ABCC5

Summary

ABCC5 (ATP binding cassette subfamily C member 5, HGNC:56) is a protein-coding gene on chromosome 3q27.1, encoding ATP-binding cassette sub-family C member 5 (O15440). ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes physiological compounds, and xenobiotics from cells.

The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MRP subfamily which is involved in multi-drug resistance. This protein functions in the cellular export of its substrate, cyclic nucleotides. This export contributes to the degradation of phosphodiesterases and possibly an elimination pathway for cyclic nucleotides. Studies show that this protein provides resistance to thiopurine anticancer drugs, 6-mercatopurine and thioguanine, and the anti-HIV drug 9-(2-phosphonylmethoxyethyl)adenine. This protein may be involved in resistance to thiopurines in acute lymphoblastic leukemia and antiretroviral nucleoside analogs in HIV-infected patients. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 10057 — RefSeq curated summary.

At a glance

• GWAS associations: 13
• Clinical variants (ClinVar): 196 total — 13 pathogenic, 4 likely-pathogenic
• Regional missense constraint (gnomAD): 1 of 3 regions constrained (≈1% of expected missense variation)
• GTEx eGene: eQTL in 41 tissues, sQTL in 22 (q < 0.05)
• ChEMBL bioactivity: 3 clinical-phase molecules tested; no curated mechanism-of-action drug
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.46 (moderately constrained)
• MANE Select transcript: NM_005688
• Notable: 196 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:56
Approved symbol	ABCC5
Name	ATP binding cassette subfamily C member 5
Location	3q27.1
Locus type	gene with protein product
Status	Approved
Aliases	MRP5, SMRP, EST277145, MOAT-C
Ensembl gene	ENSG00000114770
Ensembl biotype	protein_coding
OMIM	605251
Entrez	10057

Gene structure

Transcript identifiers

Ensembl transcripts: 51 — 37 protein_coding, 12 nonsense_mediated_decay, 1 retained_intron, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000334444

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 6, TSL 2: 1, TSL 4: 1, TSL 5: 5

ENST00000334444, ENST00000265586, ENST00000382494, ENST00000392579, ENST00000427120, ENST00000437205, ENST00000437341, ENST00000438979, ENST00000443376, ENST00000443497, ENST00000446941, ENST00000476402, ENST00000492216, ENST00000898238, ENST00000915403, ENST00000956861, ENST00000956862, ENST00000956863, ENST00000956864, ENST00000956865, ENST00000956866, ENST00000956867, ENST00000956868, ENST00000989186, ENST00000989187, ENST00000989188, ENST00000989189, ENST00000989190, ENST00001039131, ENST00001039132, ENST00001039135, ENST00001039136, ENST00001039137, ENST00001039138, ENST00001039139, ENST00001039140, ENST00001039141, ENST00001039142, ENST00001039143, ENST00001039146, ENST00001039147, ENST00001039148, ENST00001039149, ENST00001085004, ENST00001085005, ENST00001085006, ENST00001090671, ENST00001090672, ENST00001123862, ENST00001123863, ENST00001145074

RefSeq mRNA: 3 — MANE Select: NM_005688 NM_001023587, NM_001320032, NM_005688

CCDS: CCDS33898, CCDS43176

Canonical transcript exons

ENST00000334444 — 30 exons

Exon	Start	End
ENSE00000780809	183987770	183987917
ENSE00000780817	183971563	183971919
ENSE00001079263	183977517	183977624
ENSE00001899220	184017830	184017884
ENSE00001913353	183919934	183921401
ENSE00002701825	184014264	184014447
ENSE00003465075	183963385	183963588
ENSE00003469725	183981727	183981874
ENSE00003487102	183965377	183965501
ENSE00003494842	183978503	183978651
ENSE00003501368	183965185	183965257
ENSE00003520167	183927330	183927443
ENSE00003520675	183928747	183928825
ENSE00003527340	183953086	183953270
ENSE00003545580	183967695	183967766
ENSE00003560602	183982774	183983007
ENSE00003563405	183959733	183959835
ENSE00003569634	183945850	183945939
ENSE00003574200	183937901	183938060
ENSE00003575348	183947324	183947510
ENSE00003585733	183989226	183989383
ENSE00003598069	183951441	183951570
ENSE00003640818	183949972	183950125
ENSE00003648090	183925555	183925719
ENSE00003656920	183949753	183949881
ENSE00003660537	183982451	183982624
ENSE00003663566	183951857	183952003
ENSE00003670552	183942727	183942916
ENSE00003678472	183961511	183961654
ENSE00003691819	183988572	183988727

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 97.41.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.8317 / max 200.9506, expressed in 1758 samples.

Highest expression (Bgee): hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex, gastrocnemius, middle temporal gyrus.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ABCC5 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 41 tissues and its splicing (sQTL) in 22 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 63 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Whole Blood	eqtl	1.7e-52	-0.37	3:184022562:G:A
Esophagus Mucosa	eqtl	4.8e-36	-0.37	3:184017498:C:G
Brain Cerebellum	eqtl	3.1e-31	+0.50	3:183922361:GA:G
Esophagus Muscularis	eqtl	7.6e-28	+0.43	3:184039634:T:G
Brain Cerebellum	sqtl	1.0e-27	-0.95	3:183922361:GA:G
Thyroid	eqtl	5.2e-18	+0.31	3:183941889:G:A
Brain Cerebellar Hemisphere	eqtl	9.9e-17	+0.35	3:183917710:T:A
Nerve Tibial	eqtl	2.0e-15	+0.13	3:183922361:GA:G
Esophagus Gastroesophageal Junction	eqtl	3.3e-14	+0.38	3:184039634:T:G
Brain Cerebellar Hemisphere	sqtl	4.1e-14	+0.74	3:183922361:GA:G
Brain Hippocampus	eqtl	6.9e-13	+0.26	3:183918722:AGGAG:A
Brain Cortex	eqtl	4.9e-12	+0.26	3:183917710:T:A
Testis	eqtl	8.0e-12	+0.17	3:183922361:GA:G
Esophagus Mucosa	sqtl	5.0e-10	+0.51	3:184017498:C:G
Brain Caudate basal ganglia	eqtl	5.7e-10	+0.18	3:183917700:C:T
Skin Sun Exposed Lower leg	eqtl	6.7e-10	+0.15	3:183916728:C:T
Pituitary	eqtl	1.6e-09	+0.28	3:183922361:GA:G
Brain Hypothalamus	eqtl	3.6e-09	+0.20	3:183917710:T:A
Brain Putamen basal ganglia	eqtl	5.3e-09	+0.20	3:183918722:AGGAG:A
Brain Anterior cingulate cortex BA24	eqtl	2.2e-08	+0.15	3:183923077:G:T

