TMEM259

Summary

TMEM259 (transmembrane protein 259, HGNC:17039) is a protein-coding gene on chromosome 19p13.3, encoding Membralin (Q4ZIN3). May have a role in the ERAD pathway required for clearance of misfolded proteins in the endoplasmic reticulum (ER).

Predicted to be involved in positive regulation of ERAD pathway and response to endoplasmic reticulum stress. Predicted to be located in endoplasmic reticulum membrane. Predicted to be active in endoplasmic reticulum.

Source: NCBI Gene 91304 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 135 total
• MANE Select transcript: NM_001033026

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17039
Approved symbol	TMEM259
Name	transmembrane protein 259
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	MGC4022, ASBABP1, MBRL
Ensembl gene	ENSG00000182087
Ensembl biotype	protein_coding
OMIM	611011
Entrez	91304

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 21 protein_coding, 6 retained_intron, 1 nonsense_mediated_decay

ENST00000333175, ENST00000356663, ENST00000586250, ENST00000586285, ENST00000586704, ENST00000589055, ENST00000589831, ENST00000592052, ENST00000592590, ENST00000592618, ENST00000593068, ENST00000607316, ENST00000902894, ENST00000902895, ENST00000902896, ENST00000902897, ENST00000902898, ENST00000902899, ENST00000902900, ENST00000902901, ENST00000902902, ENST00000902903, ENST00000925026, ENST00000925027, ENST00000925028, ENST00000925029, ENST00000941279, ENST00000941280

RefSeq mRNA: 2 — MANE Select: NM_001033026 NM_001033026, NM_033420

CCDS: CCDS12052, CCDS32862

Canonical transcript exons

ENST00000356663 — 11 exons

Exon	Start	End
ENSE00001350193	1012066	1012188
ENSE00002806299	1009653	1010895
ENSE00003695749	1014192	1014473
ENSE00003696665	1011580	1011663
ENSE00003698514	1011367	1011499
ENSE00003699306	1013241	1013340
ENSE00003700453	1012463	1012573
ENSE00003700776	1011741	1011798
ENSE00003700834	1011096	1011195
ENSE00003702315	1011892	1011992
ENSE00003850202	1020772	1021123

Expression profiles

Bgee: expression breadth ubiquitous, 262 present calls, max score 98.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 86.0044 / max 1269.6346, expressed in 1827 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
177958	86.0044	1827

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adenohypophysis	UBERON:0002196	98.99	gold quality
granulocyte	CL:0000094	98.97	gold quality
metanephros cortex	UBERON:0010533	98.93	gold quality
right uterine tube	UBERON:0001302	98.87	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.84	gold quality
right lobe of thyroid gland	UBERON:0001119	98.79	gold quality
left lobe of thyroid gland	UBERON:0001120	98.77	gold quality
small intestine Peyer’s patch	UBERON:0003454	98.76	gold quality
tibial nerve	UBERON:0001323	98.72	gold quality
endocervix	UBERON:0000458	98.67	gold quality
mucosa of stomach	UBERON:0001199	98.66	gold quality
body of stomach	UBERON:0001161	98.65	gold quality
left uterine tube	UBERON:0001303	98.64	gold quality
body of uterus	UBERON:0009853	98.59	gold quality
transverse colon	UBERON:0001157	98.58	gold quality
cerebellar hemisphere	UBERON:0002245	98.57	gold quality
skin of abdomen	UBERON:0001416	98.56	gold quality
lower esophagus mucosa	UBERON:0035834	98.56	gold quality
ectocervix	UBERON:0012249	98.53	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.53	gold quality
right ovary	UBERON:0002118	98.52	gold quality
skin of leg	UBERON:0001511	98.48	gold quality
apex of heart	UBERON:0002098	98.48	gold quality
left ovary	UBERON:0002119	98.45	gold quality
minor salivary gland	UBERON:0001830	98.43	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.43	gold quality
cerebellar cortex	UBERON:0002129	98.42	gold quality
right lung	UBERON:0002167	98.42	gold quality
left adrenal gland cortex	UBERON:0035825	98.38	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.38	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.06

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

23 targeting TMEM259, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-4679	99.76	69.19	1229
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-6757-3P	99.63	66.88	1089
HSA-MIR-7112-5P	99.59	65.76	104
HSA-MIR-1324	99.46	66.57	1302
HSA-MIR-6853-3P	99.36	70.79	1558
HSA-MIR-1206	99.30	69.32	1016
HSA-MIR-3199	99.17	65.19	696
HSA-MIR-8052	99.17	65.01	719
HSA-MIR-328-5P	99.08	64.65	1000
HSA-MIR-6749-3P	99.00	65.73	1443
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-4252	98.45	66.37	987
HSA-MIR-4660	97.79	67.44	1328

