TMEM14C

Summary

TMEM14C (transmembrane protein 14C, HGNC:20952) is a protein-coding gene on chromosome 6p24.2, encoding Transmembrane protein 14C (Q9P0S9). Required for normal heme biosynthesis.

Predicted to be involved in regulation of heme biosynthetic process. Predicted to act upstream of or within erythrocyte differentiation; mitochondrial transport; and nitrogen compound transport. Located in mitochondrion.

Source: NCBI Gene 51522 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 40 total
• Druggable target: yes
• MANE Select transcript: NM_016462

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20952
Approved symbol	TMEM14C
Name	transmembrane protein 14C
Location	6p24.2
Locus type	gene with protein product
Status	Approved
Aliases	HSPC194, bA421M1.6, NET26
Ensembl gene	ENSG00000111843
Ensembl biotype	protein_coding
OMIM	615318
Entrez	51522

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 18 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000229563, ENST00000466421, ENST00000467415, ENST00000495549, ENST00000541412, ENST00000852872, ENST00000852873, ENST00000852874, ENST00000852875, ENST00000852876, ENST00000852877, ENST00000916629, ENST00000916630, ENST00000916631, ENST00000916632, ENST00000916633, ENST00000916634, ENST00000916635, ENST00000916636, ENST00000916637, ENST00000916638

RefSeq mRNA: 2 — MANE Select: NM_016462 NM_001165258, NM_016462

CCDS: CCDS4514

Canonical transcript exons

ENST00000229563 — 6 exons

Exon	Start	End
ENSE00001009131	10724570	10724633
ENSE00001917181	10723070	10723241
ENSE00003528839	10730615	10731127
ENSE00003550805	10724961	10725037
ENSE00003648764	10725907	10726008
ENSE00003658501	10728640	10728727

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 99.14.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 180.5653 / max 1265.9112, expressed in 1827 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
65779	133.6011	1826
65780	45.5208	1819
65778	1.4434	797

Top tissues by expression

134 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	99.14	gold quality
right adrenal gland cortex	UBERON:0035827	98.58	gold quality
right adrenal gland	UBERON:0001233	98.53	gold quality
left adrenal gland	UBERON:0001234	98.43	gold quality
left adrenal gland cortex	UBERON:0035825	98.41	gold quality
endocervix	UBERON:0000458	98.13	gold quality
descending thoracic aorta	UBERON:0002345	98.12	gold quality
left uterine tube	UBERON:0001303	98.06	gold quality
left coronary artery	UBERON:0001626	98.06	gold quality
adrenal gland	UBERON:0002369	98.03	gold quality
fallopian tube	UBERON:0003889	98.03	gold quality
thoracic aorta	UBERON:0001515	98.02	gold quality
prostate gland	UBERON:0002367	98.01	gold quality
ascending aorta	UBERON:0001496	97.99	gold quality
gall bladder	UBERON:0002110	97.98	gold quality
right coronary artery	UBERON:0001625	97.96	gold quality
fundus of stomach	UBERON:0001160	97.88	gold quality
heart left ventricle	UBERON:0002084	97.86	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.85	gold quality
heart	UBERON:0000948	97.83	gold quality
tibial artery	UBERON:0007610	97.83	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.83	gold quality
popliteal artery	UBERON:0002250	97.82	gold quality
metanephros cortex	UBERON:0010533	97.82	gold quality
omental fat pad	UBERON:0010414	97.80	gold quality
stromal cell of endometrium	CL:0002255	97.79	gold quality
mucosa of stomach	UBERON:0001199	97.79	gold quality
endometrium	UBERON:0001295	97.79	gold quality
body of uterus	UBERON:0009853	97.78	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.78	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-9388	yes	9.33
E-MTAB-3929	no	47.38
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

29 targeting TMEM14C, 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-1277-5P	100.00	73.95	5056
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-2681-5P	99.75	67.64	1655
HSA-MIR-4480	99.42	66.02	735
HSA-MIR-6510-5P	99.14	66.59	1081
HSA-MIR-622	98.99	66.48	1050
HSA-MIR-4326	98.97	67.63	962
HSA-MIR-4464	98.95	67.73	820
HSA-MIR-4748	98.95	67.53	810
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-6796-3P	98.68	65.49	689
HSA-MIR-6804-5P	98.39	65.77	1084
HSA-MIR-4773	98.35	67.30	1710
HSA-MIR-5087	98.01	69.09	965
HSA-MIR-3190-3P	97.61	66.95	1406
HSA-MIR-320E	97.49	65.96	865
HSA-MIR-6509-5P	97.39	68.27	969
HSA-MIR-193A-5P	95.70	65.33	613
HSA-MIR-6890-5P	92.89	65.83	442

