TMPPE

Summary

TMPPE (transmembrane protein with metallophosphoesterase domain, HGNC:33865) is a protein-coding gene on chromosome 3p22.3, encoding Transmembrane protein with metallophosphoesterase domain (Q6ZT21).

Predicted to enable hydrolase activity and metal ion binding activity. Predicted to be located in membrane.

Source: NCBI Gene 643853 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 7 total — 2 pathogenic
• MANE Select transcript: NM_001039770

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:33865
Approved symbol	TMPPE
Name	transmembrane protein with metallophosphoesterase domain
Location	3p22.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ45032
Ensembl gene	ENSG00000188167
Ensembl biotype	protein_coding
Entrez	643853

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000342462, ENST00000416695

RefSeq mRNA: 2 — MANE Select: NM_001039770 NM_001039770, NM_001136238

CCDS: CCDS33732, CCDS46786

Canonical transcript exons

ENST00000342462 — 2 exons

Exon	Start	End
ENSE00001376990	33090422	33094303
ENSE00003844606	33096719	33097146

Expression profiles

Bgee: expression breadth ubiquitous, 132 present calls, max score 78.25.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.6480 / max 29.3657, expressed in 1717 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
41614	27.8495	1820
41612	4.6480	1717

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	78.25	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.92	gold quality
monocyte	CL:0000576	75.35	gold quality
leukocyte	CL:0000738	74.92	gold quality
bone marrow cell	CL:0002092	74.42	gold quality
bone marrow	UBERON:0002371	74.37	gold quality
thymus	UBERON:0002370	72.93	silver quality
colonic epithelium	UBERON:0000397	72.05	gold quality
quadriceps femoris	UBERON:0001377	69.42	gold quality
islet of Langerhans	UBERON:0000006	68.10	gold quality
adrenal tissue	UBERON:0018303	67.85	gold quality
cerebellar vermis	UBERON:0004720	67.75	gold quality
tonsil	UBERON:0002372	67.71	gold quality
stromal cell of endometrium	CL:0002255	67.08	gold quality
placenta	UBERON:0001987	65.08	gold quality
blood	UBERON:0000178	64.80	gold quality
vermiform appendix	UBERON:0001154	64.21	gold quality
duodenum	UBERON:0002114	63.36	gold quality
rectum	UBERON:0001052	62.40	gold quality
lymph node	UBERON:0000029	62.15	gold quality
smooth muscle tissue	UBERON:0001135	61.55	gold quality
granulocyte	CL:0000094	61.49	gold quality
muscle tissue	UBERON:0002385	60.86	gold quality
cortical plate	UBERON:0005343	60.71	gold quality
urinary bladder	UBERON:0001255	60.57	gold quality
skeletal muscle tissue	UBERON:0001134	60.16	silver quality
endometrium	UBERON:0001295	58.77	gold quality
pancreas	UBERON:0001264	58.64	gold quality
prefrontal cortex	UBERON:0000451	58.32	gold quality
skin of leg	UBERON:0001511	58.23	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.10

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

82 targeting TMPPE, 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-4533	100.00	69.48	2758
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-150-5P	99.99	66.69	1976
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-1229-3P	99.97	66.49	906
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-10395-5P	99.86	67.35	676

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmppe	ENSDARG00000036059
mus_musculus	Tmppe	ENSMUSG00000079260
rattus_norvegicus	Tmppe	ENSRNOG00000066638
caenorhabditis_elegans		WBGENE00011965
caenorhabditis_elegans		WBGENE00018226

Protein

Protein identifiers

Transmembrane protein with metallophosphoesterase domain — Q6ZT21 (reviewed: Q6ZT21)

All UniProt accessions (1): Q6ZT21

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Membrane.

Cofactor. Binds 2 divalent metal cations.