Literature-anchored findings (GeneRIF, showing 2)

• genomic organization and expression (membralin) (PMID:12638133)
• Study provides first characterization of human membralin and suggests that membralin is a novel tumor-associated marker in ovarian serous carcinomas. (PMID:16084606)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmem259	ENSDARG00000060442
mus_musculus	Tmem259	ENSMUSG00000013858
rattus_norvegicus	Tmem259	ENSRNOG00000012808
drosophila_melanogaster	CG8405	FBGN0034071
caenorhabditis_elegans		WBGENE00021985

Paralogs (1): NUF2 (ENSG00000143228)

Protein

Protein identifiers

Membralin — Q4ZIN3 (reviewed: Q4ZIN3)

Alternative names: Transmembrane protein 259

All UniProt accessions (5): A0A0A0MTU3, Q4ZIN3, U3KPU1, U3KPY4, U3KQQ5

UniProt curated annotations — full annotation on UniProt →

Function. May have a role in the ERAD pathway required for clearance of misfolded proteins in the endoplasmic reticulum (ER). Promotes survival of motor neurons, probably by protecting against ER stress.

Subunit / interactions. Interacts with ERLIN2.

Subcellular location. Endoplasmic reticulum membrane.

Similarity. Belongs to the membralin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q4ZIN3-1	1, Long, Membralin-1	yes
Q4ZIN3-2	2, Short, Membralin-2, Membralin-3

RefSeq proteins (2): NP_001028198, NP_219488 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019144	Membralin	Family

Pfam: PF09746

UniProt features (17 total): transmembrane region 4, compositionally biased region 3, region of interest 3, modified residue 2, splice variant 2, initiator methionine 1, chain 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q4ZIN3-F1	65.48	0.12

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): 2, 29

Glycosylation sites (1): 189

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 149 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, ELVIDGE_HYPOXIA_DN, MODULE_52, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, LFA1_Q6, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, PATIL_LIVER_CANCER, GTGCCTT_MIR506, RICKMAN_METASTASIS_DN, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CATABOLIC_PROCESS, GOBP_REGULATION_OF_RESPONSE_TO_STRESS

GO Biological Process (2): response to endoplasmic reticulum stress (GO:0034976), positive regulation of ERAD pathway (GO:1904294)

GO Molecular Function (0):

GO Cellular Component (3): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular response to stress	1
ERAD pathway	1
positive regulation of proteasomal protein catabolic process	1
regulation of ERAD pathway	1
positive regulation of response to endoplasmic reticulum stress	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cellular anatomical structure	1

Protein interactions and networks

STRING

888 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMEM259	TMUB1	Q9BVT8	851
TMEM259	TMUB2	Q71RG4	663
TMEM259	RNF185	Q96GF1	654
TMEM259	MED16	Q9Y2X0	546
TMEM259	FAM174C	Q9BVV8	537
TMEM259	EMC1	Q8N766	522
TMEM259	SEL1L	Q9UBV2	520
TMEM259	TMEM186	Q96B77	514
TMEM259	NGLY1	Q96IV0	505
TMEM259	C6orf120	Q7Z4R8	504
TMEM259	PLPPR3	Q6T4P5	499
TMEM259	CACHD1	Q5VU97	476
TMEM259	RBIS	Q8N0T1	462
TMEM259	NSFL1C	Q9UNZ2	449
TMEM259	STT3A	P46977	440
TMEM259	RNF170	Q96K19	440

IntAct

105 interactions, top by confidence:

A	B	Type	Score
BCL2	BCL2L11	psi-mi:“MI:0914”(association)	0.930
ERLIN2	ERLIN1	psi-mi:“MI:0914”(association)	0.740
VMA12	ATP6AP2	psi-mi:“MI:0914”(association)	0.640
B3GAT3	GOLIM4	psi-mi:“MI:0914”(association)	0.640
ANKRD46	ATRN	psi-mi:“MI:0914”(association)	0.640
ASPH	STXBP3	psi-mi:“MI:0914”(association)	0.640
CANX	PGRMC1	psi-mi:“MI:0914”(association)	0.570
YIPF3	TMEM120B	psi-mi:“MI:0914”(association)	0.530
EMC6	EMC8	psi-mi:“MI:0914”(association)	0.530
B3GALT2	LTN1	psi-mi:“MI:0914”(association)	0.530
SPSB2	ARHGEF10	psi-mi:“MI:0914”(association)	0.530
DIPK1A	TMEM259	psi-mi:“MI:0914”(association)	0.530
ABHD14A	TMEM259	psi-mi:“MI:0914”(association)	0.530
SPSB4	ARHGEF10	psi-mi:“MI:0914”(association)	0.530
ANKH	FAM234B	psi-mi:“MI:0914”(association)	0.530
TMEM259	PLOD3	psi-mi:“MI:0915”(physical association)	0.400
TMEM223	TMEM259	psi-mi:“MI:0915”(physical association)	0.400
TMEM259	ADRB2	psi-mi:“MI:0915”(physical association)	0.370
	ESYT2	psi-mi:“MI:0914”(association)	0.350
E5	ESYT2	psi-mi:“MI:0914”(association)	0.350
	HAX1	psi-mi:“MI:0914”(association)	0.350
CNR2	ILVBL	psi-mi:“MI:0914”(association)	0.350
STYK1	XPO1	psi-mi:“MI:0914”(association)	0.350
STYK1	MYO1C	psi-mi:“MI:0914”(association)	0.350
APOA2	TMEM131L	psi-mi:“MI:0914”(association)	0.350
GPR88	POTEF	psi-mi:“MI:0914”(association)	0.350
SPSB4	CCDC85C	psi-mi:“MI:0914”(association)	0.350
OR6T1	PSMD11	psi-mi:“MI:0914”(association)	0.350
CLSTN1	NOP56	psi-mi:“MI:0914”(association)	0.350
MS4A15	ABCD4	psi-mi:“MI:0914”(association)	0.350

BioGRID (155): TMEM259 (Affinity Capture-MS), TMEM259 (Affinity Capture-MS), TMEM259 (Affinity Capture-MS), TMEM259 (Affinity Capture-MS), TMEM259 (Affinity Capture-MS), TMEM259 (Affinity Capture-MS), TMEM259 (Affinity Capture-MS), TMEM259 (Affinity Capture-MS), TMEM259 (Affinity Capture-MS), TMEM259 (Affinity Capture-MS), TMEM259 (Affinity Capture-MS), TMEM259 (Affinity Capture-MS), TMEM259 (Affinity Capture-MS), TMEM259 (Affinity Capture-MS), TMEM259 (Affinity Capture-MS)

ESM2 similar proteins: A0A494C086, A0A494C0Z2, A0A494C191, A0JPH4, A6NHP3, A6NIY4, A6NJR5, A6NLX3, A6NNV3, A6QLI5, B0BNE4, O08918, O60543, O70302, O75916, P0CI01, P0DTA3, P0DUD1, P0DUD2, P0DUD3, P0DUD4, P0DUX0, P0DUX1, P0DV79, P24864, P39949, P49805, Q12967, Q495Y7, Q495Y8, Q4VXA5, Q4ZIN3, Q5IBH6, Q5IBH7, Q5MJ70, Q5SYB0, Q5XIQ2, Q5ZJR9, Q61457, Q6AYG1

Diamond homologs: Q4ZIN3, Q8CIV2

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 149 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
Defective CFTR causes cystic fibrosis	7	16.4×	1e-04
AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)	7	14.4×	1e-04
ABC-family protein mediated transport	7	9.1×	1e-03
Class A/1 (Rhodopsin-like receptors)	9	7.1×	6e-04
Transport of small molecules	16	4.3×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
ERAD pathway	7	10.1×	5e-03
transmembrane transport	7	9.4×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	115
Likely benign	7
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1750 predictions. Top by Δscore:

Variant	Effect	Δscore
19:1010891:GAATG:G	acceptor_gain	1.0000
19:1010892:AATG:A	acceptor_gain	1.0000
19:1010893:ATG:A	acceptor_gain	1.0000
19:1010894:TG:T	acceptor_gain	1.0000
19:1010896:C:A	acceptor_loss	1.0000
19:1010896:C:CC	acceptor_gain	1.0000
19:1010900:G:T	acceptor_gain	1.0000
19:1011090:CCTCA:C	donor_loss	1.0000
19:1011091:CTCA:C	donor_loss	1.0000
19:1011093:CA:C	donor_loss	1.0000
19:1011094:A:C	donor_loss	1.0000
19:1011193:AACCT:A	acceptor_loss	1.0000
19:1011194:ACCT:A	acceptor_loss	1.0000
19:1011195:CCTGC:C	acceptor_loss	1.0000
19:1011197:T:A	acceptor_loss	1.0000
19:1011362:CTCA:C	donor_loss	1.0000
19:1011364:CA:C	donor_loss	1.0000
19:1011365:A:AC	donor_gain	1.0000
19:1011365:ACCG:A	donor_gain	1.0000
19:1011366:C:CC	donor_gain	1.0000
19:1011366:CCG:C	donor_gain	1.0000
19:1011366:CCGC:C	donor_gain	1.0000
19:1011366:CCGCA:C	donor_gain	1.0000
19:1011495:CATCC:C	acceptor_gain	1.0000
19:1011498:CCCTG:C	acceptor_loss	1.0000
19:1011499:CCTGC:C	acceptor_loss	1.0000
19:1011500:CTG:C	acceptor_loss	1.0000
19:1011501:T:G	acceptor_loss	1.0000
19:1011664:C:CC	acceptor_gain	1.0000
19:1011735:ACTC:A	donor_loss	1.0000