FANTOM5 promoters

1 alternative TSS:

Promoter ID	TPM avg	Samples expressed
45863	12.8317	1758

Top tissues by expression

showing 100 of 301 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	97.41	gold quality
cerebellar hemisphere	UBERON:0002245	97.28	gold quality
cerebellar cortex	UBERON:0002129	97.18	gold quality
gastrocnemius	UBERON:0001388	97.10	gold quality
middle temporal gyrus	UBERON:0002771	97.10	gold quality
pigmented layer of retina	UBERON:0001782	96.82	gold quality
retina	UBERON:0000966	96.79	gold quality
muscle of leg	UBERON:0001383	96.29	gold quality
cerebellum	UBERON:0002037	96.09	gold quality
tibialis anterior	UBERON:0001385	95.97	gold quality
apex of heart	UBERON:0002098	94.96	gold quality
primary visual cortex	UBERON:0002436	94.68	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.63	gold quality
Brodmann (1909) area 23	UBERON:0013554	94.45	gold quality
lower esophagus mucosa	UBERON:0035834	94.32	gold quality
right frontal lobe	UBERON:0002810	93.86	gold quality
body of stomach	UBERON:0001161	93.74	gold quality
right atrium auricular region	UBERON:0006631	93.64	gold quality
muscle organ	UBERON:0001630	93.57	gold quality
skeletal muscle organ	UBERON:0014892	93.57	gold quality
esophagus mucosa	UBERON:0002469	93.30	gold quality
vagina	UBERON:0000996	92.89	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.88	gold quality
deltoid	UBERON:0001476	92.82	gold quality
endometrium epithelium	UBERON:0004811	92.34	gold quality
heart left ventricle	UBERON:0002084	92.32	gold quality
adenohypophysis	UBERON:0002196	92.27	gold quality
stomach	UBERON:0000945	92.26	gold quality
metanephros cortex	UBERON:0010533	92.17	gold quality
pituitary gland	UBERON:0000007	92.16	gold quality
adrenal tissue	UBERON:0018303	92.10	gold quality
cardiac ventricle	UBERON:0002082	92.08	gold quality
nucleus accumbens	UBERON:0001882	91.88	gold quality
cardiac atrium	UBERON:0002081	91.83	gold quality
cingulate cortex	UBERON:0003027	91.75	gold quality
anterior cingulate cortex	UBERON:0009835	91.69	gold quality
caudate nucleus	UBERON:0001873	91.66	gold quality
putamen	UBERON:0001874	91.55	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	91.53	gold quality
spleen	UBERON:0002106	91.17	gold quality
occipital lobe	UBERON:0002021	91.10	gold quality
heart	UBERON:0000948	91.07	gold quality
bronchial epithelial cell	CL:0002328	91.06	gold quality
esophagus	UBERON:0001043	91.05	gold quality
middle frontal gyrus	UBERON:0002702	90.77	gold quality
nerve	UBERON:0001021	90.76	gold quality
tibial nerve	UBERON:0001323	90.76	gold quality
cortical plate	UBERON:0005343	90.53	gold quality
cerebellar vermis	UBERON:0004720	90.43	gold quality
epithelium of bronchus	UBERON:0002031	90.39	gold quality
brain	UBERON:0000955	90.30	gold quality
central nervous system	UBERON:0001017	90.22	gold quality
rectum	UBERON:0001052	90.22	gold quality
transverse colon	UBERON:0001157	90.19	gold quality
neocortex	UBERON:0001950	90.06	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	90.02	gold quality
bronchus	UBERON:0002185	89.99	gold quality
right ovary	UBERON:0002118	89.98	gold quality
forebrain	UBERON:0001890	89.94	gold quality
tibia	UBERON:0000979	89.93	gold quality
Brodmann (1909) area 10	UBERON:0013541	89.89	gold quality
telencephalon	UBERON:0001893	89.85	gold quality
ectocervix	UBERON:0012249	89.85	gold quality
hypothalamus	UBERON:0001898	89.79	gold quality
choroid plexus epithelium	UBERON:0003911	89.74	gold quality
cerebral cortex	UBERON:0000956	89.68	gold quality
body of uterus	UBERON:0009853	89.68	gold quality
left ovary	UBERON:0002119	89.61	gold quality
sural nerve	UBERON:0015488	89.61	gold quality
