ATP11C

Summary

ATP11C (ATPase phospholipid transporting 11C (ATP11C blood group), HGNC:13554) is a protein-coding gene on chromosome Xq27.1, encoding Phospholipid-transporting ATPase IG (Q8NB49). Catalytic component of a P4-ATPase flippase complex which catalyzes the hydrolysis of ATP coupled to the transport of aminophospholipids, phosphatidylserines (PS) and phosphatidylethanolamines (PE), from the outer to the inner leaflet of the plasma membrane.

Enables phosphatidylethanolamine flippase activity and phosphatidylserine flippase activity. Involved in phospholipid translocation. Located in endoplasmic reticulum and plasma membrane. Part of phospholipid-translocating ATPase complex. Implicated in X-linked congenital hemolytic anemia.

Source: NCBI Gene 286410 — RefSeq curated summary.

At a glance

• Gene–disease (curated): X-linked congenital hemolytic anemia (Limited, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 388 total — 6 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 5
• MANE Select transcript: NM_001353812

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13554
Approved symbol	ATP11C
Name	ATPase phospholipid transporting 11C (ATP11C blood group)
Location	Xq27.1
Locus type	gene with protein product
Status	Approved
Aliases	ATPIG, ATPIQ
Ensembl gene	ENSG00000101974
Ensembl biotype	protein_coding
OMIM	300516
Entrez	286410

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 7 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000327569, ENST00000361648, ENST00000370557, ENST00000422228, ENST00000433868, ENST00000450801, ENST00000460773, ENST00000485626, ENST00000682941

RefSeq mRNA: 5 — MANE Select: NM_001353812 NM_001010986, NM_001353810, NM_001353811, NM_001353812, NM_173694

CCDS: CCDS14668, CCDS35410, CCDS94677

Canonical transcript exons

ENST00000682941 — 30 exons

Exon	Start	End
ENSE00000874436	139797176	139797326
ENSE00000979454	139802236	139802339
ENSE00001300491	139798679	139798743
ENSE00001378936	139800060	139800110
ENSE00001680568	139798273	139798354
ENSE00003493542	139750025	139750152
ENSE00003500784	139737916	139738069
ENSE00003511467	139743559	139743624
ENSE00003516279	139789327	139789488
ENSE00003527861	139816863	139816943
ENSE00003533895	139819338	139819427
ENSE00003549258	139785226	139785299
ENSE00003562166	139731651	139731755
ENSE00003568165	139788192	139788343
ENSE00003577502	139745722	139745857
ENSE00003577734	139796273	139796470
ENSE00003581631	139804471	139804599
ENSE00003594212	139761961	139762106
ENSE00003601114	139814878	139814985
ENSE00003636235	139783164	139783267
ENSE00003637323	139787173	139787244
ENSE00003645449	139782547	139782728
ENSE00003646996	139740991	139741094
ENSE00003648631	139826704	139826823
ENSE00003675172	139774690	139774953
ENSE00003678009	139763316	139763418
ENSE00003683599	139768260	139768434
ENSE00003688836	139757808	139757867
ENSE00003917264	139932016	139933053
ENSE00003922290	139726348	139728962

Expression profiles

Bgee: expression breadth ubiquitous, 250 present calls, max score 93.84.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.5738 / max 126.1870, expressed in 1711 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
200722	8.0438	1699
200721	0.4099	199
200716	0.0814	30
200717	0.0388	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
seminal vesicle	UBERON:0000998	93.84	gold quality
calcaneal tendon	UBERON:0003701	92.85	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	92.66	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.21	gold quality
cauda epididymis	UBERON:0004360	90.97	gold quality
liver	UBERON:0002107	90.74	gold quality
parietal pleura	UBERON:0002400	90.49	gold quality
superficial temporal artery	UBERON:0001614	89.99	gold quality
visceral pleura	UBERON:0002401	89.55	gold quality
right lobe of liver	UBERON:0001114	89.45	gold quality
germinal epithelium of ovary	UBERON:0001304	88.16	gold quality
lymph node	UBERON:0000029	87.06	gold quality
epithelial cell of pancreas	CL:0000083	86.64	gold quality
stromal cell of endometrium	CL:0002255	86.51	gold quality
urinary bladder	UBERON:0001255	86.26	gold quality
saphenous vein	UBERON:0007318	86.23	gold quality
subcutaneous adipose tissue	UBERON:0002190	86.21	gold quality
ovary	UBERON:0000992	86.15	gold quality
left coronary artery	UBERON:0001626	86.14	gold quality
body of uterus	UBERON:0009853	86.07	gold quality
layer of synovial tissue	UBERON:0007616	85.96	gold quality
adipose tissue	UBERON:0001013	85.90	gold quality
coronary artery	UBERON:0001621	85.76	gold quality
myometrium	UBERON:0001296	85.74	gold quality
tibial artery	UBERON:0007610	85.64	gold quality
popliteal artery	UBERON:0002250	85.63	gold quality
ileal mucosa	UBERON:0000331	85.62	gold quality
right ovary	UBERON:0002118	85.55	gold quality
tendon	UBERON:0000043	85.42	gold quality
aorta	UBERON:0000947	85.33	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-119	yes	12.21
E-ANND-3	yes	9.86

