XKR4

Summary

XKR4 (XK related 4, HGNC:29394) is a protein-coding gene on chromosome 8q12.1, encoding XK-related protein 4 (Q5GH76). Phospholipid scramblase that promotes phosphatidylserine exposure on apoptotic cell surface.

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

Source: NCBI Gene 114786 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 79 total — 1 pathogenic
• MANE Select transcript: NM_052898

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29394
Approved symbol	XKR4
Name	XK related 4
Location	8q12.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1889
Ensembl gene	ENSG00000206579
Ensembl biotype	protein_coding
Entrez	114786

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000327381, ENST00000518261

RefSeq mRNA: 1 — MANE Select: NM_052898 NM_052898

CCDS: CCDS34893

Canonical transcript exons

ENST00000327381 — 3 exons

Exon	Start	End
ENSE00001307012	55357678	55357877
ENSE00001329870	55102028	55103294
ENSE00003623005	55523281	55542054

Expression profiles

Bgee: expression breadth ubiquitous, 166 present calls, max score 94.39.

FANTOM5 (CAGE): breadth broad, TPM avg 1.1634 / max 66.0814, expressed in 267 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
88889	0.8137	231
88888	0.2625	127
88890	0.0871	46

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	94.39	gold quality
middle temporal gyrus	UBERON:0002771	93.13	gold quality
Brodmann (1909) area 46	UBERON:0006483	91.81	gold quality
entorhinal cortex	UBERON:0002728	91.76	gold quality
Brodmann (1909) area 23	UBERON:0013554	90.43	gold quality
dorsal root ganglion	UBERON:0000044	87.40	gold quality
parietal lobe	UBERON:0001872	85.65	gold quality
sural nerve	UBERON:0015488	85.62	gold quality
postcentral gyrus	UBERON:0002581	85.37	gold quality
superior frontal gyrus	UBERON:0002661	84.87	gold quality
trigeminal ganglion	UBERON:0001675	83.08	gold quality
cerebellar vermis	UBERON:0004720	79.43	gold quality
cortical plate	UBERON:0005343	79.29	gold quality
occipital lobe	UBERON:0002021	79.10	gold quality
endothelial cell	CL:0000115	78.64	gold quality
dorsal plus ventral thalamus	UBERON:0001897	78.26	gold quality
primary visual cortex	UBERON:0002436	76.87	gold quality
lateral globus pallidus	UBERON:0002476	75.82	gold quality
colonic epithelium	UBERON:0000397	74.67	gold quality
temporal lobe	UBERON:0001871	74.33	gold quality
nipple	UBERON:0002030	74.08	gold quality
substantia nigra pars compacta	UBERON:0001965	72.45	gold quality
superior vestibular nucleus	UBERON:0007227	72.36	gold quality
cardiac muscle of right atrium	UBERON:0003379	72.23	gold quality
medulla oblongata	UBERON:0001896	72.11	gold quality
ventral tegmental area	UBERON:0002691	72.11	gold quality
left ventricle myocardium	UBERON:0006566	71.11	gold quality
prefrontal cortex	UBERON:0000451	70.88	gold quality
substantia nigra pars reticulata	UBERON:0001966	70.73	gold quality
frontal cortex	UBERON:0001870	70.66	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-MTAB-11268	yes	6810.83
E-HCAD-35	yes	1751.62
E-HCAD-25	yes	47.24
E-MTAB-8410	yes	18.35
E-CURD-46	yes	11.65
E-MTAB-3929	yes	10.99
E-ANND-3	yes	5.81
E-GEOD-83139	no	72.58

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

197 targeting XKR4, 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-6867-5P	100.00	82.21	3464
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
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-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-146A-5P	99.96	68.93	988

Literature-anchored findings (GeneRIF, showing 3)