prefrontal cortex	UBERON:0000451	89.52	gold quality
frontal cortex	UBERON:0001870	89.50	gold quality
frontal lobe	UBERON:0016525	89.49	gold quality
right adrenal gland	UBERON:0001233	89.35	gold quality
buccal mucosa cell	CL:0002336	89.11	gold quality
amygdala	UBERON:0001876	89.10	gold quality
right adrenal gland cortex	UBERON:0035827	89.08	gold quality
fundus of stomach	UBERON:0001160	88.95	gold quality
small intestine Peyer’s patch	UBERON:0003454	88.94	gold quality
gall bladder	UBERON:0002110	88.93	gold quality
Ammon’s horn	UBERON:0001954	88.69	gold quality
right coronary artery	UBERON:0001625	88.67	gold quality
lower esophagus	UBERON:0013473	88.66	gold quality
lower esophagus muscularis layer	UBERON:0035833	88.63	gold quality
skeletal muscle tissue	UBERON:0001134	88.44	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	88.40	gold quality
ganglionic eminence	UBERON:0004023	88.25	gold quality
spinal cord	UBERON:0002240	88.24	gold quality
medial globus pallidus	UBERON:0002477	88.23	gold quality
ovary	UBERON:0000992	88.21	gold quality
muscle layer of sigmoid colon	UBERON:0035805	88.21	gold quality
left adrenal gland	UBERON:0001234	88.11	gold quality
left adrenal gland cortex	UBERON:0035825	88.11	gold quality
endocervix	UBERON:0000458	88.10	gold quality
gingival epithelium	UBERON:0001949	87.68	gold quality
mucosa of stomach	UBERON:0001199	87.67	gold quality
adrenal gland	UBERON:0002369	87.63	gold quality
esophagus squamous epithelium	UBERON:0006920	87.63	gold quality
adult mammalian kidney	UBERON:0000082	87.60	gold quality
urinary bladder	UBERON:0001255	87.42	gold quality
heart right ventricle	UBERON:0002080	87.42	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-135922	yes	13.44
E-MTAB-7249	yes	11.11
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 77 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Choroid plexus	tissue	323.0
Retina	tissue	116.9
Stomach 1	tissue	77.7	low
Postcentral gyrus	tissue	63.2
Nucleus accumbens	tissue	55.6
Skeletal muscle	tissue	54.9	not detected
Locus coeruleus	tissue	52.6
Hippocampus	tissue	51.1	not detected
Pituitary gland	tissue	41.4
Tongue	tissue	37.6
Vagina	tissue	35.3	not detected
Cerebral cortex	tissue	29.7	low
Somatosensory cortex	tissue	29.7
Putamen	tissue	29.2
Basal ganglia	tissue	29.0	not detected
Occipital cortex	tissue	27.6
Caudate putamen	tissue	27.2
Cerebellum	tissue	26.9	not detected
Spleen	tissue	26.5	not detected
Heart muscle	tissue	24.7	medium
Ventral forebrain	tissue	24.2
Temporal cortex	tissue	24.0
Insular cortex	tissue	23.9
Prefrontal cortex	tissue	23.3
Motor cortex	tissue	23.3
Hippocampal formation	tissue	23.3
Entorhinal cortex	tissue	23.3
Frontal cortex	tissue	23.2
Spinal cord	tissue	22.9
Retrosplenial and cingulate cortex	tissue	22.9
Skin 1	tissue	22.7	not detected
Parathyroid gland	tissue	22.6	not detected
Retrosplenial cortex	tissue	22.6
Superior colliculi	tissue	22.4
Medulla oblongata	tissue	21.6
Pons	tissue	21.5
Urinary bladder	tissue	21.4	not detected
Bone marrow	tissue	21.2	not detected
Esophagus	tissue	20.8	not detected
Rectum	tissue	20.8	low
Endometrium 1	tissue	20.3	not detected
Midbrain	tissue	20.0
Thalamus	tissue	19.8
Amygdala	tissue	19.0
Substantia nigra	tissue	18.9
Olfactory bulb	tissue	18.7
Septum	tissue	18.2
Colon	tissue	17.5	low
Hypothalamus	tissue	17.2
Gallbladder	tissue	16.8	low
Placenta	tissue	16.1	medium
Adrenal gland	tissue	16.1	not detected
Kidney	tissue	15.6	medium
Periaqueductal gray	tissue	15.4
Appendix	tissue	15.4	medium
Smooth muscle	tissue	15.0	medium
Ovary	tissue	14.8	not detected
Prostate	tissue	14.7	not detected
Testis	tissue	14.4	not detected
Thymus	tissue	14.2

