TTC1

Summary

TTC1 (tetratricopeptide repeat domain 1, HGNC:12391) is a protein-coding gene on chromosome 5q33.3, encoding Tetratricopeptide repeat protein 1 (Q99614). Adapter protein that plays a role downstream of GNA15 to stimulate Ras activation and subsequent phosphorylation of ERK1/2 independently of phospholipase Cbeta signaling. It is a common-essential gene (DepMap: required in 97.3% of cancer cell lines).

This gene encodes a protein that belongs to the tetratrico peptide repeat superfamily of proteins. The encoded protein plays a role in protein-protein interactions, and binds to the Galpha subunit of G protein-coupled receptors to activate the Ras signaling pathway. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 7265 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 32 total
• Cancer dependency (DepMap): dependent in 97.3% of screened cell lines (common-essential)
• MANE Select transcript: NM_003314

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12391
Approved symbol	TTC1
Name	tetratricopeptide repeat domain 1
Location	5q33.3
Locus type	gene with protein product
Status	Approved
Aliases	TPR1
Ensembl gene	ENSG00000113312
Ensembl biotype	protein_coding
OMIM	601963
Entrez	7265

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 14 protein_coding, 8 retained_intron, 2 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000231238, ENST00000518560, ENST00000520274, ENST00000522073, ENST00000522793, ENST00000682131, ENST00000682151, ENST00000682172, ENST00000682220, ENST00000682245, ENST00000682255, ENST00000682457, ENST00000682719, ENST00000683219, ENST00000683281, ENST00000683631, ENST00000684018, ENST00000684137, ENST00000684515, ENST00000684527, ENST00000894227, ENST00000894228, ENST00000894229, ENST00000912911, ENST00000912912, ENST00000963824

RefSeq mRNA: 2 — MANE Select: NM_003314 NM_001282500, NM_003314

CCDS: CCDS4348

Canonical transcript exons

ENST00000231238 — 8 exons

Exon	Start	End
ENSE00000917404	160035140	160035200
ENSE00000917405	160036691	160036803
ENSE00000972667	160010500	160010858
ENSE00001561815	160009139	160009193
ENSE00003349343	160064932	160065543
ENSE00003567282	160051129	160051183
ENSE00003590214	160043133	160043169
ENSE00003613762	160049514	160049662

Expression profiles

Bgee: expression breadth ubiquitous, 297 present calls, max score 97.29.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 60.4197 / max 3058.0518, expressed in 1819 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
59881	59.9702	1819
59882	0.3067	126
59883	0.1187	37
59884	0.0241	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	97.29	gold quality
calcaneal tendon	UBERON:0003701	96.46	gold quality
cingulate cortex	UBERON:0003027	96.39	gold quality
heart left ventricle	UBERON:0002084	96.37	gold quality
anterior cingulate cortex	UBERON:0009835	96.37	gold quality
cardiac ventricle	UBERON:0002082	96.30	gold quality
right frontal lobe	UBERON:0002810	96.15	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	96.03	gold quality
Brodmann (1909) area 9	UBERON:0013540	95.99	gold quality
prefrontal cortex	UBERON:0000451	95.85	gold quality
islet of Langerhans	UBERON:0000006	95.82	gold quality
amygdala	UBERON:0001876	95.82	gold quality
right atrium auricular region	UBERON:0006631	95.71	gold quality
substantia nigra	UBERON:0002038	95.62	gold quality
frontal pole	UBERON:0002795	95.62	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.61	gold quality
heart	UBERON:0000948	95.56	gold quality
substantia nigra pars compacta	UBERON:0001965	95.54	gold quality
Brodmann (1909) area 10	UBERON:0013541	95.50	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	95.48	gold quality
gastrocnemius	UBERON:0001388	95.44	gold quality
muscle of leg	UBERON:0001383	95.42	gold quality
cardiac atrium	UBERON:0002081	95.42	gold quality
hypothalamus	UBERON:0001898	95.40	gold quality
heart right ventricle	UBERON:0002080	95.40	gold quality
spinal cord	UBERON:0002240	95.40	gold quality
midbrain	UBERON:0001891	95.27	gold quality
nucleus accumbens	UBERON:0001882	95.18	gold quality
caudate nucleus	UBERON:0001873	95.14	gold quality
triceps brachii	UBERON:0001509	95.06	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-6379	no	907.01
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