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, ARID3A, CEBPB, CUX1, DNMT1, ETS1, GLI3, LEF1, MYC, MYCN, PAX5, PITX2, POU2F1, POU2F2, PREB, REL, RELA, RELB, SATB1, SPI1, STAT6, TCF3, TFE3, TXK

miRNA regulators (miRDB)

252 targeting ATP11C, 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-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-3148	99.97	75.06	6478

Literature-anchored findings (GeneRIF, showing 14)

• ATP11C and CDC50A are required for aminophospholipid translocation from the outer to the inner plasma membrane leaflet; that is, they display flippase activity. (PMID:24904167)
• Atp11c mediates the transport of bile acids and organic anions across the sinusoidal membrane by regulating organic anion transporting polypeptides. (PMID:26399598)
• our analyses of a patient with mild hemolytic anemia identified ATP11C as a major flippase in human erythrocytes and showed that genetic mutation of ATP11C causes congenital mild hemolytic anemia inherited as an X-linked recessive trait. (PMID:26944472)
• A characteristic di-leucine motif (SVRPLL) in the C-terminal cytoplasmic region of ATP11C becomes functional upon PKCalpha activation. Moreover, endocytosis of ATP11C is induced by Ca(2+)-signaling via Gq-coupled receptors. (PMID:29123098)
• results indicated that the extracellular domain of CDC50A has important roles both in CDC50A’s ability to chaperone ATP11C to the plasma membrane and in inducing ATP11C’s ATP hydrolysis-coupled flippase activity. (PMID:29276178)
• Data show that P4-ATPase flippase complex alpha subunit ATP11C (ATP11C) was absent in the patient’s erythrocyte membranes. (PMID:31253392)
• The cytoplasmic C-terminal region of the ATP11C variant determines its localization at the polarized plasma membrane. (PMID:31371488)
• Crystal structure of a human plasma membrane phospholipid flippase. (PMID:32493773)
• Transport Cycle of Plasma Membrane Flippase ATP11C by Cryo-EM. (PMID:32997992)
• Reduction in flippase activity contributes to surface presentation of phosphatidylserine in human senescent erythrocytes. (PMID:33103382)
• The ratio of ATP11C/PLSCR1 mRNA transcripts has clinical significance in sickle cell anemia. (PMID:34651249)
• Two types of type IV P-type ATPases independently re-establish the asymmetrical distribution of phosphatidylserine in plasma membranes. (PMID:36162506)
• ATP11C promotes the differentiation of pre-B cells into immature B cells but does not affect their IL-7-dependent proliferation. (PMID:36753036)
• A novel missense variant in ATP11C is associated with reduced red blood cell phosphatidylserine flippase activity and mild hereditary hemolytic anemia. (PMID:37671681)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	atp11c	ENSDARG00000036442
mus_musculus	Atp11c	ENSMUSG00000062949
rattus_norvegicus	Atp11c	ENSRNOG00000003472
drosophila_melanogaster	CG9981	FBGN0030746
drosophila_melanogaster	CG4301	FBGN0030747
drosophila_melanogaster	CG31729	FBGN0051729
caenorhabditis_elegans	tat-5	WBGENE00009498
caenorhabditis_elegans		WBGENE00017174

Paralogs (13): ATP9A (ENSG00000054793), ATP11B (ENSG00000058063), ATP11A (ENSG00000068650), ATP8B1 (ENSG00000081923), ATP8B4 (ENSG00000104043), ATP10B (ENSG00000118322), ATP8A1 (ENSG00000124406), ATP8B3 (ENSG00000130270), ATP8A2 (ENSG00000132932), ATP8B2 (ENSG00000143515), ATP10D (ENSG00000145246), ATP9B (ENSG00000166377), ATP10A (ENSG00000206190)

Protein

Protein identifiers

Phospholipid-transporting ATPase IG — Q8NB49 (reviewed: Q8NB49)

Alternative names: ATPase IQ, ATPase class VI type 11C, P4-ATPase flippase complex alpha subunit ATP11C

All UniProt accessions (6): Q8NB49, A0A067XG54, A0A067XG57, A0A804HIW2, H7C0E8, H7C113

UniProt curated annotations — full annotation on UniProt →

Function. Catalytic component of a P4-ATPase flippase complex which catalyzes the hydrolysis of ATP coupled to the transport of aminophospholipids, phosphatidylserines (PS) and phosphatidylethanolamines (PE), from the outer to the inner leaflet of the plasma membrane. Major PS-flippase in immune cell subsets. In erythrocyte plasma membrane, it is required to maintain PS in the inner leaflet preventing its exposure on the surface. This asymmetric distribution is critical for the survival of erythrocytes in circulation since externalized PS is a phagocytic signal for erythrocyte clearance by splenic macrophages. Required for B cell differentiation past the pro-B cell stage. Seems to mediate PS flipping in pro-B cells. May be involved in the transport of cholestatic bile acids.