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Temporo-occipital transitional zone (71.9), Cerebellar cortex (71.4), Vermis (70.9), Flocculonodular lobe (70.8), Ventromedial nucleus (67.5).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AHR

miRNA regulators (miRDB)

Targeting ABCC5 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 146 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-548P	99.98	72.25	3784
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-590-3P	99.96	74.34	6478
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-3658	99.96	73.87	4379

Functional genomics

gnomAD constraint: pLI 0.999, LOEUF 0.455, missense Z 4.84 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000334444 splits into 3 regions with different missense tolerance; 1 is missense-constrained (≈1% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
3:183,921,303–183,942,750	163 / 269.7	0.60	no
3:183,942,751–183,942,795	3 / 16.5	0.18	yes (p 9.0e-04)
3:183,942,796–184,014,392	1142 / 1527.1	0.75	no

Literature-anchored findings (GeneRIF, showing 40)

• MRP4 and MRP5 are low affinity cyclic nucleotide transporters that may at best function as overflow pumps, decreasing steep increases in cGMP levels under conditions where cGMP synthesis is strongly induced and phosphodiesterase activity is limiting (PMID:12637526)
• MRP1 and MRP5 increase with trophoblast maturation, suggesting a particular role for these proteins in the organ functional developmen (PMID:12646196)
• the affinity of MRP4 and MRP5 for nucleotide-based substrates is low. (PMID:12695538)
• Localized in cardiac and cardiovascular myocytes as well as endothelial cells with increased expression in ischemic cardiomyopathy. MRP5-mediated cellular export may represent novel, disease-dependent pathway for cGMP removal from cardiac cells. (PMID:14507663)
• MRP5 expression depends on gestational age and varies throughout the differentiation process. (PMID:15631998)
• Upregulation of MRP5 expression is associated with pancreatic carcinoma (PMID:15688370)
• analysis of linkage disequilibrium at the nucleotide analogue transporter ABCC5 gene locus (PMID:15861033)
• Plant flavonoids were able to reverse drug resistance in human cells transfected with ABCC5 (PMID:16156793)
• We have isolated three novel ABCC5 splice variants and characterized their role in the regulation of ABCC5 gene expression. One ABCC5 splice variant produces a truncated ABCC5 protein isoform with thus far unknown functional properties in the retina. (PMID:17521428)
• cGMP may be a physiological regulator of hyaluronan export at the level of the export MRP5 (PMID:17540771)
• analysis of the outward facing state of the human P-glycoprotein (ABCB1), and comparison to a model of the human MRP5 (ABCC5) (PMID:17803828)
• Celecoxib upregulates MRP5 in colon cancer and results in lack of synergy with standard chemotherapy. (PMID:18690847)
• MRP3, MRP4, and MRP5 are upregulated in 5-fluorouracil-resistant cells, and MRP5 contributes to 5-FU resistance in pancreatic carcinoma cells. (PMID:19077464)
• Sodium influx is not directly coupled to MRP4/5-mediated cyclic nucleotide efflux, is independent of the status of transporter activity, and determines the baseline membrane potential, which in turns modulates MRP4/5-mediated cyclic nucleotide efflux. (PMID:19903828)
• Results identify key membrane transporters OATP2B1, MRP1, MRP4, and MRP5 as modulators of skeletal muscle statin exposure and toxicity. (PMID:19940267)
• MDR1, MRP2, MRP3 and MRP5 levels are decreased by tetramethylpyrazine in human hepatocellular carcinoma cells (PMID:19956884)
• Results support the idea that isolating survivin and MRP5+ CTCs may help in the selection of metastatic colorectal cancer patients resistant to standard 5-FU and L-OHP based chemotherapy, for which alternative regimens may be appropriate. (PMID:20597995)
• This gene-wide tagging study revealed no association between ABCC2, ABCC5 and ABCG2 genetic polymorphisms and multidrug resistance in epilepsy (PMID:21449672)
• Findings show that the gene expression of ATP-dependent efflux transporters MRP1, -3, -4, -5, and p-gp fluctuated during stem cell-derived retinal pigment epithelial cells (hESC-RPE) maturation. (PMID:22272278)
• The present results imply that MRP5 index may hold a prognostic role in patients with glioblastoma multiforme (PMID:22278731)
• PDE5 is highly expressed and increases ( approximately 130%) during growth whereas ABCC5 exhibited low to moderate expression, with a moderate increase ( approximately 40%) during growth (PMID:22843873)
• ABCC5 functions as a mediator of breast cancer skeletal metastasis. ABCC5 expression in breast cancer cells is important for efficient osteoclast-mediated bone resorption. (PMID:23174366)
• Further research is needed to clarify whether MRP5 is indicative of malignant pathological features in meningiomas and whether possible therapeutic implications exist (PMID:23271324)
• This locus was associated with an increase in risk of PACG in a separate case-control study of 4,276 primary angle closure glaucoma cases and 18,801 controls (per-allele OR = 1.13 [95% CI: 1.06-1.22], P = 0.00046). (PMID:24603532)
• cCMP is a substrate for MRP5 (PMID:25017019)
• The blockade of ABC transporter MRP5 could help to improve drug effectiveness, reduce tumour growth and prevent recurrence in glioblastoma multiforme. (PMID:25028266)
• ABCC5 transporter is a novel type 2 diabetes susceptibility gene in European and African American populations. (PMID:25117150)
• The present study investigated the time course and dose dependency of the induction of three efflux proteins, P-gp, MRP1 and MRP5, in response to gemcitabine exposure in Capan-2 pancreatic cancer cell line at transcriptional and translational levels. (PMID:25564970)
• We identified several genes (FasL, MSH2, ABCC5, CASP3, and CYP3A4)that showed association with PFS in patients with osteosarcoma. These pharmacogenetic risk factors might be useful to predict treatment outcome (PMID:25829401)
• To identify substrates of orphan transporter ATP-binding cassette subfamily C member 5 (ABCC5), identified a class of metabolites, N-lactoyl-amino acids, and found that a protease, cytosolic nonspecific dipeptidase 2 (CNDP2), catalyzes their formation. (PMID:25964343)
• Survivors of childhood acute lymphoblastic leukemia treated with doxorubicin with the ABCC5 TT-1629 genotype had an average of 8-12% reduction of ventricular ejection and shortening fractions. (PMID:26345518)
• genetic association study in population in Mexico: Data suggest SNPs in ABCC5 (3933+313T>C) are not associated with adverse reactions to methotrexate; they protect against myelosuppression in pediatric patients with ALL (acute lymphoblastic leukemia). (PMID:26353179)
• ABCC5 is a general glutamate conjugate and analog transporter that affects the disposition of endogenous metabolites, toxins, and drugs. (PMID:26515061)
• our work indicated that decreased SLC34A2 expression sensitized BCSCs to doxorubicin via SLC34A2-Bmi1-ABCC5 signaling and shed new light on understanding the mechanism of chemoresistance in BCSCs. This study not only bridges the missing link between stem cell-related transcription factor (Bmi1) and ABC transporter (ABCC5) but also contributes to development of potential therapeutics against breast cancer. (PMID:26546432)
• Deletions of ABCC5 predict good tumor response to neoadjuvant chemotherapy in breast cancer. (PMID:26799285)
• ABCC5 polymorphisms may explain partially the interpatient variability in doxorubicin disposition. (PMID:26975227)
• This study is the first to identify the roles of FOXM1 in drug efflux and paclitaxel resistance by regulating the gene transcription of abcc5, one of the ABC transporters. Small molecular inhibitors of FOXM1 or ABCC5 have the potential to overcome paclitaxel chemoresistance in nasopharyngeal carcinoma (NPC)patients. (PMID:28277541)
• These findings enrich the allelic spectrum of ABCC5 in PACG. We identified no tagging SNP responsible for the association of the whole region. (PMID:28813580)
• MRP5 nitration by NO-releasing gemcitabine encapsulated in liposomes confers sensitivity in chemoresistant pancreatic adenocarcinoma cells. (PMID:32828758)
• Association of Single-Nucleotide Polymorphisms in ABCC5 Gene with Primary Angle Closure Glaucoma and the Ocular Biometric Parameters in a Northern Chinese Population. (PMID:32906129)