22 targeting TTC1, 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-6867-5P	100.00	82.21	3464
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-556-3P	99.74	68.75	1203
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-208A-5P	99.42	70.83	1913
HSA-MIR-208B-5P	99.42	70.83	1952
HSA-MIR-140-3P	99.04	67.69	1324
HSA-MIR-873-5P	98.84	66.90	1348
HSA-MIR-6847-5P	97.93	66.74	1808
HSA-MIR-3691-3P	97.90	65.97	791
HSA-MIR-3620-3P	97.78	64.88	772
HSA-MIR-4675	97.69	64.82	774
HSA-MIR-4741	97.69	64.14	883
HSA-MIR-3690	96.44	65.18	737
HSA-MIR-4772-5P	95.60	68.04	617

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 97.3% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 5)

• Data show that tetratricopeptide repeat 1 is a novel adaptor protein for Ras and selected Galpha proteins that may be involved in protein-protein interaction relating to G-protein signaling. (PMID:12748287)
• Results report cooperative interactions involving Hsp70, Hsp40, and TPR1 that enhance Hsp70-dependent folding of chemically denatured substrates. (PMID:14503850)
• beta3 region of Galpha16 is essential for interaction with TPR1 and the subsequent activation of Ras (PMID:21486497)
• TPR1 is required for Galpha14 to stimulate Ras-dependent signaling pathways, but not for the propagation of signals along Ras-independent pathways. (PMID:22711498)
• The crystal structure of monopolar spindle 1 (Mps1) N-terminal region TPR domain has been determined. (PMID:23067341)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ttc1	ENSDARG00000044567
mus_musculus	Ttc1	ENSMUSG00000041278
rattus_norvegicus	Ttc1	ENSRNOG00000003980
drosophila_melanogaster	Ttc1	FBGN0038428

Paralogs (18): RPAP3 (ENSG00000005175), TOMM34 (ENSG00000025772), ST13 (ENSG00000100380), STUB1 (ENSG00000103266), SPAG1 (ENSG00000104450), SGTA (ENSG00000104969), TTC31 (ENSG00000115282), UNC45A (ENSG00000140553), UNC45B (ENSG00000141161), SPATA16 (ENSG00000144962), TTC12 (ENSG00000149292), TOMM70 (ENSG00000154174), SUGT1 (ENSG00000165416), STIP1 (ENSG00000168439), TTC32 (ENSG00000183891), SGTB (ENSG00000197860), TTC4 (ENSG00000243725), DNAAF4 (ENSG00000256061)

Protein

Protein identifiers

Tetratricopeptide repeat protein 1 — Q99614 (reviewed: Q99614)

All UniProt accessions (8): A0A804HHT7, A0A804HIB8, Q99614, A0A804HJM4, A0A804HKC5, A0A804HKI4, A0A804HL30, H0YB37

UniProt curated annotations — full annotation on UniProt →

Function. Adapter protein that plays a role downstream of GNA15 to stimulate Ras activation and subsequent phosphorylation of ERK1/2 independently of phospholipase Cbeta signaling. Mechanistically, interacts with GNA15 and SOS2 to form a macromolecular signaling complex which has a high affinity for HRAS. Additionally, participates in signaling via other G-alpha proteins like GNA14, activating NF-kappa-B through Ras and ERK pathways. Beyond signaling, supports protein homeostasis by cooperating with HSP40 in the HSP70 chaperone cycle, promoting protein folding through the regulated dissociation of the HSP70 inhibitor HSPBP1.

