGNC:11872) is a protein-coding gene on chromosome 15q21.2, encoding Tropomodulin-2 (Q9NZR1). Blocks the elongation and depolymerization of the actin filaments at the pointed end.

This gene encodes a neuronal-specific member of the tropomodulin family of actin-regulatory proteins. The encoded protein caps the pointed end of actin filaments preventing both elongation and depolymerization. The capping activity of this protein is dependent on its association with tropomyosin. Alternatively spliced transcript variants encoding different isoforms have been described.

Source: NCBI Gene 29767 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 60 total
• MANE Select transcript: NM_014548

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11872
Approved symbol	TMOD2
Name	tropomodulin 2
Location	15q21.2
Locus type	gene with protein product
Status	Approved
Aliases	NTMOD
Ensembl gene	ENSG00000128872
Ensembl biotype	protein_coding
OMIM	602928
Entrez	29767

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 5 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000249700, ENST00000435126, ENST00000539962, ENST00000560576, ENST00000561300, ENST00000561407, ENST00000864860, ENST00000965098

RefSeq mRNA: 2 — MANE Select: NM_014548 NM_001142885, NM_014548

CCDS: CCDS10144, CCDS45260

Canonical transcript exons

ENST00000249700 — 10 exons

Exon	Start	End
ENSE00000688729	51776932	51777018
ENSE00000884711	51781044	51781174
ENSE00000942071	51806377	51806521
ENSE00001620554	51782721	51782828
ENSE00001664598	51773712	51773834
ENSE00001771868	51798197	51798340
ENSE00001888929	51808420	51816363
ENSE00001911185	51751597	51751712
ENSE00003514063	51766373	51766567
ENSE00003558803	51768262	51768418

Expression profiles

Bgee: expression breadth ubiquitous, 246 present calls, max score 99.34.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.6775 / max 717.6807, expressed in 1541 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
146668	8.7487	1400
146669	5.0008	879
146678	1.3221	225
207519	0.3051	114
146670	0.1985	81
146676	0.0749	37
146677	0.0275	19

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 23	UBERON:0013554	99.34	gold quality
endothelial cell	CL:0000115	99.24	gold quality
middle temporal gyrus	UBERON:0002771	98.60	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.06	gold quality
primary visual cortex	UBERON:0002436	97.62	gold quality
cortical plate	UBERON:0005343	97.28	gold quality
entorhinal cortex	UBERON:0002728	97.12	gold quality
substantia nigra pars compacta	UBERON:0001965	97.03	gold quality
parietal lobe	UBERON:0001872	96.97	gold quality
lateral globus pallidus	UBERON:0002476	96.87	gold quality
postcentral gyrus	UBERON:0002581	96.86	gold quality
pons	UBERON:0000988	96.46	gold quality
substantia nigra pars reticulata	UBERON:0001966	96.41	gold quality
superior frontal gyrus	UBERON:0002661	96.37	gold quality
occipital lobe	UBERON:0002021	96.18	gold quality
medial globus pallidus	UBERON:0002477	95.89	gold quality
globus pallidus	UBERON:0001875	95.76	gold quality
superior vestibular nucleus	UBERON:0007227	95.23	gold quality
prefrontal cortex	UBERON:0000451	95.16	gold quality
temporal lobe	UBERON:0001871	95.12	gold quality
anterior cingulate cortex	UBERON:0009835	95.03	gold quality
cingulate cortex	UBERON:0003027	94.85	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	94.83	gold quality
neocortex	UBERON:0001950	94.53	gold quality
frontal cortex	UBERON:0001870	94.38	gold quality
frontal lobe	UBERON:0016525	94.38	gold quality
right frontal lobe	UBERON:0002810	94.37	gold quality
dorsal root ganglion	UBERON:0000044	94.28	gold quality
cerebral cortex	UBERON:0000956	94.14	gold quality
sural nerve	UBERON:0015488	94.08	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.14
E-MTAB-6142	no	28.41

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

334 targeting TMOD2, 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-8485	100.00	77.57	4731
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-371B-5P	99.99	75.34	4759