Similarity. Belongs to the metallophosphoesterase superfamily. LOC643853 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6ZT21-1	1	yes
Q6ZT21-2	2

RefSeq proteins (2): NP_001034859, NP_001129710 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004843	Calcineurin-like_PHP	Domain
IPR029052	Metallo-depent_PP-like	Homologous_superfamily
IPR051158	Metallophosphoesterase	Family

Pfam: PF00149

UniProt features (17 total): binding site 7, transmembrane region 5, sequence conflict 3, chain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6ZT21-F1	91.59	0.72

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 (7): 277; 391; 393; 214; 216; 246; 246

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 34 (showing top): chr3p22, MILI_PSEUDOPODIA_CHEMOTAXIS_DN, CHENG_IMPRINTED_BY_ESTRADIOL, FOXD2_TARGET_GENES, IRF5_TARGET_GENES, PCGF1_TARGET_GENES, SFMBT1_TARGET_GENES, UBN1_TARGET_GENES, ZNF175_TARGET_GENES, ZSCAN2_TARGET_GENES, MIR4500, MIR4533, MIR1299, MIR875_3P, LET_7B_5P

GO Biological Process (0):

GO Molecular Function (3): hydrolase activity (GO:0016787), metal ion binding (GO:0046872), protein binding (GO:0005515)

GO Cellular Component (1): membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
catalytic activity	1
cation binding	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

432 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMPPE	SLC66A3	Q8N755	599
TMPPE	TMEM41A	Q96HV5	589
TMPPE	ZNF319	Q9P2F9	474
TMPPE	LYSMD4	Q5XG99	474
TMPPE	YIPF4	Q9BSR8	451
TMPPE	RIMOC1	A6NDU8	447
TMPPE	DOLPP1	Q86YN1	446
TMPPE	UNC50	Q53HI1	432
TMPPE	FNDC3A	Q9Y2H6	417
TMPPE	INKA1	Q96EL1	400
TMPPE	SFXN4	Q6P4A7	382
TMPPE	HAUS4	Q9H6D7	375
TMPPE	NTMT2	Q5VVY1	355
TMPPE	GPR62	Q9BZJ7	354
TMPPE	STOX2	Q9P2F5	351

IntAct

147 interactions, top by confidence:

A	B	Type	Score
ENTREP1	WWP2	psi-mi:“MI:0914”(association)	0.850
TMPPE	SCN3B	psi-mi:“MI:0915”(physical association)	0.670
TMPPE	REEP4	psi-mi:“MI:0915”(physical association)	0.560
STX8	TMPPE	psi-mi:“MI:0915”(physical association)	0.560
TMPPE	GPR152	psi-mi:“MI:0915”(physical association)	0.560
YIPF1	TMPPE	psi-mi:“MI:0915”(physical association)	0.560
TMPPE	CYB561	psi-mi:“MI:0915”(physical association)	0.560
STX3	TMPPE	psi-mi:“MI:0915”(physical association)	0.560
TMPPE	PLPPR1	psi-mi:“MI:0915”(physical association)	0.560
TMPPE	SSMEM1	psi-mi:“MI:0915”(physical association)	0.560
KLRC1	TMPPE	psi-mi:“MI:0915”(physical association)	0.560
ASGR2	TMPPE	psi-mi:“MI:0915”(physical association)	0.560
TUSC5	TMPPE	psi-mi:“MI:0915”(physical association)	0.560
MS4A1	TMPPE	psi-mi:“MI:0915”(physical association)	0.560
	TMPPE	psi-mi:“MI:0915”(physical association)	0.560
LEMD1	TMPPE	psi-mi:“MI:0915”(physical association)	0.560
TMPPE	FIS1	psi-mi:“MI:0915”(physical association)	0.560
TMPPE	STX8	psi-mi:“MI:0915”(physical association)	0.560
TMPPE	SLAMF6	psi-mi:“MI:0915”(physical association)	0.560
KCNJ6	TMPPE	psi-mi:“MI:0915”(physical association)	0.560
TMPPE	IER3IP1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (95): TMPPE (Affinity Capture-MS), TMPPE (Affinity Capture-MS), TMPPE (Affinity Capture-MS), TMPPE (Affinity Capture-MS), TMPPE (Affinity Capture-MS), TMPPE (Affinity Capture-MS), TMPPE (Affinity Capture-MS), TMPPE (Affinity Capture-MS), TMPPE (Affinity Capture-MS), TMPPE (Affinity Capture-MS), TMPPE (Affinity Capture-MS), TMPPE (Affinity Capture-MS), TMPPE (Affinity Capture-MS), TMPPE (Affinity Capture-MS), TMPPE (Affinity Capture-MS)