Subunit / interactions. Interacts with the GAP domain of NF1. Interacts (via TPR repeats) with HSP90AA1 and HSPA8. Interacts with GNA15 regardless of its activation state. Interacts with HRAS. Interacts with SOS2. Interacts with HSP40/DNAJB1 and HSP70/HSPA1A.

RefSeq proteins (2): NP_001269429, NP_003305* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR019734	TPR_rpt	Repeat
IPR052769	TPR_domain_protein	Family

Pfam: PF00515, PF13181

UniProt features (12 total): repeat 3, compositionally biased region 3, modified residue 2, chain 1, sequence variant 1, sequence conflict 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99614-F1	78.14	0.60

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 (2): 83, 90

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 175 (showing top): GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, MORF_HDAC1, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GCM_RING1, GOBP_PROTEIN_MATURATION, AP1_Q4_01, MILI_PSEUDOPODIA_HAPTOTAXIS_UP, GCM_DPF2, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, TGANTCA_AP1_C, GOBP_PROTEIN_FOLDING, NRF2_Q4, STONER_ESOPHAGEAL_CARCINOGENESIS_UP, GOBP_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS

GO Biological Process (5): protein folding (GO:0006457), positive regulation of inflammatory response (GO:0050729), chemokine-mediated signaling pathway (GO:0070098), positive regulation of neuroinflammatory response (GO:0150078), inflammatory response (GO:0006954)

GO Molecular Function (3): protein-macromolecule adaptor activity (GO:0030674), obsolete unfolded protein binding (GO:0051082), protein binding (GO:0005515)

GO Cellular Component (3): cytoplasm (GO:0005737), peroxisomal membrane (GO:0005778), cytosol (GO:0005829)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
cellular process	1
protein maturation	1
inflammatory response	1
positive regulation of defense response	1
positive regulation of response to external stimulus	1
regulation of inflammatory response	1
G protein-coupled receptor signaling pathway	1
cytokine-mediated signaling pathway	1
cellular response to chemokine	1
positive regulation of inflammatory response	1
neuroinflammatory response	1
regulation of neuroinflammatory response	1
defense response	1
protein binding	1
molecular adaptor activity	1
binding	1
intracellular anatomical structure	1
peroxisome	1
microbody membrane	1
cytoplasm	1

Protein interactions and networks

STRING

1536 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TTC1	HSPA4	P34932	972
TTC1	HSP90AA1	P07900	810
TTC1	HSPA8	P11142	777
TTC1	NF1	P21359	737
TTC1	HSP90AB1	P08238	710
TTC1	PEX5	P50542	703
TTC1	DNAJC7	Q99615	683
TTC1	STIP1	P31948	604
TTC1	CNP	P09543	540
TTC1	PRPF40A	O75400	479
TTC1	FKBP4	Q02790	472
TTC1	FANCG	O15287	453
TTC1	LEO1	Q8WVC0	445
TTC1	HRAS	P01112	440
TTC1	CEP15	Q9HBI5	433

IntAct

148 interactions, top by confidence:

A	B	Type	Score
TTC1	RNF41	psi-mi:“MI:0915”(physical association)	0.900
RNF41	TTC1	psi-mi:“MI:0915”(physical association)	0.900
TTC1	VAPB	psi-mi:“MI:0914”(association)	0.790
VAPB	FAM83G	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
SYT11	TTC1	psi-mi:“MI:0914”(association)	0.640
VAPA	FAM83G	psi-mi:“MI:0914”(association)	0.640
TTC1		psi-mi:“MI:0915”(physical association)	0.560
	TTC1	psi-mi:“MI:0915”(physical association)	0.560
PSTPIP1	TTC1	psi-mi:“MI:0915”(physical association)	0.560
TTC1	HSPA8	psi-mi:“MI:0915”(physical association)	0.560
TTC1	CYB5R1	psi-mi:“MI:0915”(physical association)	0.560
GRN	TTC1	psi-mi:“MI:0915”(physical association)	0.560
TTC1	HSPB1	psi-mi:“MI:0915”(physical association)	0.560
TTC1	WFS1	psi-mi:“MI:0915”(physical association)	0.560
HTT	TTC1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (228): RNF41 (Two-hybrid), TTC1 (Affinity Capture-MS), TTC1 (Affinity Capture-MS), VAPA (Affinity Capture-MS), VAPB (Affinity Capture-MS), RNF41 (Affinity Capture-MS), TTC1 (Affinity Capture-MS), TTC1 (Affinity Capture-MS), TTC1 (Affinity Capture-MS), TTC1 (Affinity Capture-MS), TTC1 (Two-hybrid), PDIA6 (Co-fractionation), TTC1 (Proximity Label-MS), TTC1 (Proximity Label-MS), TTC1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0P0VG31, A0A2H5Q1B8, A4K2V0, A8XHX1, F1RBN2, O14085, O14217, P19878, P27124, P30416, Q02790, Q06AN9, Q07617, Q13217, Q13451, Q15785, Q20683, Q27968, Q32NU8, Q3KRD5, Q3ZBR5, Q5JNB5, Q5RF88, Q5U2X2, Q5ZI13, Q5ZKQ3, Q64378, Q68FQ7, Q6AZT2, Q6ES52, Q6NU95, Q7XJS0, Q7ZU45, Q80ZX8, Q91YW3, Q91Z38, Q95L05, Q99614, Q9CYG7, Q9D706

Diamond homologs: A4K2V0, A6HD62, A6ZRW3, D7REX8, F1RBN2, F4IRM4, F4JTI1, F4K487, F4KCL7, O13754, O14217, O16259, O35814, O48802, O54981, O94826, O95801, P07213, P23231, P25638, P31948, P33313, P38825, P53041, P53042, Q07617, Q12118, Q13451, Q15785, Q32PZ3, Q3KRD5, Q3ZBR5, Q43207, Q4R8N7, Q5EA11, Q5PPS5, Q5R8D8, Q5RAP0, Q5U2X2, Q5VJS5

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 131 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
Attenuation phase	6	26.6×	4e-05
HSF1-dependent transactivation	5	17.2×	2e-03
Regulation of HSF1-mediated heat shock response	7	10.6×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein folding	11	9.6×	2e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	20
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1349 predictions. Top by Δscore:

Variant	Effect	Δscore
5:160009191:GTT:G	donor_gain	1.0000
5:160009194:G:GG	donor_gain	1.0000
5:160010854:AACAG:A	donor_gain	1.0000
5:160010855:ACAG:A	donor_gain	1.0000
5:160010856:CAG:C	donor_gain	1.0000
5:160010857:AG:A	donor_gain	1.0000
5:160010858:GG:G	donor_gain	1.0000
5:160010859:G:GG	donor_gain	1.0000
5:160036690:GATT:G	acceptor_gain	1.0000
5:160049512:A:AG	acceptor_gain	1.0000
5:160049513:G:GG	acceptor_gain	1.0000
5:160049513:GCA:G	acceptor_gain	1.0000
5:160049646:C:T	donor_gain	1.0000
5:160049654:GCTT:G	donor_gain	1.0000
5:160051127:A:AG	acceptor_gain	1.0000
5:160051128:G:GG	acceptor_gain	1.0000
5:160051128:GA:G	acceptor_gain	1.0000
5:160051179:GTTAG:G	donor_gain	1.0000
5:160051181:TAGG:T	donor_loss	1.0000
5:160051182:AGGT:A	donor_loss	1.0000
5:160051183:GGT:G	donor_loss	1.0000
5:160051184:G:A	donor_loss	1.0000
5:160051184:G:GG	donor_gain	1.0000
5:160051185:TAAGC:T	donor_loss	1.0000
5:160064931:GGTAA:G	acceptor_gain	1.0000
5:160065006:G:GT	donor_gain	1.0000
5:160009189:AGGTT:A	donor_gain	0.9900
5:160009190:GGTTG:G	donor_gain	0.9900
5:160009192:TT:T	donor_gain	0.9900
5:160009192:TTGTG:T	donor_loss	0.9900