Literature-anchored findings (GeneRIF, showing 2)

• levels of TM1, TM2 and TM3 are reduced in human transitional cell carcinoma cells, but significantly upregulated by inhibition of the mitogen-activated protein kinase-signaling pathway (PMID:15095301)
• Hexavalent chromium causes centrosome amplification by inhibiting the binding between TMOD2 and NPM2. (PMID:36963620)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Tmod2	ENSMUSG00000032186
rattus_norvegicus	Tmod2	ENSRNOG00000010447
drosophila_melanogaster	tmod	FBGN0082582
caenorhabditis_elegans	unc-94	WBGENE00006823

Paralogs (6): TMOD1 (ENSG00000136842), TMOD3 (ENSG00000138594), TMOD4 (ENSG00000163157), LMOD3 (ENSG00000163380), LMOD1 (ENSG00000163431), LMOD2 (ENSG00000170807)

Protein

Protein identifiers

Tropomodulin-2 — Q9NZR1 (reviewed: Q9NZR1)

Alternative names: Neuronal tropomodulin

All UniProt accessions (3): Q9NZR1, G5EA42, H0YMA2

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. Neuronal-tissue specific.

Similarity. Belongs to the tropomodulin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NZR1-1	1	yes
Q9NZR1-2	2

RefSeq proteins (2): NP_001136357, NP_055363* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004934	TMOD	Family
IPR032675	LRR_dom_sf	Homologous_superfamily

Pfam: PF03250

UniProt features (5 total): chain 1, modified residue 1, splice variant 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NZR1-F1	83.80	0.49

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 25

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-390522	Striated Muscle Contraction

MSigDB gene sets: 255 (showing top): GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GCM_MAP4K4, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, BENPORATH_ES_WITH_H3K27ME3, GOBP_COGNITION, GOBP_BEHAVIOR, TTCCGTT_MIR191, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_ACTIN_FILAMENT_DEPOLYMERIZATION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, GOBP_CELL_CELL_SIGNALING, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_REGULATION_OF_ACTIN_FILAMENT_BASED_PROCESS

GO Biological Process (8): muscle contraction (GO:0006936), actin filament organization (GO:0007015), neuron-neuron synaptic transmission (GO:0007270), nervous system development (GO:0007399), learning or memory (GO:0007611), myofibril assembly (GO:0030239), positive regulation of G protein-coupled receptor signaling pathway (GO:0045745), 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 (5): cytoskeleton (GO:0005856), striated muscle thin filament (GO:0005865), myofibril (GO:0030016), synapse (GO:0045202), 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
chemical synaptic transmission	1
system development	1
behavior	1
cognition	1
cellular component assembly involved in morphogenesis	1
actomyosin structure organization	1
striated muscle cell development	1
membraneless organelle assembly	1
G protein-coupled receptor signaling pathway	1
regulation of G protein-coupled receptor signaling pathway	1
positive regulation of signal transduction	1
actin filament capping	1
binding	1
intracellular membraneless organelle	1
actin cytoskeleton	1
sarcomere	1
myofilament	1
contractile muscle fiber	1
cell junction	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

944 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMOD2	ADD1	P35611	956
TMOD2	ADD2	P35612	943
TMOD2	ADD3	Q9UEY8	937
TMOD2	NEB	P20929	934
TMOD2	DMTN	Q08495	890
TMOD2	CARMIL2	Q6F5E8	882
TMOD2	EPB41	P11171	820
TMOD2	CAPZA2	P47755	793
TMOD2	CAPZA1	P52907	791
TMOD2	MYPN	Q86TC9	787
TMOD2	CGNL1	Q0VF96	760
TMOD2	ANK1	P16157	711
TMOD2	ANK2	Q01484	699
TMOD2	TTN	Q8WZ42	699
TMOD2	ANK3	Q12955	690