ESM2 similar proteins: A4IG53, A5PJK1, B1WC86, D2I2M6, F1N2K1, O95479, P58242, P70665, P82450, P98192, Q05AK6, Q08BG1, Q0P5H1, Q1JPD2, Q1LWG4, Q4V7R2, Q53F39, Q5R748, Q5RET5, Q5RFU0, Q5ZK82, Q61139, Q640M6, Q641Z7, Q658P3, Q6L5F5, Q6UX53, Q6ZT21, Q7G7C7, Q80XL7, Q8BMD6, Q8C7K6, Q8NBM8, Q8R2R1, Q8WTR4, Q92485, Q95KC9, Q99PR0, Q9D0Z3, Q9ES71

Diamond homologs: A5PJK1, O25685, O67153, Q08BG1, Q09320, Q6ZT21, Q9PP77, Q9RRY7, Q9ZM43, O34870, P37049

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	1
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
639876	NC_000003.12:g.(?33096991)(33124599_?)del	Pathogenic
92911	NM_000404.4(GLB1):c.51dup (p.Leu18fs)	Pathogenic

SpliceAI

488 predictions. Top by Δscore:

Variant	Effect	Δscore
3:33097010:CG:C	donor_gain	1.0000
3:33096714:CGCA:C	donor_loss	0.9900
3:33096715:GCAC:G	donor_loss	0.9900
3:33096716:CA:C	donor_loss	0.9900
3:33097009:A:AC	donor_gain	0.9900
3:33097010:C:CC	donor_gain	0.9900
3:33097010:CGCG:C	donor_gain	0.9900
3:33096718:CCT:C	donor_gain	0.9800
3:33096725:TCAA:T	donor_gain	0.9800
3:33096726:CAAC:C	donor_gain	0.9800
3:33096727:AACA:A	donor_gain	0.9800
3:33097006:CTTAC:C	donor_loss	0.9800
3:33097007:T:TC	donor_loss	0.9800
3:33097008:T:TC	donor_loss	0.9800
3:33097009:ACG:A	donor_gain	0.9800
3:33097010:CGC:C	donor_gain	0.9800
3:33093789:C:CC	acceptor_gain	0.9700
3:33096731:CCTCG:C	donor_gain	0.9700
3:33097009:ACGCG:A	donor_gain	0.9700
3:33097010:CGCGC:C	donor_gain	0.9700
3:33093786:CCG:C	acceptor_gain	0.9600
3:33093787:CG:C	acceptor_gain	0.9600
3:33093787:CGC:C	acceptor_gain	0.9600
3:33093877:C:CC	acceptor_gain	0.9600
3:33096717:A:AC	donor_gain	0.9600
3:33096718:C:CC	donor_gain	0.9600
3:33093784:TGCCG:T	acceptor_gain	0.9500
3:33097088:C:CT	donor_gain	0.9400
3:33097089:C:CT	donor_gain	0.9000
3:33097008:TACG:T	donor_gain	0.8900

AlphaMissense

2941 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:33092918:G:C	S426R	0.996
3:33092918:G:T	S426R	0.996
3:33092920:T:G	S426R	0.996
3:33093555:T:A	D214V	0.996
3:33093039:A:G	L386P	0.994
3:33093462:C:A	G245V	0.994
3:33093091:G:C	H369D	0.992
3:33093556:C:G	D214H	0.992
3:33093665:G:C	S177R	0.992
3:33093665:G:T	S177R	0.992
3:33093667:T:G	S177R	0.992
3:33093033:A:T	L388H	0.991
3:33093459:T:A	D246V	0.991
3:33093554:G:C	D214E	0.991
3:33093554:G:T	D214E	0.991
3:33093555:T:G	D214A	0.991
3:33093291:T:A	N302I	0.990
3:33093899:A:C	S99R	0.990
3:33093899:A:T	S99R	0.990
3:33093901:T:G	S99R	0.990
3:33092885:C:A	R437S	0.989
3:33092885:C:G	R437S	0.989
3:33092922:A:T	V425D	0.989
3:33093369:C:A	G276V	0.989
3:33093459:T:C	D246G	0.989
3:33093459:T:G	D246A	0.989
3:33093199:C:A	G333W	0.988
3:33092886:C:G	R437T	0.987
3:33093075:G:T	A374D	0.987
3:33093201:G:T	A332D	0.987