AlphaMissense

1955 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:160064959:T:A	V258D	1.000
5:160064962:T:A	L259H	1.000
5:160064974:G:A	G263E	1.000
5:160064991:T:C	F269L	1.000
5:160064992:T:C	F269S	1.000
5:160064993:C:A	F269L	1.000
5:160064993:C:G	F269L	1.000
5:160049554:G:C	R194S	0.999
5:160049554:G:T	R194S	0.999
5:160049558:G:C	A196P	0.999
5:160049594:G:C	A208P	0.999
5:160051154:G:C	R239P	0.999
5:160064938:T:C	L251S	0.999
5:160064950:G:A	G255E	0.999
5:160064962:T:C	L259P	0.999
5:160064977:T:A	L264H	0.999
5:160064977:T:C	L264P	0.999
5:160064992:T:G	F269C	0.999
5:160065024:T:G	Y280D	0.999
5:160065027:T:C	S281P	0.999
5:160065031:T:A	I282N	0.999
5:160065036:T:C	F284L	0.999
5:160065037:T:C	F284S	0.999
5:160065037:T:G	F284C	0.999
5:160065038:C:A	F284L	0.999
5:160065038:C:G	F284L	0.999
5:160035169:G:C	K120N	0.998
5:160035169:G:T	K120N	0.998
5:160035177:G:A	G123E	0.998
5:160035188:T:C	F127L	0.998

dbSNP variants (sampled 300 via entrez): RS1000014600 (5:160013155 T>C), RS1000093511 (5:160044196 A>G), RS1000109032 (5:160050858 T>C), RS1000124473 (5:160044643 G>A,T), RS1000215598 (5:160038477 T>C), RS1000233822 (5:160014221 G>A,C), RS1000272174 (5:160028936 A>G), RS1000352648 (5:160038370 C>T), RS1000413013 (5:160031541 G>A), RS1000445753 (5:160034810 G>A,T), RS1000461035 (5:160046045 A>G), RS1000512100 (5:160047955 T>C), RS1000696105 (5:160055394 C>T), RS1000866087 (5:160033015 C>T), RS1000898547 (5:160017421 C>T)

Disease associations

OMIM: gene MIM:601963 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST007094_96	Diastolic blood pressure	8.000000e-08
GCST007096_153	Pulse pressure	4.000000e-07
GCST007099_256	Systolic blood pressure	4.000000e-11
GCST010083_67	Hemoglobin levels	3.000000e-09

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0006336	diastolic blood pressure
EFO:0005763	pulse pressure measurement
EFO:0006335	systolic blood pressure
EFO:0004509	hemoglobin measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	2
sodium arsenite	affects cotreatment, increases abundance, increases expression	2
bisphenol S	increases expression, decreases methylation	2
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
arsenite	affects binding, increases reaction	1
butyraldehyde	increases expression	1
manganese chloride	increases expression, affects cotreatment, increases abundance	1
coumarin	increases phosphorylation	1
cupric oxide	increases expression	1
4-aminophenylarsenoxide	decreases reaction, affects binding	1
beta-methylcholine	affects expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
LDN 193189	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
Arsenic Trioxide	affects binding, decreases reaction	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Benzo(a)pyrene	decreases methylation	1
Caffeine	increases phosphorylation	1
Dinitrochlorobenzene	affects binding	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Ivermectin	decreases expression	1
Manganese	increases abundance, increases expression, affects cotreatment	1
Thiram	increases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	increases methylation	1

Clinical trials (associated diseases)

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