Subunit / interactions. Component of a P4-ATPase flippase complex which consists of a catalytic alpha subunit ATP11C and an accessory beta subunit TMEM30A.

Subcellular location. Cell membrane. Endoplasmic reticulum membrane. Early endosome membrane. Recycling endosome membrane.

Tissue specificity. Widely expressed.

Post-translational modifications. Proteolytically cleaved by CASP3, CASP6 and CASP7. Phosphorylated at Ser-1116 likely by PRKCA; this creates a functional di-leucine motif that is sufficient for endocytosis.

Disease relevance. Hemolytic anemia, congenital, X-linked (HACXL) [MIM:301015] An X-linked hematologic disease characterized by shortened survival of erythrocytes due to congenital hemolysis that cannot be compensated by bone marrow activity. Clinical features are mild jaundice and anemia. Red cells morphology is normal. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. The flippase activity is inactivated by caspase-mediated cleavage in apoptotic cells, allowing for PS exposure on the cell surface and engulfment of apoptotic cells by macrophages. The ATPase activity is up-regulated by aminophospholipids PS and PE and down-regulated by Increasing intracellular Ca2+ levels.

Domain organisation. The di-leucine motif is required for sorting to clathrin-coated endosomes upon ca(2+)-dependent PRKCA activation.

Similarity. Belongs to the cation transport ATPase (P-type) (TC 3.A.3) family. Type IV subfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
Q8NB49-1	1	yes
Q8NB49-2	2
Q8NB49-3	3
Q8NB49-4	4

RefSeq proteins (5): NP_001010986, NP_001340739, NP_001340740, NP_001340741, NP_775965 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001757	P_typ_ATPase	Family
IPR006539	P-type_ATPase_IV	Family
IPR008250	ATPase_P-typ_transduc_dom_A_sf	Homologous_superfamily
IPR018303	ATPase_P-typ_P_site	PTM
IPR023214	HAD_sf	Homologous_superfamily
IPR023298	ATPase_P-typ_TM_dom_sf	Homologous_superfamily
IPR023299	ATPase_P-typ_cyto_dom_N	Homologous_superfamily
IPR032630	P_typ_ATPase_c	Domain
IPR032631	P-type_ATPase_N	Domain
IPR036412	HAD-like_sf	Homologous_superfamily
IPR044492	P_typ_ATPase_HD_dom	Domain
IPR059000	ATPase_P-type_domA	Domain

Pfam: PF00122, PF13246, PF16209, PF16212

Enzyme classification (BRENDA):

• EC 7.6.2.1 — P-type phospholipid transporter (BRENDA: 22 organisms, 260 substrates, 62 inhibitors, 53 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.016–2.215	41
P-NITROPHENYL PHOSPHATE	1.17–1.46	3
ACETYL PHOSPHATE	1.03–1.31	2
1-PALMITOYL-2-OLEOYL-SN-GLYCERO-3-PHOSPHO-L-SERI	0.111	1

Catalyzed reactions (Rhea), 2 shown:

• a 1,2-diacyl-sn-glycero-3-phospho-L-serine(out) + ATP + H2O = a 1,2-diacyl-sn-glycero-3-phospho-L-serine(in) + ADP + phosphate + H(+) (RHEA:38567)
• a 1,2-diacyl-sn-glycero-3-phosphoethanolamine(out) + ATP + H2O = a 1,2-diacyl-sn-glycero-3-phosphoethanolamine(in) + ADP + phosphate + H(+) (RHEA:66132)

UniProt features (190 total): strand 46, helix 43, mutagenesis site 26, binding site 18, turn 15, topological domain 11, transmembrane region 10, sequence variant 6, modified residue 4, site 3, splice variant 3, sequence conflict 2, chain 1, short sequence motif 1, active site 1

Structure

Experimental structures (PDB)

13 structures.