Cross-species orthologs

14 orthologs

Organism	Symbol	Gene ID
danio_rerio	abcc5	ENSDARG00000061233
mus_musculus	Abcc5	ENSMUSG00000022822
rattus_norvegicus	Abcc5	ENSRNOG00000029178
drosophila_melanogaster	l(2)03659	FBGN0010549
drosophila_melanogaster	CG7627	FBGN0032026
drosophila_melanogaster	MRP	FBGN0032456
drosophila_melanogaster	CG9270	FBGN0032908
drosophila_melanogaster	CG10505	FBGN0034612
drosophila_melanogaster	Mrp5	FBGN0038740
drosophila_melanogaster	rdog	FBGN0039644
drosophila_melanogaster	CG11898	FBGN0039645
drosophila_melanogaster	CG31792	FBGN0051792
drosophila_melanogaster	Mrp4	FBGN0263316
caenorhabditis_elegans		WBGENE00000477

Paralogs (11): CFTR (ENSG00000001626), ABCC8 (ENSG00000006071), ABCC2 (ENSG00000023839), ABCC9 (ENSG00000069431), ABCC6 (ENSG00000091262), ABCC1 (ENSG00000103222), ABCC3 (ENSG00000108846), ABCC11 (ENSG00000121270), ABCC10 (ENSG00000124574), ABCC4 (ENSG00000125257), ABCC12 (ENSG00000140798)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1351644) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 9 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased circulating calcium level	1
decreased leukocyte cell number	1
increased startle reflex	1
limb grasping	1
decreased eosinophil cell number	1
decreased lymphocyte cell number	1
impaired glucose tolerance	1
decreased circulating glucose level	1
increased blood urea nitrogen level	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Oryza sativa Indica Group	A2XCD4	100.0%	Diamond
Saccharomyces cerevisiae S288C	P0CE69	100.0%	Diamond
Oryza sativa Japonica Group	Q10RX7	100.0%	Diamond
Oryctolagus cuniculus	P82451	98.1%	Diamond
Cricetus cricetus	Q09427	98.0%	Diamond
Macaca fascicularis	Q864R9	97.6%	Diamond
Arabidopsis thaliana	Q7FB56	94.8%	Diamond
Canis lupus familiaris	Q6UR05	93.1%	Diamond
Bos taurus	Q8HXQ5	93.1%	Diamond
Zea mays	A7KVC2	90.5%	Diamond
Dictyostelium discoideum	Q8ST87	86.2%	Diamond
Gallus gallus	Q5F364	79.0%	Diamond
Schizosaccharomyces pombe 972h-	Q10185	63.4%	Diamond
Nakaseomyces glabratus CBS 138	Q6FWS5	55.3%	Diamond
Glarea lozoyensis ATCC 20868	S3D778	51.9%	Diamond
Pyricularia oryzae 70-15	G4N2B5	47.9%	Diamond
Cryptococcus neoformans H99	J9VQH1	42.5%	Diamond
Mycosarcoma maydis	A0A0D1CZ63	41.8%	Diamond
Staphylococcus epidermidis	P23212	41.1%	Diamond
Aspergillus nidulans FGSC A4	A0A1U8QTJ9	40.6%	Diamond
Leishmania tarentolae	P21441	40.3%	Diamond
Fusarium graminearum PH-1	I1R9B3	39.0%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
HTR3D	protein-coding	200909
ABCC5-AS1	ncRNA	100873982
HTR3C	protein-coding	170572
MIR4448	ncRNA	100616127
PARL	protein-coding	55486

Protein

Protein identifiers

ATP-binding cassette sub-family C member 5 — O15440 (reviewed: O15440)

Alternative names: Multi-specific organic anion transporter C, Multidrug resistance-associated protein 5, SMRP, pABC11

All UniProt accessions (7): O15440, A5PKY6, C9JZL5, E9PET4, F8WCY8, F8WDH3, H7C271

UniProt curated annotations — full annotation on UniProt →

Function. ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes physiological compounds, and xenobiotics from cells. Mediates ATP-dependent transport of endogenous metabolites such as cAMP and cGMP, folic acid and N-lactoyl-amino acids (in vitro). Also acts as a general glutamate conjugate and analog transporter that can limit the brain levels of endogenous metabolites, drugs, and toxins. Confers resistance to the antiviral agent PMEA. Able to transport several anticancer drugs including methotrexate, and nucleotide analogs in vitro, however it does with low affinity, thus the exact role of ABCC5 in mediating resistance still needs to be elucidated. Acts as a heme transporter required for the translocation of cytosolic heme to the secretory pathway. May play a role in energy metabolism by regulating the glucagon-like peptide 1 (GLP-1) secretion from enteroendocrine cells.

Subcellular location. Basolateral cell membrane. Golgi apparatus lumen. Endosome membrane. Cytoplasmic granule. Apical cell membrane.

Tissue specificity. Predominant isoform in retinal pigment epithelium, bladder, and stomach. Ubiquitously expressed, but levels in brain and muscle are especially high. All isoforms are equally expressed in retina.

Activity regulation. cGMP transport is highly sensitive to inhibitors of cGMP phosphodiesterase, such as zaprinast, trequinsin and sildenafil.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. Although other labs have confirmed the ability of ABCC5 to transport cGMP in an ATP-dependent manner, they obtained a much lower affinity for this substrate. The authors conclude that ABCC5 is a low-affinity cyclic nucleotide transporter a major function in cGMP excretion is unlikely.

Similarity. Belongs to the ABC transporter superfamily. ABCC family. Conjugate transporter (TC 3.A.1.208) subfamily.