• Two SNPs located in genes coding for as yet uncharacterized proteins expressed in the cerebellum, XKR4 in 8q12.1, and FAM190A in 4q22.1 suggest association with association with attention deficit hyperactivity disorder. [XkR4] (PMID:20607790)
• Findings suggest that the SNPs in XKR4 and near FOXE1 are involved in the regulation of TSH levels. (PMID:24852370)
• Caspase cleavage releases a nuclear protein fragment that stimulates phospholipid scrambling at the plasma membrane. (PMID:33725486)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	xkr4	ENSDARG00000104264
mus_musculus	Xkr4	ENSMUSG00000051951
rattus_norvegicus	Xkr4	ENSRNOG00000027276

Paralogs (5): XKR8 (ENSG00000158156), XKR6 (ENSG00000171044), XKR9 (ENSG00000221947), XKR7 (ENSG00000260903), XKR5 (ENSG00000275591)

Protein

Protein identifiers

XK-related protein 4 — Q5GH76 (reviewed: Q5GH76)

All UniProt accessions (1): Q5GH76

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.

Subunit / interactions. Homodimer; homodimerization takes place upon caspase cleavage. Interacts with the processed C-terminus of XRCC4 (protein XRCC4, C-terminus); interaction promotes the phospholipid scramblase activity.

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 4, processed form, leading to its activation.

Activity regulation. Phospholipid scramblase activity is activated upon caspase cleavage to generate the XK-related protein 4, processed form. Does not act prior the onset of apoptosis. Homodimerizes upon caspase cleavage. Phospholipid scramblase activity is activated following interaction with the processed C-terminus of XRCC4 (protein XRCC4, C-terminus).

Similarity. Belongs to the XK family.

RefSeq proteins (1): NP_443130* (*=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 (19 total): transmembrane region 10, compositionally biased region 3, chain 2, region of interest 2, site 1, modified residue 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
9BOJ	ELECTRON MICROSCOPY	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5GH76-F1	65.76	0.28

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): 567–568 (cleavage; by caspase-3, caspase-6 and caspase-7)

Post-translational modifications (1): 200

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 118 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, ATACCTC_MIR202, GOBP_PLASMA_MEMBRANE_ORGANIZATION, GOBP_APOPTOTIC_CELL_CLEARANCE, GOBP_VESICLE_MEDIATED_TRANSPORT, CTATGCA_MIR153, GOBP_REGULATION_OF_MEMBRANE_LIPID_DISTRIBUTION, GOBP_ORGANOPHOSPHATE_ESTER_TRANSPORT, CAGCAGG_MIR370, KINSEY_TARGETS_OF_EWSR1_FLII_FUSION_DN, GOBP_ENDOMEMBRANE_SYSTEM_ORGANIZATION, GOBP_APOPTOTIC_PROCESS_INVOLVED_IN_DEVELOPMENT, SABATES_COLORECTAL_ADENOMA_DN, GOBP_PHOSPHOLIPID_TRANSPORT, GOBP_MEMBRANE_ORGANIZATION

GO Biological Process (4): engulfment of apoptotic cell (GO:0043652), phosphatidylserine exposure on apoptotic cell surface (GO:0070782), apoptotic process involved in development (GO:1902742), 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
execution phase of apoptosis	2
phagocytosis, engulfment	1
apoptotic cell clearance	1
plasma membrane phospholipid scrambling	1
phospholipid scramblase activity	1
apoptotic process	1
anatomical structure development	1
programmed cell death	1
apoptotic signaling pathway	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

910 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
XKR4	TMEM68	Q96MH6	790
XKR4	CHCHD7	Q9BUK0	621
XKR4	PLAG1	Q6DJT9	608
XKR4	FAM110B	Q8TC76	594
XKR4	BPNT2	Q9NX62	546
XKR4	SDR16C5	Q8N3Y7	532
XKR4	ATP11C	Q8NB49	532
XKR4	KEL	P23276	530
XKR4	STC2	O76061	484
XKR4	CAPN6	Q9Y6Q1	437
XKR4	MSANTD4	Q8NCY6	425
XKR4	NUDCD3	Q8IVD9	425
XKR4	PENK	P01210	413
XKR4	SLC9A4	Q6AI14	400
XKR4	ANKRD49	Q8WVL7	399