PDB	Method	Resolution (Å)
9VKG	ELECTRON MICROSCOPY	2.39
9VNT	ELECTRON MICROSCOPY	2.51
9VSL	ELECTRON MICROSCOPY	2.88
7BSV	ELECTRON MICROSCOPY	3
7BSQ	ELECTRON MICROSCOPY	3.2
7BSU	ELECTRON MICROSCOPY	3.2
7BSS	ELECTRON MICROSCOPY	3.3
7VSH	ELECTRON MICROSCOPY	3.4
9VQ2	ELECTRON MICROSCOPY	3.4
6LKN	X-RAY DIFFRACTION	3.9
7BSW	ELECTRON MICROSCOPY	3.9
7VSG	ELECTRON MICROSCOPY	3.9
7BSP	ELECTRON MICROSCOPY	4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NB49-F1	83.31	0.42

Functional residue map

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

Catalytic / active sites (4): 412 (4-aspartylphosphate intermediate); 442–443 (cleavage; by casp3, casp6 and casp7); 448–449 (cleavage; by casp3); 484–485 (cleavage; by casp3 and casp7)

Ligand- & substrate-binding residues (18): 412; 412; 413; 414; 414; 501; 543; 566; 597; 677; 678; 679 …

Post-translational modifications (4): 445, 1108, 1116, 1126

Mutagenesis-validated functional residues (26):

Position	Phenotype
66	decreases atpase activity.
69	decreases atpase activity.
72	decreases atpase activity.
75	impairs atpase flippase activity.
93	decreases atpase activity.
101	impairs atpase flippase activity.
184	has no effect on endoplasmic reticulum to plasma membrane trafficking. impairs atpase flippase activity.
352	impairs atpase flippase activity.
353	decreases atpase activity.
355	impairs atpase flippase activity.
356	has no effect on atpase flippase activity.
360	decreases atpase flippase activity.
360	has minor effect on atpase flippase activity.
412	impairs endoplasmic reticulum to plasma membrane trafficking.
442	impairs caspase-mediated cleavage; when associated with a-448 and a-484.
448	impairs caspase-mediated cleavage; when associated with a-442 and a-484.
484	impairs caspase-mediated cleavage; when associated with a-442 and a-448.
883	decreases atpase flippase activity.
884	decreases atpase flippase activity.
915	decreases atpase flippase activity.
1116	impairs sorting to endosomal compartments in response to ca(2+) signaling.
1116	localizes to endosomal compartments in the absence of ca(2+) signaling.
1120	impairs sorting to endosomal compartments in response to ca(2+) signaling.
1121	impairs sorting to endosomal compartments in response to ca(2+) signaling.
1122	has no effect on sorting to endosomal compartments in response to ca(2+) signaling.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-936837	Ion transport by P-type ATPases
R-HSA-382551	Transport of small molecules
R-HSA-983712	Ion channel transport

MSigDB gene sets: 269 (showing top): WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, HORIUCHI_WTAP_TARGETS_DN, GOCC_VACUOLAR_MEMBRANE, NKX25_02, ATGCAGT_MIR217, CACCAGC_MIR138, GOBP_REGULATION_OF_MEMBRANE_LIPID_DISTRIBUTION, GOBP_ORGANOPHOSPHATE_ESTER_TRANSPORT, WEI_MYCN_TARGETS_WITH_E_BOX, WANG_LMO4_TARGETS_DN, ATTACAT_MIR3803P, TGANTCA_AP1_C, DODD_NASOPHARYNGEAL_CARCINOMA_UP, AACTTT_UNKNOWN, GOBP_PHOSPHOLIPID_TRANSPORT

GO Biological Process (8): monoatomic ion transmembrane transport (GO:0034220), phospholipid translocation (GO:0045332), pre-B cell differentiation (GO:0002329), lipid transport (GO:0006869), phospholipid transport (GO:0015914), lipid translocation (GO:0034204), positive regulation of B cell differentiation (GO:0045579), aminophospholipid translocation (GO:0140331)

GO Molecular Function (11): magnesium ion binding (GO:0000287), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), phosphatidylethanolamine flippase activity (GO:0090555), phosphatidylserine floppase activity (GO:0090556), ATPase-coupled intramembrane lipid carrier activity (GO:0140326), phosphatidylserine flippase activity (GO:0140346), nucleotide binding (GO:0000166), transporter activity (GO:0005215), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (12): lysosomal membrane (GO:0005765), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), early endosome membrane (GO:0031901), recycling endosome (GO:0055037), recycling endosome membrane (GO:0055038), phospholipid-translocating ATPase complex (GO:1990531), endosome (GO:0005768), early endosome (GO:0005769), endomembrane system (GO:0012505), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Ion channel transport	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
lipid transport	2
ATP-dependent activity	2
glycerophospholipid flippase activity	2
endomembrane system	2
endosome membrane	2
endosome	2
cellular anatomical structure	2
monoatomic ion transport	1
transmembrane transport	1
phospholipid transport	1
lipid translocation	1
immature B cell differentiation	1
transport	1
lipid localization	1
organophosphate ester transport	1
regulation of membrane lipid distribution	1
B cell differentiation	1
regulation of B cell differentiation	1
positive regulation of lymphocyte differentiation	1
positive regulation of B cell activation	1
aminophospholipid transport	1
phospholipid translocation	1
metal ion binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
floppase activity	1
intramembrane lipid carrier activity	1
aminophospholipid flippase activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
molecular_function	1
binding	1
cation binding	1
lysosome	1
lytic vacuole membrane	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1