Literature-anchored findings (GeneRIF, showing 3)

• Required for functional heme biosynthesis in erythroid cells. (PMID:19656490)
• Phase I First-in-Human Dose Escalation Study of the oral SF3B1 modulator H3B-8800 in myeloid neoplasms. (PMID:34172893)
• Coordinated missplicing of TMEM14C and ABCB7 causes ring sideroblast formation in SF3B1-mutant myelodysplastic syndrome. (PMID:34861039)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmem14ca	ENSDARG00000110836
danio_rerio	tmem14cb	ENSDARG00000114991
mus_musculus	Tmem14c	ENSMUSG00000021361
rattus_norvegicus	Tmem14cl1	ENSRNOG00000022144
drosophila_melanogaster	CG5532	FBGN0034902

Paralogs (2): TMEM14A (ENSG00000096092), TMEM14B (ENSG00000137210)

Protein

Protein identifiers

Transmembrane protein 14C — Q9P0S9 (reviewed: Q9P0S9)

All UniProt accessions (1): Q9P0S9

UniProt curated annotations — full annotation on UniProt →

Function. Required for normal heme biosynthesis.

Subcellular location. Mitochondrion membrane.

Similarity. Belongs to the TMEM14 family.

RefSeq proteins (2): NP_001158730, NP_057546* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005349	TMEM14	Family
IPR044890	TMEM14_sf	Homologous_superfamily

Pfam: PF03647

UniProt features (17 total): transmembrane region 4, helix 4, strand 4, sequence variant 4, chain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2LOS	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P0S9-F1	61.28	0.00

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 179 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, GOBP_MYELOID_CELL_HOMEOSTASIS, chr6p24, GOBP_ERYTHROCYTE_HOMEOSTASIS, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_TETRAPYRROLE_BIOSYNTHETIC_PROCESS, GOBP_MITOCHONDRIAL_TRANSPORT, GOLDRATH_ANTIGEN_RESPONSE, GOBP_PORPHYRIN_CONTAINING_COMPOUND_METABOLIC_PROCESS, MCBRYAN_PUBERTAL_BREAST_4_5WK_DN, GOBP_TETRAPYRROLE_METABOLIC_PROCESS, GOBP_PIGMENT_METABOLIC_PROCESS, GOCC_MITOCHONDRIAL_ENVELOPE, MCBRYAN_PUBERTAL_BREAST_5_6WK_UP

GO Biological Process (4): heme biosynthetic process (GO:0006783), mitochondrial transport (GO:0006839), erythrocyte differentiation (GO:0030218), transmembrane transport (GO:0055085)

GO Molecular Function (2): transmembrane transporter activity (GO:0022857), protein binding (GO:0005515)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial membrane (GO:0031966), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
porphyrin-containing compound biosynthetic process	1
heme metabolic process	1
pigment biosynthetic process	1
intracellular transport	1
myeloid cell differentiation	1
erythrocyte homeostasis	1
transport	1
cellular process	1
transporter activity	1
transmembrane transport	1
binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
mitochondrion	1
mitochondrial envelope	1
organelle membrane	1
cellular anatomical structure	1

Protein interactions and networks

STRING

916 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMEM14C	ABCB7	O75027	806
TMEM14C	ABCB10	Q9NRK6	709
TMEM14C	FECH	P22830	698
TMEM14C	SLC25A39	Q9BZJ4	636
TMEM14C	ISCA1	Q9BUE6	583
TMEM14C	ENOSF1	Q7L5Y1	570
TMEM14C	IBA57	Q5T440	568
TMEM14C	SLC25A37	Q9NYZ2	554
TMEM14C	PPOX	P50336	540
TMEM14C	SLC25A38	Q96DW6	500
TMEM14C	ABCB6	Q9NP58	498
TMEM14C	CPOX	P36551	490
TMEM14C	COASY	Q13057	477
TMEM14C	ALAS2	P22557	476
TMEM14C	UQCC1	Q9NVA1	471

IntAct

134 interactions, top by confidence:

A	B	Type	Score
TMEM14C	KASH5	psi-mi:“MI:0915”(physical association)	0.560
TMEM14C	CYB5R3	psi-mi:“MI:0915”(physical association)	0.560
TMEM14C	PDZK1IP1	psi-mi:“MI:0915”(physical association)	0.560
TMEM14C	NCAPH2	psi-mi:“MI:0915”(physical association)	0.560
TMEM14C	ELOVL7	psi-mi:“MI:0915”(physical association)	0.560
TMEM14C	TMX2	psi-mi:“MI:0915”(physical association)	0.560
TMEM14C	VSIR	psi-mi:“MI:0915”(physical association)	0.560
TMEM14C	SLC10A6	psi-mi:“MI:0915”(physical association)	0.560
TMEM14C	HSD17B13	psi-mi:“MI:0915”(physical association)	0.560
TMEM14C	GORAB	psi-mi:“MI:0915”(physical association)	0.560
TMEM14C	EBP	psi-mi:“MI:0915”(physical association)	0.560
STX1A	TMEM14C	psi-mi:“MI:0915”(physical association)	0.560
TMEM79	TMEM14C	psi-mi:“MI:0915”(physical association)	0.560
MFF	TMEM14C	psi-mi:“MI:0915”(physical association)	0.560
BCL2L13	TMEM14C	psi-mi:“MI:0915”(physical association)	0.560
SDC3	TMEM14C	psi-mi:“MI:0915”(physical association)	0.560
CREB3L1	TMEM14C	psi-mi:“MI:0915”(physical association)	0.560
BIK	TMEM14C	psi-mi:“MI:0915”(physical association)	0.560
	TMEM14C	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (66): CCDC155 (Two-hybrid), TMEM14C (Two-hybrid), TMEM14C (Two-hybrid), TMEM14C (Proximity Label-MS), TMEM14C (Co-fractionation), TMEM14C (Two-hybrid), TMEM14C (Two-hybrid), TMEM14C (Two-hybrid), TMEM14C (Two-hybrid), TMEM14C (Two-hybrid), TMEM14C (Two-hybrid), TMEM14C (Two-hybrid), TMEM14C (Two-hybrid), TMEM14C (Two-hybrid), TMEM14C (Two-hybrid)

ESM2 similar proteins: A4DA06, A8MWL7, A9UY97, O14238, O64847, P0CS25, P25338, P38166, P46964, P47131, P63030, P63031, P93829, Q0P436, Q12116, Q18319, Q22252, Q28GF5, Q295N5, Q3SZ36, Q3TUD9, Q3ZCG2, Q3ZCI1, Q4V7N7, Q55GU4, Q5F410, Q5R751, Q6C741, Q6CMQ1, Q6DGF8, Q74Z81, Q750M8, Q75JB5, Q7KSC4, Q8INQ7, Q8IQ56, Q8NNK3, Q924P2, Q96B42, Q9C6T7

Diamond homologs: A8MWL7, O64847, P47131, P56982, P56983, P56984, Q0P436, Q3ZCI1, Q5R751, Q6UXP3, Q75JB5, Q924P2, Q9C6T7, Q9CQN6, Q9LJU6, Q9NUH8, Q9P0S9, Q9W1K0, Q9Y6G1, Q8LPG1, Q94A32, Q9P7G3, Q93V66, Q9ZVH7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	18
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

750 predictions. Top by Δscore:

Variant	Effect	Δscore
6:10724632:GT:G	donor_gain	1.0000
6:10724960:GA:G	acceptor_gain	1.0000
6:10725034:GCAG:G	donor_gain	1.0000
6:10725990:A:T	donor_gain	1.0000
6:10723237:GACCG:G	donor_gain	0.9900
6:10723248:G:GG	donor_gain	0.9900
6:10723256:G:GT	donor_gain	0.9900
6:10724634:G:GG	donor_gain	0.9900
6:10724955:TTTCA:T	acceptor_loss	0.9900
6:10724956:TTCA:T	acceptor_loss	0.9900
6:10724957:TCAGA:T	acceptor_loss	0.9900
6:10724958:CAG:C	acceptor_gain	0.9900
6:10724959:A:AG	acceptor_gain	0.9900
6:10724959:AGA:A	acceptor_gain	0.9900
6:10724959:AGAGT:A	acceptor_gain	0.9900
6:10724960:G:C	acceptor_gain	0.9900
6:10724960:G:GA	acceptor_loss	0.9900
6:10724960:G:GG	acceptor_gain	0.9900
6:10724960:GAGT:G	acceptor_gain	0.9900
6:10724960:GAGTG:G	acceptor_gain	0.9900
6:10725033:AGCAG:A	donor_loss	0.9900
6:10725035:CAGG:C	donor_loss	0.9900
6:10725036:AG:A	donor_loss	0.9900
6:10725037:GGTAG:G	donor_loss	0.9900
6:10725038:GT:G	donor_loss	0.9900
6:10725039:T:G	donor_loss	0.9900
6:10723023:G:GT	donor_gain	0.9800
6:10723256:G:T	donor_gain	0.9800
6:10728709:GTT:G	donor_gain	0.9800
6:10728710:TTT:T	donor_gain	0.9800