dbSNP variants (sampled 300 via entrez): RS1000366776 (3:33098115 T>C), RS1000505969 (3:33094534 G>A,C), RS1000620624 (3:33094837 G>A), RS1000751478 (3:33092062 G>A,C), RS1001188082 (3:33098391 A>G,T), RS1001209302 (3:33095765 A>C), RS1001761604 (3:33092642 G>A,C), RS1003413248 (3:33096859 C>T), RS1003640802 (3:33091026 G>A,T), RS1003758538 (3:33095529 A>T), RS1003913649 (3:33094985 C>A), RS1003924814 (3:33094618 T>C), RS1004152979 (3:33091297 A>G), RS1004153520 (3:33095862 T>C), RS1004580254 (3:33092363 G>A)

Disease associations

OMIM: gene `` | disease phenotypes: MIM:253010, MIM:610682

GenCC curated gene-disease

Mondo (3): mucopolysaccharidosis type 4B (MONDO:0009660), GM1 gangliosidosis (MONDO:0018149), osteogenesis imperfecta type 7 (MONDO:0012536)

Orphanet (3): Mucopolysaccharidosis type 4B (Orphanet:309310), GM1 gangliosidosis (Orphanet:354), Mucopolysaccharidosis type 4 (Orphanet:582)

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST007995_15	Asthma (childhood onset)	3.000000e-10
GCST008916_8	Asthma	5.000000e-09
GCST009798_68	Asthma	3.000000e-12

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D016537	Gangliosidosis, GM1	C10.228.140.163.100.435.825.300.400; C16.320.565.189.435.825.300.400; C16.320.565.398.641.803.350.360; C16.320.565.595.554.825.300.400; C18.452.132.100.435.825.300.400; C18.452.584.563.641.803.350.360; C18.452.648.189.435.825.300.400; C18.452.648.398.641.803.350.360; C18.452.648.595.554.825.300.400

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
aristolochic acid I	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
abrine	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Doxorubicin	decreases expression	1
Estradiol	increases expression	1
Ozone	affects expression, increases abundance	1
Smoke	decreases expression	1
Okadaic Acid	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07054515	PHASE3	RECRUITING	A Study to Evaluate the Safety and Efficacy of Oral Nizubaglustat (AZ-3102) in Late-infantile and Juvenile Forms of Niemann-Pick Type C Disease, GM1 Gangliosidosis or GM2 Gangliosidosis
NCT00383448	PHASE2	COMPLETED	HSCT for High Risk Inherited Inborn Errors
NCT00176904	PHASE2/PHASE3	COMPLETED	Stem Cell Transplant for Inborn Errors of Metabolism
NCT04273269	PHASE1/PHASE2	TERMINATED	A Safety and Efficacy Study of LYS-GM101 Gene Therapy in Patients With GM1 Gangliosidosis
NCT04713475	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Study of Safety, Tolerability and Efficacy of PBGM01 in Pediatric Participants With GM1 Gangliosidosis
NCT00668187	Not specified	RECRUITING	A Natural History Study of the Gangliosidoses
NCT04041102	Not specified	COMPLETED	Natural History Study of Infantile and Juvenile GM1 Gangliosidosis (GM1) Patients
NCT04310163	Not specified	COMPLETED	Interviews and Video Capture in Patients With GM1 Gangliosidosis
NCT04320329	Not specified	UNKNOWN	Natural History of Morquio B and Late-Onset of GM1 Gangliosidosis
NCT04470713	Not specified	COMPLETED	Natural History Study for Pediatric Patients With Early Onset of Either GM1 Gangliosidosis, GM2 Gangliosidoses, or Gaucher Disease Type 2
NCT04624789	Not specified	UNKNOWN	Registry Gangliosidoses
NCT05109793	Not specified	COMPLETED	GM1 and GM2 Gangliosidosis PROspective Neurological Disease TrajectOry Study (PRONTO)
NCT05368038	Not specified	ENROLLING_BY_INVITATION	ScreenPlus: A Comprehensive, Flexible, Multi-disorder Newborn Screening Program
NCT06539169	Not specified	RECRUITING	FLOWER: Following Longitudinal Outcomes With Epidemiology for Rare Diseases