Isoforms (5)

UniProt ID	Names	Canonical?
O15440-1	1	yes
O15440-2	2, SV1
O15440-3	3, SV2
O15440-4	4, SV3
O15440-5	5

RefSeq proteins (3): NP_001018881, NP_001306961, NP_005679* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003439	ABC_transporter-like_ATP-bd	Domain
IPR003593	AAA+_ATPase	Domain
IPR011527	ABC1_TM_dom	Domain
IPR017871	ABC_transporter-like_CS	Conserved_site
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR036640	ABC1_TM_sf	Homologous_superfamily
IPR050173	ABC_transporter_C-like	Family

Pfam: PF00005, PF00664

Enzyme classification (BRENDA)

• EC 7.6.2.3 — ABC-type glutathione-S-conjugate transporter (BRENDA: 8 organisms, 145 substrates, 63 inhibitors, 16 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

7 substrates with measured Km, best-characterized 7. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0865–0.91	5
MONOMETHYLARSONOUS ACID DIGLUTATHIONE[SIDE 1]	0.023–0.033	4
S-(2,4-DINITROPHENYL)GLUTATHIONE[SIDE 1]	0.0141–0.032	2
S-(LEUKOTRIENE C4)GLUTATHIONE[SIDE 1]	0.0001	2
4-(GLUTATHIONE-S-YL)-QUINOLINE-1-OXIDE[SIDE 1]	0.0095	1
ARSENIC TRIGLUTATHIONE[SIDE 1]	0.0003	1
S-GLUTATHIONE[SIDE 1]	12	1

Catalyzed reactions (Rhea)

• 3’,5’-cyclic AMP(in) + ATP + H2O = 3’,5’-cyclic AMP(out) + ADP + phosphate + H(+) (RHEA:66184)
• 3’,5’-cyclic GMP(in) + ATP + H2O = 3’,5’-cyclic GMP(out) + ADP + phosphate + H(+) (RHEA:66188)
• N-[(S)-lactoyl]-L-phenylalanine(in) + ATP + H2O = N-[(S)-lactoyl]-L-phenylalanine(out) + ADP + phosphate + H(+) (RHEA:66720)
• N-acetyl-L-aspartyl-L-glutamate(in) + ATP + H2O = N-acetyl-L-aspartyl-L-glutamate(out) + ADP + phosphate + H(+) (RHEA:66728)
• N-acetyl-L-aspartyl-L-glutamyl-L-glutamate(in) + ATP + H2O = N-acetyl-L-aspartyl-L-glutamyl-L-glutamate(out) + ADP + phosphate + H(+) (RHEA:66732)
• beta-citrylglutamate(in) + ATP + H2O = beta-citrylglutamate(out) + ADP + phosphate + H(+) (RHEA:66736)
• N-acetyl-L-glutamate(in) + ATP + H2O = N-acetyl-L-glutamate(out) + ADP + phosphate + H(+) (RHEA:66740)
• N-acetyl-L-aspartate(in) + ATP + H2O = N-acetyl-L-aspartate(out) + ADP + phosphate + H(+) (RHEA:66744)
• (2S)-2-[5-amino-1-(beta-D-ribosyl)imidazole-4-carboxamido]succinate(in) + ATP + H2O = (2S)-2-[5-amino-1-(beta-D-ribosyl)imidazole-4-carboxamido]succinate(out) + ADP + phosphate + H(+) (RHEA:66752)
• domoate(in) + ATP + H2O = domoate(out) + ADP + phosphate + H(+) (RHEA:66756)
• kainate(in) + ATP + H2O = kainate(out) + ADP + phosphate + H(+) (RHEA:66760)
• folate(in) + ATP + H2O = folate(out) + ADP + phosphate + H(+) (RHEA:66764)

UniProt features (151 total): helix 60, strand 30, transmembrane region 13, turn 9, glycosylation site 8, splice variant 7, modified residue 6, domain 4, compositionally biased region 4, sequence conflict 4, region of interest 3, binding site 2, chain 1

Structure

Experimental structures (PDB)

6 structures by resolution:

PDB	Title	Method	Resolution (Å)
8WI0	wt-hMRP5 inward-open	ELECTRON MICROSCOPY	2.93
8WI4	m6-hMRP5 inward open	ELECTRON MICROSCOPY	3.2
8WI3	ND-hMRP5-inward open	ELECTRON MICROSCOPY	3.38
8WI5	M5PI-bound hMRP5	ELECTRON MICROSCOPY	3.46
8KCI	ATP-bound hMRP5 outward-open	ELECTRON MICROSCOPY	3.94
8WI2	RD-hMRP5-inward open	ELECTRON MICROSCOPY	4.06

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15440-F1	78.13	0.36

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Metabolic proteins, Transporters, Primary Active Transporters, Predicted membrane proteins, Predicted intracellular proteins, Cancer-related genes, Candidate cancer biomarkers

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cell junctions; plasma membrane; nucleoplasm

Antibody reliability (HPA): IH uncertain · IF approved

Functional residue map

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

Ligand- & substrate-binding residues (2)

Position	Role
595–602	ATP
1227–1234	ATP

Post-translational modifications (6)

Type	Positions
Phosphoserine	14, 19, 60, 505, 509
Phosphothreonine	513

Glycosylation sites (8)

Type	Positions
N-linked (glcnac…) asparagine	494, 636, 684, 890, 897, 1044, 1329, 1417

Function

Pathways and Gene Ontology

Reactome pathways

4 curated (TAS) of 9; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

9 pathways:

ID	Pathway	Evidence
R-HSA-382556	ABC-family protein mediated transport	curated
R-HSA-9748787	Azathioprine ADME	curated
R-HSA-2142845	Hyaluronan metabolism	curated
R-HSA-9753281	Paracetamol ADME	curated
R-HSA-9748784	Drug ADME	—
R-HSA-1630316	Glycosaminoglycan metabolism	—
R-HSA-1430728	Metabolism	—
R-HSA-71387	Metabolism of carbohydrates and carbohydrate derivatives	—
R-HSA-382551	Transport of small molecules	—

MSigDB gene sets: 414 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_UP, SHEPARD_BMYB_MORPHOLINO_UP, GOBP_CIRCULATORY_SYSTEM_PROCESS, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_IRON_COORDINATION_ENTITY_TRANSPORT, BROWNE_HCMV_INFECTION_8HR_UP, GOBP_TRANSITION_METAL_ION_TRANSPORT, GOBP_MODIFIED_AMINO_ACID_TRANSPORT, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, MODULE_493, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, TGACCTY_ERR1_Q2, FOXO4_01, GOBP_XENOBIOTIC_TRANSMEMBRANE_TRANSPORT, GOBP_IRON_ION_TRANSPORT

