XKR9

Summary

XKR9 (XK related 9, HGNC:20937) is a protein-coding gene on chromosome 8q13.3, encoding XK-related protein 9 (Q5GH70). Phospholipid scramblase that promotes phosphatidylserine exposure on apoptotic cell surface.

Predicted to enable phospholipid scramblase activity. Predicted to be involved in phosphatidylserine exposure on apoptotic cell surface. Predicted to be located in plasma membrane. Predicted to be active in membrane.

Source: NCBI Gene 389668 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 68 total
• MANE Select transcript: NM_001011720

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20937
Approved symbol	XKR9
Name	XK related 9
Location	8q13.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000221947
Ensembl biotype	protein_coding
Entrez	389668

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 7 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000408926, ENST00000519350, ENST00000520030, ENST00000520092, ENST00000520273, ENST00000920915, ENST00000920916, ENST00000920917, ENST00000970137

RefSeq mRNA: 4 — MANE Select: NM_001011720 NM_001011720, NM_001287258, NM_001287259, NM_001287260

CCDS: CCDS34905

Canonical transcript exons

ENST00000408926 — 5 exons

Exon	Start	End
ENSE00001566336	70680781	70681330
ENSE00001567963	70733796	70735942
ENSE00001755335	70674818	70674899
ENSE00003547898	70706933	70707153
ENSE00003894525	70669339	70669538

Expression profiles

Bgee: expression breadth ubiquitous, 129 present calls, max score 81.65.

FANTOM5 (CAGE): breadth broad, TPM avg 1.0520 / max 43.0608, expressed in 463 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
89317	1.0520	463

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.65	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	79.59	gold quality
duodenum	UBERON:0002114	75.18	gold quality
right testis	UBERON:0004534	73.39	gold quality
testis	UBERON:0000473	72.71	gold quality
gall bladder	UBERON:0002110	71.91	gold quality
left testis	UBERON:0004533	71.83	gold quality
right lobe of liver	UBERON:0001114	70.98	gold quality
calcaneal tendon	UBERON:0003701	70.60	gold quality
islet of Langerhans	UBERON:0000006	67.95	gold quality
liver	UBERON:0002107	67.55	gold quality
right adrenal gland cortex	UBERON:0035827	67.55	gold quality
right adrenal gland	UBERON:0001233	67.36	gold quality
left adrenal gland	UBERON:0001234	65.42	gold quality
left adrenal gland cortex	UBERON:0035825	65.23	gold quality
adrenal gland	UBERON:0002369	64.31	gold quality
corpus callosum	UBERON:0002336	62.22	gold quality
small intestine	UBERON:0002108	61.90	gold quality
Brodmann (1909) area 9	UBERON:0013540	61.11	gold quality
small intestine Peyer’s patch	UBERON:0003454	61.10	gold quality
mucosa of stomach	UBERON:0001199	59.53	gold quality
lymph node	UBERON:0000029	59.19	gold quality
tonsil	UBERON:0002372	59.05	gold quality
prefrontal cortex	UBERON:0000451	58.87	gold quality
urinary bladder	UBERON:0001255	58.78	gold quality
vermiform appendix	UBERON:0001154	57.95	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	57.94	gold quality
superior frontal gyrus	UBERON:0002661	57.41	gold quality
smooth muscle tissue	UBERON:0001135	57.29	gold quality
mucosa of transverse colon	UBERON:0004991	57.14	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.67

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

104 targeting XKR9, 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-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4447	99.85	67.81	2900

Literature-anchored findings (GeneRIF, showing 2)

• This genome-wide study of never smokers from the general population identified two independent regions related to erythrocyte cadmium. The strongest locus covers the XKR9 and LACTB2 genes, which both could have related functions in cadmium absorption and metabolism (PMID:27005419)
• Cryo-EM structures of the caspase-activated protein XKR9 involved in apoptotic lipid scrambling. (PMID:34263724)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	xkr9	ENSDARG00000026500
mus_musculus	Xkr9	ENSMUSG00000067813
rattus_norvegicus	Xkr9	ENSRNOG00000040289
drosophila_melanogaster	CG18635	FBGN0034279

Paralogs (5): XKR8 (ENSG00000158156), XKR6 (ENSG00000171044), XKR4 (ENSG00000206579), XKR7 (ENSG00000260903), XKR5 (ENSG00000275591)

Protein

Protein identifiers

XK-related protein 9 — Q5GH70 (reviewed: Q5GH70)

All UniProt accessions (3): Q5GH70, E5RFF6, E5RI45

UniProt curated annotations — full annotation on UniProt →

Function. Phospholipid scramblase that promotes phosphatidylserine exposure on apoptotic cell surface. Phosphatidylserine is a specific marker only present at the surface of apoptotic cells and acts as a specific signal for engulfment.