Protein interactions and networks

STRING

1480 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATP11C	CDC50A	Q9NV96	947
ATP11C	SNTG2	Q9NY99	873
ATP11C	XKR8	Q9H6D3	831
ATP11C	SOX3	P35714	793
ATP11C	F9	P00740	667
ATP11C	XKR9	Q5GH70	644
ATP11C	ANO6	Q4KMQ2	605
ATP11C	CDC50B	Q3MIR4	604
ATP11C	XKR4	Q5GH76	532
ATP11C	ATOSB	Q7L5A3	527
ATP11C	ADGRB1	O14514	443
ATP11C	QDPR	P09417	426
ATP11C	NEO1	Q92859	425
ATP11C	ITIH3	Q06033	414
ATP11C	RXRB	P28702	406
ATP11C	CARHSP1	Q9Y2V2	406

IntAct

95 interactions, top by confidence:

A	B	Type	Score
TMEM30A	ATP11C	psi-mi:“MI:0915”(physical association)	0.690
ATP11C	TMEM30A	psi-mi:“MI:0915”(physical association)	0.690
SLC12A2	CLGN	psi-mi:“MI:0914”(association)	0.640
SLC17A5	LGALS8	psi-mi:“MI:0914”(association)	0.640
GPR21	TMEM120B	psi-mi:“MI:0914”(association)	0.530
TMEM63A	AP3B1	psi-mi:“MI:0914”(association)	0.530
GCNT3	BCKDK	psi-mi:“MI:0914”(association)	0.530
TMEM185A	TSPAN6	psi-mi:“MI:0914”(association)	0.530
ATP6V0A2	B4GALT3	psi-mi:“MI:0914”(association)	0.530
P2RY1	SLC19A2	psi-mi:“MI:0914”(association)	0.530
PTGIR	TMEM63A	psi-mi:“MI:0914”(association)	0.530
SEMA7A	SGPL1	psi-mi:“MI:0914”(association)	0.530
STS	GJA1	psi-mi:“MI:0914”(association)	0.530
NRN1	SLC1A1	psi-mi:“MI:0914”(association)	0.530
SLC2A1	ATP11C	psi-mi:“MI:0914”(association)	0.530
SIDT2	AP3D1	psi-mi:“MI:0914”(association)	0.530
ANKH	FAM234B	psi-mi:“MI:0914”(association)	0.530
ATP11C	SFPQ	psi-mi:“MI:0915”(physical association)	0.400
BFRF1A	SHTN1	psi-mi:“MI:0914”(association)	0.350
K8.1	EXOC5	psi-mi:“MI:0914”(association)	0.350
NS3	C15orf61	psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350
	TMEM223	psi-mi:“MI:0914”(association)	0.350
Npc1	ESYT2	psi-mi:“MI:0914”(association)	0.350
DYRK1A	TEX13D	psi-mi:“MI:0914”(association)	0.350
ARRDC5	PLPP1	psi-mi:“MI:0914”(association)	0.350
CANX	HLA-A	psi-mi:“MI:0914”(association)	0.350
OSBP	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (165): ATP11C (Affinity Capture-MS), ATP11C (Affinity Capture-MS), ATP11C (Affinity Capture-MS), ATP11C (Affinity Capture-MS), ATP11C (Affinity Capture-MS), ATP11C (Affinity Capture-MS), ATP11C (Affinity Capture-MS), ATP11C (Affinity Capture-MS), ATP11C (Affinity Capture-MS), ATP11C (Affinity Capture-MS), ATP11C (Proximity Label-MS), ATP11C (Affinity Capture-MS), ATP11C (Affinity Capture-MS), ATP11C (Affinity Capture-MS), ATP11C (Affinity Capture-MS)

ESM2 similar proteins: A1A4J6, D4ABB8, F1Q4S1, G5EBH1, O14072, O43520, O43861, O70228, O75110, P09626, P19156, P20648, P27112, P40527, P50996, P57792, P90747, P98195, P98196, P98197, P98198, P98199, Q10309, Q27533, Q3TYU2, Q4VNC1, Q4WYP6, Q5XF89, Q5XF90, Q5ZKB7, Q64436, Q6DFW5, Q8NB49, Q92126, Q93084, Q95JN5, Q9EPE9, Q9H7F0, Q9HD20, Q9LI83

Diamond homologs: A1A4J6, A3FIN4, B1AWN4, C7EXK4, D4AA47, D4ABB8, F1Q4S1, G0S196, G2X7W6, G5EBH1, O36028, O43520, O43861, O54827, O60312, O60423, O94296, O94823, P32660, P39524, P40527, P57792, P70704, P98195, P98196, P98197, P98198, P98199, P98200, P98204, P98205, Q09891, Q10309, Q12675, Q148W0, Q29449, Q37145, Q5BL50, Q6DFW5, Q6UQ17