GO Biological Process (15): xenobiotic metabolic process (GO:0006805), xenobiotic transmembrane transport (GO:0006855), purine nucleotide transport (GO:0015865), hyaluronan biosynthetic process (GO:0030213), glutathione transmembrane transport (GO:0034775), heme transmembrane transport (GO:0035351), xenobiotic transport (GO:0042908), transmembrane transport (GO:0055085), cAMP transport (GO:0070730), cGMP transport (GO:0070731), folate transmembrane transport (GO:0098838), export across plasma membrane (GO:0140115), transport across blood-brain barrier (GO:0150104), carbohydrate derivative transport (GO:1901264), xenobiotic detoxification by transmembrane export across the plasma membrane (GO:1990961)

GO Molecular Function (12): ATP binding (GO:0005524), ABC-type xenobiotic transporter activity (GO:0008559), purine nucleotide transmembrane transporter activity (GO:0015216), heme transmembrane transporter activity (GO:0015232), efflux transmembrane transporter activity (GO:0015562), ATP hydrolysis activity (GO:0016887), transmembrane transporter activity (GO:0022857), glutathione transmembrane transporter activity (GO:0034634), ATPase-coupled transmembrane transporter activity (GO:0042626), xenobiotic transmembrane transporter activity (GO:0042910), ABC-type transporter activity (GO:0140359), nucleotide binding (GO:0000166)

GO Cellular Component (6): Golgi lumen (GO:0005796), plasma membrane (GO:0005886), endosome membrane (GO:0010008), membrane (GO:0016020), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324)

Reactome top-level categories

5 top-level categories:

Category	Pathways
Drug ADME	2
Glycosaminoglycan metabolism	1
Transport of small molecules	1
Metabolism of carbohydrates and carbohydrate derivatives	1
Metabolism	1

GO top-level categories

56 GO namespaces:

Category	Terms
transmembrane transport	3
transport	3
transmembrane transporter activity	3
xenobiotic transport	2
heme transport	2
purine ribonucleotide transport	2
cyclic nucleotide transport	2
ATP-dependent activity	2
plasma membrane region	2
metabolic process	1
cellular response to xenobiotic stimulus	1
nucleotide transport	1
glycosaminoglycan biosynthetic process	1
hyaluronan metabolic process	1
glutathione transport	1
tripeptide transmembrane transport	1
iron ion transmembrane transport	1
cellular process	1
adenine nucleotide transport	1
guanine nucleotide transport	1
folic acid transport	1
vitamin transmembrane transport	1
carboxylic acid transmembrane transport	1
export from cell	1
vascular transport	1
xenobiotic export from cell	1
detoxification	1
export across plasma membrane	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
anion binding	1
xenobiotic transmembrane transporter activity	1
ABC-type transporter activity	1
nucleotide transmembrane transporter activity	1
purine nucleotide transport	1
ribonucleoside triphosphate phosphatase activity	1
transporter activity	1
glutathione transmembrane transport	1
tripeptide transmembrane transporter activity	1
modified amino acid transmembrane transporter activity	1
sulfur compound transmembrane transporter activity	1
primary active transmembrane transporter activity	1
ATP hydrolysis activity	1
ATPase-coupled transmembrane transporter activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
Golgi apparatus	1
intracellular organelle lumen	1
membrane	1
cell periphery	1
endosome	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
cellular anatomical structure	1
basal plasma membrane	1
apical part of cell	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 20 of 33 annotations. The rest are phylogenetic / computational / electronic (IEA).

20 experimentally-supported GO terms:

GO term	NS	Evidence
cAMP transport	BP	mutant phenotype
cGMP transport	BP	mutant phenotype
export across plasma membrane	BP	direct assay
folate transmembrane transport	BP	mutant phenotype
glutathione transmembrane transport	BP	direct assay
heme transmembrane transport	BP	mutant phenotype
hyaluronan biosynthetic process	BP	mutant phenotype
purine nucleotide transport	BP	direct assay
xenobiotic transport	BP	direct assay
apical plasma membrane	CC	direct assay
basolateral plasma membrane	CC	direct assay
membrane	CC	direct assay
plasma membrane	CC	direct assay
ABC-type transporter activity	MF	mutant phenotype
ABC-type xenobiotic transporter activity	MF	mutant phenotype
efflux transmembrane transporter activity	MF	direct assay
glutathione transmembrane transporter activity	MF	direct assay
heme transmembrane transporter activity	MF	mutant phenotype
purine nucleotide transmembrane transporter activity	MF	direct assay
xenobiotic transmembrane transporter activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,044 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ABCC5	MRPS7	Q9Y2R9	935
ABCC5	ABCF2	Q9UG63	599
ABCC5	ABCG1	P45844	592
ABCC5	ABCG4	Q9H172	576
ABCC5	SLCO2B1	O94956	561
ABCC5	SLC28A3	Q9HAS3	542
ABCC5	SLC28A1	O00337	527
ABCC5	SLC29A1	Q99808	523
ABCC5	ABCE1	P61221	522
ABCC5	SLC22A7	Q9Y694	519
ABCC5	SLCO1A2	P46721	498
ABCC5	SLCO1B1	Q9Y6L6	467
ABCC5	ABCD4	O14678	464
ABCC5	ABCF3	Q9NUQ8	461
ABCC5	SLC22A8	Q8TCC7	460

IntAct

Human interaction partners of ABCC5 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

10 partners by confidence:

Partner	Interaction type	MIscore	Records
SCN3B	association	0.530	2
H1-1	physical association	0.400	1
H1-5	physical association	0.400	1
AK2	physical association	0.370	1
RBP5	physical association	0.370	1
SERPINA3	physical association	0.370	1
SMC2	physical association	0.370	1
NUP58	association	0.350	1
SLC16A13	association	0.350	1
TIAM1	physical association	0.000	1