IntAct

6 interactions, top by confidence:

A	B	Type	Score
SCRIB	XKR4	psi-mi:“MI:0407”(direct interaction)	0.440
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400
CEP135	AIMP1	psi-mi:“MI:0914”(association)	0.350
SYNGAP1	IGLON5	psi-mi:“MI:0914”(association)	0.350
XKR4	CCNC	psi-mi:“MI:0914”(association)	0.350

BioGRID (9): XKR4 (Affinity Capture-MS), ATP6V0C (Affinity Capture-MS), C9orf64 (Affinity Capture-MS), DGCR6 (Affinity Capture-MS), ATP6V0A2 (Affinity Capture-MS), SDK2 (Affinity Capture-MS), CCNC (Affinity Capture-MS), XKR4 (Cross-Linking-MS (XL-MS)), XKR4 (Affinity Capture-RNA)

ESM2 similar proteins: A6NKL6, A6NNE9, A6P320, D3YYI7, E9Q0B3, F5H4A9, O60346, P0C1G7, P0C7U0, P0DPB3, P39881, P53349, Q0P496, Q13233, Q147X3, Q2TBI2, Q3TZ87, Q49LS4, Q52L14, Q5GH59, Q5GH67, Q5GH76, Q5VV17, Q62925, Q66JB6, Q6NS60, Q80TE3, Q86VE0, Q86YJ5, Q8BGW2, Q8CBH7, Q8R554, Q8TC41, Q8TE49, Q8TF61, Q96EP1, Q96SQ7, Q99MX7, Q99NA2, Q9BXQ6

Diamond homologs: A8Y2U2, O17386, Q49LS4, Q5GH59, Q5GH67, Q5GH76, E9Q6C8, Q49LS1, Q49LS6, Q49LS7, Q49LS8, Q49LS9, Q4VV71, Q5GH56, Q5GH57, Q5GH64, Q5GH72, Q5GH73, Q49LS3, Q5GH62, Q5GH66, Q6UX68, Q8C0T0, Q9H6D3, Q49LS0, Q49LR9, Q5GH70, Q9QXY7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	70
Likely benign	3
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
443619	GRCh37/hg19 8p23.1-q24.3(chr8:12490999-146295771)x3	Pathogenic

SpliceAI

2893 predictions. Top by Δscore:

Variant	Effect	Δscore
8:55523276:TGTA:T	acceptor_loss	1.0000
8:55523277:GTAG:G	acceptor_loss	1.0000
8:55142286:A:T	donor_gain	0.9900
8:55184545:G:GT	donor_gain	0.9900
8:55251399:GCATA:G	donor_gain	0.9900
8:55251403:A:G	donor_gain	0.9900
8:55357677:GAT:G	acceptor_gain	0.9900
8:55357873:CCAAG:C	donor_loss	0.9900
8:55357874:CAAG:C	donor_loss	0.9900
8:55357875:AAGG:A	donor_loss	0.9900
8:55357878:GT:G	donor_loss	0.9900
8:55357879:T:G	donor_loss	0.9900
8:55523276:TGTAG:T	acceptor_gain	0.9900
8:55523277:GTAGG:G	acceptor_gain	0.9900
8:55523278:TAGG:T	acceptor_gain	0.9900
8:55523279:A:AG	acceptor_gain	0.9900
8:55523279:AG:A	acceptor_gain	0.9900
8:55523279:AGGT:A	acceptor_gain	0.9900
8:55523280:G:GT	acceptor_gain	0.9900
8:55523280:GG:G	acceptor_gain	0.9900
8:55523280:GGT:G	acceptor_gain	0.9900
8:55103292:G:GT	donor_gain	0.9800
8:55357673:TCTA:T	acceptor_loss	0.9800
8:55357674:CTA:C	acceptor_loss	0.9800
8:55357675:TA:T	acceptor_loss	0.9800
8:55357676:A:AG	acceptor_gain	0.9800
8:55357677:G:GG	acceptor_gain	0.9800
8:55449325:A:AG	donor_gain	0.9800
8:55523275:TTGTA:T	acceptor_gain	0.9800
8:55523280:GGTTT:G	acceptor_gain	0.9800