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 138 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
R-HSA-425393	7	10.6×	4e-04
SLC-mediated transmembrane transport	14	9.6×	5e-08
Transport of small molecules	18	5.3×	8e-07

GO biological processes:

GO term	Partners	Fold	FDR
amino acid transport	6	16.0×	3e-04
monoatomic ion transport	11	14.7×	2e-07
transport across blood-brain barrier	9	13.8×	8e-06
transmembrane transport	8	11.5×	1e-04
chloride transmembrane transport	5	10.1×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	1
Uncertain significance	134
Likely benign	15
Benign	6

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
1252084	NM_001353812.2(ATP11C):c.1666+2T>C	Pathogenic
154558	GRCh38/hg38 Xp22.33-q28(chrX:10701-156003229)x3	Pathogenic
187822	GRCh37/hg19 Xq27.1-28(chrX:138125974-147236414)x2	Pathogenic
57992	GRCh38/hg38 Xq27.1(chrX:139333024-140959375)x0	Pathogenic
665638	NC_000023.10:g.(?138612860)(139587225_?)del	Pathogenic
688458	GRCh37/hg19 Xq27.1-28(chrX:138120235-147240344)x2	Pathogenic
560168	NM_001353812.2(ATP11C):c.1244C>A (p.Thr415Asn)	Likely pathogenic

SpliceAI

4269 predictions. Top by Δscore:

Variant	Effect	Δscore
X:139750018:AACTT:A	donor_loss	1.0000
X:139750019:A:C	donor_gain	1.0000
X:139750019:ACTTA:A	donor_loss	1.0000
X:139750020:CTTA:C	donor_loss	1.0000
X:139750021:T:TC	donor_loss	1.0000
X:139750022:T:TG	donor_loss	1.0000
X:139750023:A:AC	donor_gain	1.0000
X:139750024:C:CT	donor_gain	1.0000
X:139750024:C:G	donor_loss	1.0000
X:139750024:CA:C	donor_gain	1.0000
X:139750024:CAT:C	donor_gain	1.0000
X:139750024:CATA:C	donor_gain	1.0000
X:139750024:CATAT:C	donor_gain	1.0000
X:139750149:GTGG:G	acceptor_gain	1.0000
X:139750150:TGG:T	acceptor_gain	1.0000
X:139750151:GG:G	acceptor_gain	1.0000
X:139750152:GC:G	acceptor_loss	1.0000
X:139750153:C:CA	acceptor_loss	1.0000
X:139750153:C:CC	acceptor_gain	1.0000
X:139750154:T:G	acceptor_loss	1.0000
X:139750158:A:AC	acceptor_gain	1.0000
X:139750158:A:C	acceptor_gain	1.0000
X:139757868:C:CC	acceptor_gain	1.0000
X:139774688:A:AC	donor_gain	1.0000
X:139774689:C:CC	donor_gain	1.0000
X:139774954:C:CC	acceptor_gain	1.0000
X:139782545:A:AC	donor_gain	1.0000
X:139782546:C:CC	donor_gain	1.0000
X:139782546:CTTGT:C	donor_gain	1.0000
X:139788187:TTTAC:T	donor_loss	1.0000

AlphaMissense

7428 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:139750117:A:C	N915K	1.000
X:139750117:A:T	N915K	1.000
X:139761961:C:A	K883N	1.000
X:139761961:C:G	K883N	1.000
X:139761995:C:A	R872I	1.000
X:139762013:C:T	G866E	1.000
X:139763350:A:C	D823E	1.000
X:139763350:A:T	D823E	1.000
X:139763351:T:A	D823V	1.000
X:139763351:T:C	D823G	1.000
X:139763351:T:G	D823A	1.000
X:139763352:C:G	D823H	1.000
X:139763353:A:C	N822K	1.000
X:139763353:A:T	N822K	1.000
X:139763360:C:T	G820D	1.000
X:139763361:C:A	G820C	1.000
X:139763361:C:G	G820R	1.000
X:139763363:T:A	D819V	1.000
X:139763366:C:A	G818V	1.000
X:139763366:C:T	G818D	1.000
X:139763367:C:G	G818R	1.000
X:139763372:G:C	S816W	1.000
X:139763375:A:G	L815P	1.000
X:139768266:T:A	K798N	1.000
X:139768266:T:G	K798N	1.000
X:139768267:T:A	K798I	1.000
X:139768268:T:G	K798Q	1.000
X:139768276:G:T	P795Q	1.000
X:139768285:C:G	R792P	1.000
X:139774879:T:A	D679V	1.000

dbSNP variants (sampled 300 via entrez): RS1000008980 (X:139737974 C>CT), RS1000029932 (X:139873087 G>T), RS1000031068 (X:139850042 T>A), RS1000032788 (X:139891232 G>A), RS1000058270 (X:139924787 T>G), RS1000068717 (X:139768331 T>A), RS1000090651 (X:139900166 C>A,G,T), RS1000138930 (X:139770762 C>A,G), RS1000205021 (X:139850415 C>A,T), RS1000223781 (X:139871927 C>T), RS1000236055 (X:139730292 G>T), RS1000263235 (X:139764339 G>A), RS1000263294 (X:139821337 A>C,T), RS1000283379 (X:139917613 A>G), RS1000299810 (X:139902375 T>A,C)