IntAct

69 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
TMOD2		psi-mi:“MI:0915”(physical association)	0.560
TMOD2	PMP22	psi-mi:“MI:0915”(physical association)	0.560
SLC25A41	NUDT19	psi-mi:“MI:0914”(association)	0.530
PLEKHG6	CST4	psi-mi:“MI:0914”(association)	0.530
SSH1	GSN	psi-mi:“MI:0914”(association)	0.530
MYO1C	TMOD1	psi-mi:“MI:0914”(association)	0.530
FOS	MYO1C	psi-mi:“MI:2364”(proximity)	0.480
TMOD2	MYDGF	psi-mi:“MI:0915”(physical association)	0.400
PARK7	SAP18	psi-mi:“MI:0914”(association)	0.350
APP	ESYT2	psi-mi:“MI:0914”(association)	0.350
PRNP	CARNS1	psi-mi:“MI:0914”(association)	0.350
LSP1	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
AVIL	DDX11L8	psi-mi:“MI:0914”(association)	0.350
TMOD2	GSN	psi-mi:“MI:0914”(association)	0.350
DBN1	GSN	psi-mi:“MI:0914”(association)	0.350
SSH1	GSN	psi-mi:“MI:0914”(association)	0.350
RBM18	GSN	psi-mi:“MI:0914”(association)	0.350
ARHGEF11	MTX2	psi-mi:“MI:0914”(association)	0.350
ARHGEF17	PRC1	psi-mi:“MI:0914”(association)	0.350
VAV1	DDX39A	psi-mi:“MI:0914”(association)	0.350
PLEKHG1	ARPC1B	psi-mi:“MI:0914”(association)	0.350
PLEKHG3	KDM1A	psi-mi:“MI:0914”(association)	0.350
CTBP1	GSN	psi-mi:“MI:0914”(association)	0.350

BioGRID (104): TMOD2 (Affinity Capture-RNA), TMOD2 (Affinity Capture-MS), TMOD2 (Affinity Capture-MS), GSN (Affinity Capture-MS), SCIN (Affinity Capture-MS), RRM2B (Affinity Capture-MS), TMOD2 (Affinity Capture-MS), PABPC3 (Co-fractionation), PAM16 (Co-fractionation), RUVBL2 (Co-fractionation), SHMT2 (Co-fractionation), SULT1C3 (Co-fractionation), TMOD2 (Co-fractionation), TMOD2 (Co-fractionation), TMOD2 (Co-fractionation)

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.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 78 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
FCGR3A-mediated phagocytosis	5	16.7×	1e-03
Regulation of actin dynamics for phagocytic cup formation	5	16.4×	1e-03
Leishmania infection	5	14.6×	1e-03
Parasitic Infection Pathways	5	14.6×	1e-03
RHO GTPase cycle	7	7.5×	1e-03
RHO GTPase Effectors	6	7.3×	4e-03
Signaling by Rho GTPases	11	6.7×	2e-04
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	11	6.6×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
axonogenesis	6	13.8×	1e-03
regulation of small GTPase mediated signal transduction	6	12.3×	2e-03
actin filament organization	7	11.9×	7e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	55
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1338 predictions. Top by Δscore:

Variant	Effect	Δscore
15:51751708:GACGG:G	donor_gain	1.0000
15:51751711:GG:G	donor_gain	1.0000
15:51751712:GG:G	donor_gain	1.0000
15:51751712:GGT:G	donor_loss	1.0000
15:51751713:G:GG	donor_gain	1.0000
15:51751714:T:A	donor_loss	1.0000
15:51766370:CAG:C	acceptor_loss	1.0000
15:51766371:A:AC	acceptor_loss	1.0000
15:51766371:A:AG	acceptor_gain	1.0000
15:51766372:G:GA	acceptor_gain	1.0000
15:51766372:GT:G	acceptor_gain	1.0000
15:51766372:GTA:G	acceptor_gain	1.0000
15:51766372:GTAT:G	acceptor_gain	1.0000
15:51766372:GTATT:G	acceptor_gain	1.0000
15:51768257:GTCA:G	acceptor_loss	1.0000
15:51768258:TCA:T	acceptor_loss	1.0000
15:51768258:TCAGA:T	acceptor_gain	1.0000
15:51768259:CA:C	acceptor_loss	1.0000
15:51768259:CAGAG:C	acceptor_gain	1.0000
15:51768260:A:AG	acceptor_gain	1.0000
15:51768260:AGAGT:A	acceptor_gain	1.0000
15:51768261:G:GA	acceptor_gain	1.0000
15:51768261:GA:G	acceptor_gain	1.0000
15:51768261:GAGT:G	acceptor_gain	1.0000
15:51768261:GAGTG:G	acceptor_gain	1.0000
15:51768414:GAAAG:G	donor_gain	1.0000
15:51768417:AG:A	donor_gain	1.0000
15:51768417:AGG:A	donor_loss	1.0000
15:51768418:GG:G	donor_gain	1.0000
15:51768418:GGT:G	donor_loss	1.0000