Subcellular location. Cell membrane.

Post-translational modifications. Undergoes proteolytic processing by caspase-3 (CASP3), caspase-6 (CASP6) and caspase-7 (CASP7) to generate the XK-related protein 9, processed form, leading to its activation.

Activity regulation. Activated upon caspase cleavage to generate the XK-related protein 9, processed form. Does not act prior the onset of apoptosis.

Similarity. Belongs to the XK family.

RefSeq proteins (4): NP_001011720, NP_001274187, NP_001274188, NP_001274189 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR018629	XK-rel	Family
IPR050895	XK-related_scramblase	Family

Pfam: PF09815

Catalyzed reactions (Rhea), 1 shown:

• a 1,2-diacyl-sn-glycero-3-phospho-L-serine(in) = a 1,2-diacyl-sn-glycero-3-phospho-L-serine(out) (RHEA:38663)

UniProt features (11 total): transmembrane region 8, chain 2, site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5GH70-F1	84.78	0.54

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 (1): 357–358 (cleavage; by caspase-3, caspase-6 and caspase-7)

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 62 (showing top): GOBP_PLASMA_MEMBRANE_ORGANIZATION, GOBP_REGULATION_OF_MEMBRANE_LIPID_DISTRIBUTION, GOBP_ORGANOPHOSPHATE_ESTER_TRANSPORT, GOBP_ENDOMEMBRANE_SYSTEM_ORGANIZATION, NIKOLSKY_BREAST_CANCER_8Q12_Q22_AMPLICON, GOBP_PHOSPHOLIPID_TRANSPORT, GOBP_MEMBRANE_ORGANIZATION, GOBP_LIPID_LOCALIZATION, GOBP_EXECUTION_PHASE_OF_APOPTOSIS, chr8q13, GOMF_LIPID_TRANSPORTER_ACTIVITY, GOMF_PHOSPHOLIPID_TRANSPORTER_ACTIVITY, GOMF_TRANSPORTER_ACTIVITY, GOBP_PLASMA_MEMBRANE_PHOSPHOLIPID_SCRAMBLING, GOBP_PHOSPHATIDYLSERINE_EXPOSURE_ON_APOPTOTIC_CELL_SURFACE

GO Biological Process (1): apoptotic process (GO:0006915)

GO Molecular Function (0):

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

294 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
XKR9	ATP11C	Q8NB49	644
XKR9	LACTB2	Q53H82	621
XKR9	ARMH1	Q6PIY5	481
XKR9	ANO6	Q4KMQ2	461
XKR9	XK	P51811	450
XKR9	OR1L4	Q8NGR5	446
XKR9	ATP11A	P98196	443
XKR9	XKRX	Q6PP77	436
XKR9	WDR83OS	Q9Y284	432
XKR9	KLHL38	Q2WGJ6	428
XKR9	ZNF696	Q9H7X3	420
XKR9	KEL	P23276	403
XKR9	TMEM68	Q96MH6	384
XKR9	FAM110B	Q8TC76	383
XKR9	IZUMO3	Q5VZ72	378

IntAct

0 interactions, top by confidence:

ESM2 similar proteins: A0MFS9, A8Y2U2, F1QXD3, F1RAX4, F4HVJ3, G5EBX4, G5ECD6, O17386, O18304, O22757, O45363, O45813, O57474, O59802, O62136, P14154, P16863, P34319, P42836, P48236, P51914, P51916, Q01608, Q06551, Q0JJZ6, Q0V990, Q18593, Q18600, Q21973, Q49LR9, Q4R690, Q54IK2, Q5GH62, Q5GH70, Q5GH77, Q5NVB9, Q6S5G4, Q6TYA9, Q8IUH4, Q8K424

Diamond homologs: Q49LR9, Q49LS0, Q49LS3, Q49LS6, Q5GH62, Q5GH70, Q9H6D3, Q49LS7, Q49LS8, Q4VV71, Q5GH59, Q5GH64, Q8C0T0, E9Q6C8, Q5GH57, Q5GH73, Q6UX68, Q49LS1, Q49LS4, Q49LS9, Q5GH56, Q5GH67, Q5GH72, Q5GH76, Q9QXY7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	53
Likely benign	5
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1059 predictions. Top by Δscore:

Variant	Effect	Δscore
8:70674900:G:GG	donor_gain	1.0000
8:70707148:G:GG	donor_gain	1.0000
8:70707152:GT:G	donor_gain	1.0000
8:70707154:G:GG	donor_gain	1.0000
8:70669513:G:GT	donor_gain	0.9900
8:70674816:A:AG	acceptor_gain	0.9900
8:70674817:G:GA	acceptor_gain	0.9900
8:70674817:GT:G	acceptor_gain	0.9900
8:70706931:A:AG	acceptor_gain	0.9900
8:70706932:G:GG	acceptor_gain	0.9900
8:70706932:GGT:G	acceptor_gain	0.9900
8:70707149:TCAGT:T	donor_gain	0.9900
8:70733790:TTGTA:T	acceptor_loss	0.9900
8:70733791:TGTAG:T	acceptor_loss	0.9900
8:70733792:GTA:G	acceptor_loss	0.9900
8:70733793:TAGAT:T	acceptor_loss	0.9900
8:70733794:A:AG	acceptor_gain	0.9900
8:70733795:G:A	acceptor_loss	0.9900
8:70733795:G:GG	acceptor_gain	0.9900
8:70733795:GAT:G	acceptor_gain	0.9900
8:70674817:GTGAA:G	acceptor_gain	0.9800
8:70674895:GACAA:G	donor_gain	0.9800
8:70706932:GGTAT:G	acceptor_gain	0.9800
8:70707150:CAGT:C	donor_gain	0.9800
8:70707151:AGT:A	donor_gain	0.9800
8:70707151:AGTGT:A	donor_loss	0.9800
8:70707152:GTG:G	donor_gain	0.9800
8:70707152:GTGTA:G	donor_loss	0.9800
8:70707153:TGT:T	donor_gain	0.9800
8:70707155:TAAG:T	donor_loss	0.9800

AlphaMissense

2477 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:70681233:A:C	S59R	0.990
8:70681235:T:A	S59R	0.990
8:70681235:T:G	S59R	0.990
8:70733957:A:C	S219R	0.982
8:70733959:T:A	S219R	0.982
8:70733959:T:G	S219R	0.982
8:70734125:T:C	F275L	0.974
8:70734127:T:A	F275L	0.974
8:70734127:T:G	F275L	0.974
8:70681242:T:A	W62R	0.968
8:70681242:T:C	W62R	0.968
8:70734296:G:A	G332R	0.965
8:70734296:G:C	G332R	0.965
8:70706933:G:C	R91S	0.964
8:70706933:G:T	R91S	0.964
8:70734105:G:A	G268E	0.964
8:70734104:G:A	G268R	0.963
8:70734104:G:C	G268R	0.963
8:70734017:T:A	W239R	0.961
8:70734017:T:C	W239R	0.961
8:70681330:G:T	R91M	0.959
8:70707090:T:C	C144R	0.954
8:70681330:G:C	R91T	0.953
8:70733863:A:C	R187S	0.953
8:70733863:A:T	R187S	0.953
8:70707061:T:A	L134H	0.951
8:70734059:T:C	F253L	0.950
8:70734061:T:A	F253L	0.950
8:70734061:T:G	F253L	0.950
8:70707100:T:C	L147P	0.949

dbSNP variants (sampled 300 via entrez): RS1000007744 (8:70867772 C>G,T), RS1000012063 (8:70801501 A>G), RS1000015678 (8:70853926 A>C,G), RS1000029149 (8:70818635 A>G), RS1000029795 (8:70759638 A>G), RS1000031356 (8:71005815 GTAAGGGTATTTCCT>G), RS1000034612 (8:70841381 T>G), RS1000038412 (8:70915420 A>G), RS1000054239 (8:70706847 T>G), RS1000064134 (8:70720076 T>C), RS1000065057 (8:70697774 T>C), RS1000081890 (8:70779928 A>G), RS1000082157 (8:70712617 GT>G), RS1000090064 (8:70929458 A>C), RS1000092526 (8:70972019 TA>T)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST003448_1	Erythrocyte cadmium concentration in never smokers	3.000000e-11
GCST003989_7	Chin dimples	8.000000e-34
GCST006288_123	Heel bone mineral density	3.000000e-09
GCST006288_659	Heel bone mineral density	6.000000e-17
GCST006288_736	Heel bone mineral density	8.000000e-09
GCST007691_31	Femoral neck bone mineral density	2.000000e-07
GCST90014033_87	Haemorrhoidal disease	5.000000e-39
GCST90020024_163	A body shape index	1.000000e-10
GCST90020024_164	A body shape index	2.000000e-08
GCST90020029_173	Waist circumference adjusted for body mass index	3.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density
EFO:0007785	femoral neck bone mineral density
EFO:0007789	BMI-adjusted waist circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

11 total (human), top 11 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, decreases expression	2
butyraldehyde	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
jinfukang	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Cadmium	decreases expression	1
Lipopolysaccharides	affects response to substance, increases expression	1
Aflatoxin B1	decreases methylation	1
Aflatoxin M1	decreases expression	1

Clinical trials (associated diseases)

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