Disease associations

OMIM: gene MIM:300516 | disease phenotypes: MIM:301015, MIM:300807, MIM:306900

GenCC curated gene-disease

Disease	Classification	Inheritance
X-linked congenital hemolytic anemia	Limited	X-linked

Mondo (3): X-linked congenital hemolytic anemia (MONDO:0060455), thrombophilia, X-linked, due to factor 9 defect (MONDO:0010432), hemophilia B (MONDO:0010604)

Orphanet (1): Hemophilia B (Orphanet:98879)

HPO phenotypes

5 total (5 of 5 shown, HPO-id order):

HPO	Term
HP:0000952	Jaundice
HP:0001419	X-linked recessive inheritance
HP:0001878	Hemolytic anemia
HP:0003577	Congenital onset
HP:0040319	Dark urine

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90002404_423	Red cell distribution width	4.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009188	Red cell distribution width

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D002836	Hemophilia B	C15.378.100.100.510; C15.378.100.141.510; C15.378.463.510; C16.320.099.510; C16.320.322.235
C567581	Thrombophilia, X-Linked, Due To Factor Ix Defect (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — P4 P-type ATPases: Phospholipid-transporting ATPases

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
Cadmium Chloride	decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
dicrotophos	decreases expression	1
geldanamycin	increases expression	1
triphenyl phosphate	affects expression	1
arsenite	affects binding, decreases reaction	1
butyraldehyde	decreases expression	1
16 alpha-ethyl-21-hydroxy-19-nor-4-pregnene-3,20-dione	decreases expression	1
manganese chloride	increases abundance, affects cotreatment, decreases expression	1
benzo(e)pyrene	increases methylation	1
coumarin	decreases phosphorylation	1
perfluorooctane sulfonic acid	decreases expression	1
azoxystrobin	decreases expression	1
CGP 52608	affects binding, increases reaction	1
deguelin	decreases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	decreases expression	1
abrine	decreases expression	1
pyrachlostrobin	decreases expression	1
jinfukang	decreases expression	1
picoxystrobin	decreases expression	1
Temozolomide	increases expression	1
Decitabine	affects expression	1
Acetaminophen	decreases expression	1
Amiodarone	increases expression	1
Antimycin A	decreases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cisplatin	affects expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SE08	HAP1 ATP11C (-) 1	Cancer cell line	Male
CVCL_XL69	HAP1 ATP11C (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00139828	PHASE4	COMPLETED	Post Marketing Study in Haemophilia B Patients Using Nonafact® (Human Coagulation Factor IX)
NCT00581126	PHASE4	COMPLETED	Study Evaluating BENEFIX in Previously Treated Patients With Hemophilia B
NCT00749476	PHASE4	COMPLETED	Study Evaluating BeneFIX in Patients With Haemophilia B, Previously Treated With Plasma Derived Factor IX
NCT01128881	PHASE4	COMPLETED	IMMUNINE Pre-Treatment Study
NCT01748201	PHASE4	COMPLETED	Viscosupplementation in Patients With Hemophilic Arthropathy
NCT02336178	PHASE4	COMPLETED	Safety and Efficacy of Benefix in Patients With Hemophilia B in Usual Care Settings in China
NCT03565237	PHASE4	COMPLETED	RIXUBIS PMS India (RIXUBIS PMS)
NCT04286412	PHASE4	COMPLETED	Nonacog Alfa Prophylaxis And Treatment Of Bleeding Episodes In Previously Treated Patients With Hemophilia B
NCT05856266	PHASE4	TERMINATED	An 18-month Low-interventional Study to Assess Joint Health in Haemophilia A and B Patients on Prophylaxis With Efmoroctocog Alfa or Eftrenonacog Alfa
NCT00037557	PHASE3	COMPLETED	Study Evaluating rFIX; BeneFIX in Severe Hemophilia B
NCT00093171	PHASE3	COMPLETED	Study Evaluating rFIX; BeneFIX® in Hemophilia B
NCT00093210	PHASE3	COMPLETED	Study Evaluating of Recombinant Human Factor IX (BeneFIX) and a New Formulation of BeneFIX (rFIX-R) in Moderate to Severe Hemophilia B
NCT00364182	PHASE3	COMPLETED	Study Comparing On-Demand Treatment With Two Prophylaxis Regimens Of BeneFIX In Patients With Severe Hemophilia B