AlphaMissense

2333 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:51798256:T:A	N264K	0.999
15:51798256:T:G	N264K	0.999
15:51782808:A:C	S238R	0.998
15:51782810:C:A	S238R	0.998
15:51782810:C:G	S238R	0.998
15:51798240:T:C	L259P	0.998
15:51773796:T:C	L123S	0.997
15:51781161:T:C	L204P	0.997
15:51781165:C:A	N205K	0.997
15:51781165:C:G	N205K	0.997
15:51798251:T:C	S263P	0.997
15:51781168:C:A	N206K	0.996
15:51781168:C:G	N206K	0.996
15:51782824:C:A	A243D	0.996
15:51773792:G:C	A122P	0.995
15:51773829:T:C	L134P	0.995
15:51798340:G:C	Q292H	0.995
15:51798340:G:T	Q292H	0.995
15:51808422:C:A	R342S	0.995
15:51773805:C:A	A126D	0.994
15:51782740:T:C	L215P	0.994
15:51798213:T:C	L250P	0.994
15:51798244:C:A	N260K	0.994
15:51798244:C:G	N260K	0.994
15:51798252:C:T	S263F	0.994
15:51798255:A:T	N264I	0.994
15:51806480:G:C	R327P	0.994
15:51766536:T:C	L32S	0.993
15:51773784:T:C	L119P	0.993
15:51781161:T:A	L204H	0.993

dbSNP variants (sampled 300 via entrez): RS1000026838 (15:51776101 C>A), RS1000032685 (15:51792182 C>T), RS1000101765 (15:51752420 T>A), RS1000137078 (15:51808114 A>G), RS1000162958 (15:51793347 A>G), RS1000198807 (15:51768946 C>A), RS1000223185 (15:51799801 A>C,T), RS1000240081 (15:51755639 CA>C), RS1000275075 (15:51811117 T>A,G), RS1000275464 (15:51799487 C>T), RS1000353761 (15:51762330 A>ACACCT), RS1000371264 (15:51769958 G>A,T), RS1000391398 (15:51811459 G>A), RS1000404801 (15:51762767 T>G), RS1000426461 (15:51805953 A>C)

Disease associations

OMIM: gene MIM:602928 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST005316_544	Intelligence (MTAG)	9.000000e-09
GCST010988_551	Adult body size	3.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

52 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	8
bisphenol A	increases expression, decreases reaction, increases abundance, affects cotreatment, affects binding (+2 more)	4
trichostatin A	affects cotreatment, increases expression, affects expression	4
sodium arsenite	affects methylation, decreases expression	2
Panobinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Butyric Acid	increases expression	2
GSK-J4	decreases expression	1
ginger extract	decreases reaction, increases abundance, increases expression	1
methylmercuric chloride	decreases expression	1
testosterone undecanoate	affects cotreatment, decreases expression	1
2-methyl-4-isothiazolin-3-one	decreases expression	1
sulforaphane	increases expression	1
potassium chromate(VI)	decreases expression	1
nickel sulfate	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
mercuric bromide	increases expression	1
lariciresinol	decreases expression	1
CGP 52608	affects binding, increases reaction	1
oxamflatin	increases expression	1
apicidin	increases expression	1
corosolic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases expression	1
abrine	decreases expression, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, increases expression	1
Docetaxel	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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