AlphaMissense

4250 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:55357824:T:C	L318P	1.000
8:55523431:G:T	R386M	1.000
8:55523499:T:A	W409R	1.000
8:55523499:T:C	W409R	1.000
8:55523541:T:C	F423L	1.000
8:55523542:T:C	F423S	1.000
8:55523542:T:G	F423C	1.000
8:55523543:C:A	F423L	1.000
8:55523543:C:G	F423L	1.000
8:55523586:G:A	G438R	1.000
8:55523586:G:C	G438R	1.000
8:55523586:G:T	G438W	1.000
8:55523587:G:A	G438E	1.000
8:55523778:G:C	G502R	1.000
8:55523991:T:C	F573L	1.000
8:55523992:T:C	F573S	1.000
8:55523993:T:A	F573L	1.000
8:55523993:T:G	F573L	1.000
8:55524093:T:A	W607R	1.000
8:55524093:T:C	W607R	1.000
8:55524095:G:C	W607C	1.000
8:55524095:G:T	W607C	1.000
8:55102975:A:C	S163R	0.999
8:55102977:C:A	S163R	0.999
8:55102977:C:G	S163R	0.999
8:55102984:T:A	W166R	0.999
8:55102984:T:C	W166R	0.999
8:55357700:G:C	G277R	0.999
8:55357772:G:C	D301H	0.999
8:55357772:G:T	D301Y	0.999

dbSNP variants (sampled 300 via entrez): RS1000003736 (8:55145258 A>G), RS1000011549 (8:55501325 C>T), RS1000012567 (8:55541580 C>G), RS1000025709 (8:55500482 A>G,T), RS1000027054 (8:55345658 C>T), RS1000039210 (8:55352433 A>G), RS1000051337 (8:55201710 G>C), RS1000052626 (8:55101426 C>A,G), RS1000054517 (8:55505014 T>C), RS1000055463 (8:55147678 T>C,G), RS1000071589 (8:55216564 C>T), RS1000075492 (8:55111754 G>A), RS1000079179 (8:55282729 A>C), RS1000083579 (8:55310621 G>T), RS1000085181 (8:55504793 T>C)

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

7 associations (top):

Study	Trait	p-value
GCST001533_3	Immune reponse to smallpox (secreted IL-1beta)	2.000000e-07
GCST002458_1	Serum thyroid-stimulating hormone levels	2.000000e-10
GCST004749_25	Lung cancer in ever smokers	2.000000e-06
GCST005194_74	Coronary artery disease	5.000000e-06
GCST007537_3	Modic changes	9.000000e-06
GCST012035_3	Sleep (1-day periodicity)	1.000000e-08
GCST90011894_8	Retinitis pigmentosa	5.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004645	response to vaccine
EFO:0004873	cytokine measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, increases methylation	6
Nickel	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
aristolochic acid I	decreases expression	1
bisphenol A	affects cotreatment, decreases methylation	1
trichostatin A	increases expression	1
CGP 52608	affects binding, increases reaction	1
entinostat	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	increases methylation	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Panobinostat	increases expression, affects cotreatment	1
Arsenic	affects methylation	1
Benzo(a)pyrene	increases methylation	1
Malathion	decreases expression	1
Phthalic Acids	decreases methylation	1
Tobacco Smoke Pollution	decreases methylation	1
Tretinoin	increases expression	1
Permethrin	decreases expression	1

Clinical trials (associated diseases)

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