NCT00851721	PHASE3	COMPLETED	Efficacy and Safety Study of Prophylactic Versus On-Demand Treatment With Feiba NF in Subjects With Hemophilia A or B and a High Titer Inhibitor
NCT00866606	PHASE3	COMPLETED	Study Evaluating On-Demand Treatment With BeneFIX In Chinese Subjects
NCT01174446	PHASE3	COMPLETED	Pivotal Study (Pharmacokinetics, Efficacy, Safety) of BAX 326 (rFIX) in Hemophilia B Patients
NCT01271868	PHASE3	TERMINATED	Study of Recombinant Factor IX Product, IB1001, in Previously Treated Pediatric Subjects With Hemophilia B
NCT01286779	PHASE3	COMPLETED	BAX 326 (rFIX) Continuation Study
NCT01335061	PHASE3	COMPLETED	Study To Compare On-Demand Treatment To A Prophylaxis Regimen Of BeneFIX In Subjects With Moderately Severe to Severe Hemophilia B
NCT01440946	PHASE3	COMPLETED	Study of Recombinant Coagulation Factor IX Fc Fusion Protein, BIIB029, in Previously Treated Pediatric Participants With Hemophilia B
NCT01507896	PHASE3	COMPLETED	BAX 326 Surgery Study in Hemophilia B Patients
NCT01662531	PHASE3	COMPLETED	A Safety, Efficacy and Pharmacokinetics Study of a Recombinant Fusion Protein Linking Coagulation Factor IX With Albumin (rIX-FP) in Children With Hemophilia B
NCT01757405	PHASE3	COMPLETED	Recombinant Factor VIIa BI (rFVIIa BI) Treatment of Acute Bleeding Episodes Per an On-demand Regimen
NCT02048111	PHASE3	WITHDRAWN	Study of Recombinant Factor IX Product, IB1001, in Previously Treated Subjects With Hemophilia B
NCT02053792	PHASE3	COMPLETED	A Safety and Efficacy Extension Study of a Recombinant Fusion Protein Linking Coagulation Factor IX With Albumin (rIX-FP) in Patients With Hemophilia B
NCT02234310	PHASE3	COMPLETED	Study to Determine the Safety and Efficacy of rFIXFc in Previously Untreated Males With Severe Hemophilia B
NCT03417102	PHASE3	COMPLETED	A Study of Fitusiran (ALN-AT3SC) in Severe Hemophilia A and B Patients With Inhibitors
NCT03417245	PHASE3	COMPLETED	A Study of Fitusiran (ALN-AT3SC) in Severe Hemophilia A and B Patients Without Inhibitors
NCT03569891	PHASE3	COMPLETED	HOPE-B: Trial of AMT-061 in Severe or Moderately Severe Hemophilia B Patients
NCT03587116	PHASE3	COMPLETED	A Study to Evaluate Prospective Efficacy and Safety Data of Current FIX Prophylaxis Replacement Therapy in Adult Hemophilia B Subjects (FIX:C≤2%) or Current FVIII Prophylaxis Replacement Therapy in Adult Hemophilia A Subjects (FVIII:C≤1%)
NCT03855280	PHASE3	COMPLETED	Evaluation of a Recombinant Factor IX Product, APVO101, in Previously-Treated Pediatric Patients With Hemophilia B
NCT03861273	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Efficacy and Safety of Factor IX Gene Therapy With PF-06838435 in Adult Males With Moderately Severe to Severe Hemophilia B
NCT03938792	PHASE3	COMPLETED	Study of the Efficacy and Safety PF-06741086 in Adult and Teenage Participants With Severe Hemophilia A or Moderately Severe to Severe Hemophilia B
NCT05145127	PHASE3	RECRUITING	Open-Label Extension Study of Marstacimab in Hemophilia Participants With or Without Inhibitors
NCT05487976	PHASE3	UNKNOWN	Clinical Study of Recombinant Human Activated Coagulation Factor VII for Injection in Patients With Hemophilia With Inhibitor
NCT05568719	PHASE3	RECRUITING	Safety and Effectiveness of Giroctocogene Fitelparvovec or Fidanacogene Elaparvovec in Patients With Hemophilia A or B Respectively
NCT05611801	PHASE3	RECRUITING	A Clinical Trial of Study Medicine (Marstacimab) in Pediatric Patients With Hemophilia A or Hemophilia B
NCT06003387	PHASE3	RECRUITING	Efficacy and Safety of CSL222 (Etranacogene Dezaparvovec) Gene Therapy in Adults With Hemophilia B With Pretreatment Adeno-associated Virus Serotype 5 (AAV5) Neutralizing Antibodies (Nabs)
NCT06399289	PHASE3	ACTIVE_NOT_RECRUITING	Recombinant Fusion Protein Linking Coagulation Factor IX With Albumin (rIX-FP) in Chinese Subjects With Hemophilia B Previously Treated With FIX Therapy
NCT06568302	PHASE3	TERMINATED	The Long-term Safety and Efficacy of SerpinPC in Subjects with Hemophilia Who Completed a Sponsored SerpinPC Clinical Trial