AlphaMissense

717 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:10725925:C:A	A39D	0.996
6:10725943:G:A	G45D	0.996
6:10728669:G:A	G77R	0.996
6:10728669:G:C	G77R	0.996
6:10725931:G:A	G41E	0.995
6:10725945:A:C	S46R	0.995
6:10725947:T:A	S46R	0.995
6:10725947:T:G	S46R	0.995
6:10728668:G:A	M76I	0.995
6:10728668:G:C	M76I	0.995
6:10728668:G:T	M76I	0.995
6:10728676:G:T	R79M	0.995
6:10725930:G:A	G41R	0.994
6:10725930:G:C	G41R	0.994
6:10725930:G:T	G41W	0.994
6:10728670:G:A	G77E	0.994
6:10728709:G:A	G90D	0.994
6:10725002:T:A	V21D	0.993
6:10725011:G:A	G24D	0.993
6:10725023:G:A	G28D	0.993
6:10725928:C:A	A40E	0.993
6:10725942:G:C	G45R	0.993
6:10728703:C:A	P88H	0.993
6:10728677:G:C	R79S	0.992
6:10728677:G:T	R79S	0.992
6:10728720:G:C	G94R	0.992
6:10724993:C:A	A18E	0.991
6:10725005:C:A	A22D	0.991
6:10725013:G:A	G25R	0.991
6:10725013:G:C	G25R	0.991

dbSNP variants (sampled 300 via entrez): RS1000075062 (6:10730890 G>A,C), RS1000462406 (6:10722636 C>A,T), RS1000743943 (6:10723195 C>G,T), RS1000760717 (6:10721305 C>A,T), RS1000811826 (6:10722412 CAG>C), RS1001112884 (6:10730518 C>A,G,T), RS1001299785 (6:10722874 T>G), RS1001335202 (6:10724906 T>C), RS1001471800 (6:10727330 C>T), RS1001644829 (6:10722691 G>A), RS1001652651 (6:10721143 A>G), RS1002155850 (6:10724836 C>A,G,T), RS1002271909 (6:10729757 G>A), RS1002605615 (6:10728426 G>A), RS1003124948 (6:10724564 C>A,G,T)

Disease associations

OMIM: gene MIM:615318 | 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
GCST004862_63	Itch intensity from mosquito bite adjusted by bite size	3.000000e-07
GCST009172_2	Response to (pegylated) interferon in HBeAg-negative hepatitis B	3.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0007859	response to interferon

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067360 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.95	Kd	112.7	nM	CHEMBL5653589
6.95	ED50	112.7	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149608: Binding affinity to human TMEM14C incubated for 45 mins by Kinobead based pull down assay	kd	0.1127	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression, decreases expression, affects cotreatment	2
Air Pollutants	decreases expression, increases abundance	2
ginger extract	affects cotreatment, affects expression, increases abundance	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, affects expression, increases abundance	1
arsenite	affects binding, increases reaction	1
perfluorooctanoic acid	increases expression	1
CD 437	decreases expression	1
chloropicrin	affects expression	1
perfluoro-n-nonanoic acid	increases expression	1
3-(4’-hydroxy-3’-adamantylbiphenyl-4-yl)acrylic acid	decreases expression	1
ICG 001	increases expression	1
gardiquimod	decreases expression, decreases reaction	1
picoxystrobin	increases expression	1
Arsenic	increases abundance, increases expression, decreases expression, affects cotreatment	1
Benzo(a)pyrene	increases methylation	1
Cadmium	increases abundance, increases expression	1
Cisplatin	increases expression	1
Doxorubicin	increases expression	1
Estradiol	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Oils, Volatile	affects cotreatment, affects expression, increases abundance	1
Rotenone	increases expression	1
Smoke	decreases expression, increases abundance	1
Valproic Acid	affects expression	1
Sodium Selenite	increases expression	1
Cadmium Chloride	increases expression, increases abundance	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652650	Binding	Binding affinity to human TMEM14C incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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