AlphaMissense

4058 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:1010861:A:G	L451P	1.000
19:1011121:A:G	L431P	1.000
19:1011147:G:C	F422L	1.000
19:1011147:G:T	F422L	1.000
19:1011149:A:G	F422L	1.000
19:1011168:G:C	F415L	1.000
19:1011168:G:T	F415L	1.000
19:1011170:A:G	F415L	1.000
19:1011374:A:G	W404R	1.000
19:1011374:A:T	W404R	1.000
19:1011431:A:G	W385R	1.000
19:1011431:A:T	W385R	1.000
19:1011499:C:T	G362E	1.000
19:1011580:C:G	G362R	1.000
19:1011580:C:T	G362R	1.000
19:1011585:A:G	L360P	1.000
19:1011585:A:T	L360H	1.000
19:1011588:G:T	A359D	1.000
19:1011591:A:T	L358Q	1.000
19:1011657:A:G	L336P	1.000
19:1011751:G:C	F330L	1.000
19:1011751:G:T	F330L	1.000
19:1011753:A:G	F330L	1.000
19:1011776:A:G	L322P	1.000
19:1011779:A:G	L321P	1.000
19:1011790:G:C	S317R	1.000
19:1011790:G:T	S317R	1.000
19:1011792:T:G	S317R	1.000
19:1011952:A:C	F294L	1.000
19:1011952:A:T	F294L	1.000

dbSNP variants (sampled 300 via entrez): RS1000026779 (19:1016156 G>A), RS1000078217 (19:1010539 G>A,C), RS1000481993 (19:1009991 C>G), RS1000726421 (19:1022781 T>C), RS1000906907 (19:1021138 C>T), RS1000919581 (19:1019745 G>A), RS1001085250 (19:1015108 G>A), RS1001217364 (19:1009352 T>C), RS1001468570 (19:1020403 C>T), RS1001476293 (19:1016536 C>T), RS1001689526 (19:1022868 T>C,G), RS1001770523 (19:1015755 A>C,G), RS1001857768 (19:1015683 T>A), RS1001910049 (19:1015525 A>G), RS1002074005 (19:1019792 C>T)

Disease associations

OMIM: gene MIM:611011 | 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
GCST004617_129	Eosinophil percentage of granulocytes	5.000000e-09
GCST004621_203	Red cell distribution width	1.000000e-12

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007996	eosinophil percentage of granulocytes
EFO:0009188	Red cell distribution width

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
Air Pollutants	increases expression, affects cotreatment, increases abundance, increases oxidation, affects expression	3
Benzo(a)pyrene	decreases expression, increases methylation, increases mutagenesis	3
Particulate Matter	increases abundance, increases expression, affects cotreatment, affects expression	3
sodium arsenite	increases expression	2
Ozone	affects cotreatment, increases oxidation, increases abundance, affects expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	increases expression	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment	1
trichostatin A	decreases expression	1
beta-lapachone	decreases expression	1
cobaltous chloride	increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
MT19c compound	decreases expression	1
Zoledronic Acid	increases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Ethanol	affects cotreatment, increases abundance, increases expression	1
Atrazine	increases expression	1
Vehicle Emissions	affects expression, increases abundance	1
Cadmium	decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	increases expression	1
Folic Acid	decreases expression	1
Gasoline	increases expression, affects cotreatment, increases abundance	1
Methotrexate	affects response to substance	1
Polycyclic Aromatic Hydrocarbons	affects cotreatment, increases abundance, increases expression	1
Rotenone	increases expression	1
Smoke	decreases expression	1
Valproic Acid	increases methylation	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B3JN	Abcam HEK293T TMEM259 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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