BioGRID (68 interactions; top human partners by supporting records): ARF6 (Proximity Label-MS; 2 records), KRAS (Proximity Label-MS; 2 records), NRAS (Proximity Label-MS; 2 records), RHOB (Proximity Label-MS; 2 records), SCN3B (Affinity Capture-MS; 2 records), TRDN (Affinity Capture-MS; 2 records), AGO2 (Affinity Capture-RNA), AK2 (Two-hybrid), AKAP8L (Cross-Linking-MS (XL-MS)), ARL4C (Proximity Label-MS), C11orf52 (Proximity Label-MS), C3orf52 (Affinity Capture-MS), CAV1 (Proximity Label-MS), CDC42 (Affinity Capture-MS), CLGN (Affinity Capture-MS)

Disease & clinical

Genetic variants

Variant evidence for ABCC5: 196 ClinVar records (17 pathogenic / likely pathogenic); 2 PharmGKB clinical annotations; 13 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	13
Likely pathogenic	4
Uncertain significance	137
Likely benign	5
Benign	4

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 17 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
57984	GRCh38/hg38 3q25.31-29(chr3:157293378-198134727)x3	Pathogenic	criteria provided, single submitter	1
1527061	GRCh37/hg19 3q26.33-27.3(chr3:182189525-187212935)x1	Pathogenic	criteria provided, single submitter	1
1527063	GRCh37/hg19 3q27.1-27.3(chr3:183178932-186838042)x1	Pathogenic	criteria provided, single submitter	1
1710512	GRCh37/hg19 3q26.33-27.2(chr3:181062175-185474509)x1	Pathogenic	criteria provided, single submitter	1
3062712	GRCh37/hg19 3q26.33-27.2(chr3:179391972-185539073)x1	Pathogenic	criteria provided, single submitter	1
3148910	GRCh37/hg19 3q26.33-29(chr3:179313373-197851444)x3	Pathogenic	criteria provided, single submitter	1
4884741	GRCh37/hg19 3q25.33-29(chr3:159829833-197837049)x3	Pathogenic	criteria provided, single submitter	1
149685	GRCh38/hg38 3q26.32-29(chr3:176168525-198118383)x3	Pathogenic	no assertion criteria provided	1
152257	GRCh38/hg38 3q25.31-29(chr3:156321878-198113452)x3	Pathogenic	no assertion criteria provided	1
153734	GRCh38/hg38 3q26.33-28(chr3:181138664-192512023)x1	Pathogenic	no assertion criteria provided	1
562847	GRCh37/hg19 3q26.33-29(chr3:182539234-197851986)x3	Pathogenic	no assertion criteria provided	1
562848	GRCh37/hg19 3q26.33-28(chr3:182650681-191275809)x1	Pathogenic	no assertion criteria provided	1
814497	GRCh37/hg19 3q26.2-28(chr3:169617690-190593854)x3	Pathogenic	no assertion criteria provided	1
151178	GRCh38/hg38 3q27.1-27.2(chr3:184010704-186288926)x1	Likely pathogenic	no assertion criteria provided	1
153971	GRCh38/hg38 3q26.33-27.3(chr3:182319764-186443121)x1	Likely pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore ABCC5’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 32 predictions of 2,675):

Position(s)	Effect	Δscore	Sites
3:183921402–183921403	acceptor_loss	1.0000	6
3:183925720–183925721	acceptor_gain	1.0000	2
3:183925720–183925721	acceptor_loss	1.0000	4
3:183925733	acceptor_gain	1.0000
3:183927328–183927329	donor_loss	1.0000	5
3:183927444–183927445	acceptor_loss	1.0000	4
3:183928826–183928827	acceptor_loss	1.0000	3
3:183938071	acceptor_gain	1.0000
3:183938078	acceptor_gain	1.0000
3:183942725–183942726	donor_loss	1.0000	5

AlphaMissense

3,794 missense substitutions predicted likely pathogenic (of 9,412 scored), across 974 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D716	8	0.996	0.998
D1354	8	0.996	0.998
D1361	8	0.995	0.998
D978	8	0.994	0.998
D709	8	0.993	0.998
H1386	8	0.993	0.999
D983	8	0.990	0.997
D1103	8	0.990	0.998
D666	8	0.989	0.995
S686	8	0.987	0.999
D283	8	0.985	0.996
D710	8	0.985	0.996
N642	8	0.976	0.999
F434	8	0.974	0.999
H948	8	0.974	0.994
D1289	8	0.973	0.991
F1280	8	0.967	0.993
F326	8	0.958	0.994
D980	8	0.953	0.992
F418	8	0.949	0.995

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Lung Squamous Cell Carcinoma)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

3 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	1.11e-06
Prostate Adenocarcinoma (TCGA)	unfavorable	0.000557
Lung Squamous Cell Carcinoma (validation)	favorable	0.000991

Disease associations

OMIM: gene MIM:605251 | disease phenotypes:

GWAS associations

13 associations:

Study	Trait	p-value
GCST90002402_731	Platelet count	4e-34
GCST90002401_436	Platelet distribution width	2e-21
GCST90002407_61	White blood cell count	9e-19
GCST90002400_168	Plateletcrit	4e-18
GCST90002394_189	Monocyte percentage of white cells	1e-17
GCST90002398_157	Neutrophil count	2e-16
GCST90002381_20	Eosinophil count	1e-14
GCST004603_186	Platelet count	4e-12
GCST90002404_494	Red cell distribution width	1e-11
GCST90002391_42	Mean corpuscular hemoglobin concentration	1e-9
GCST90002380_29	Basophil percentage of white cells	4e-9
GCST002383_1	Anterior chamber depth	8e-9
GCST009379_167	Type 2 diabetes	2e-8

EFO canonical traits (from GWAS)

9 canonical traits:

EFO ID	Trait name
EFO:0004309	platelet count
EFO:0007992	basophil percentage of leukocytes
EFO:0004842	eosinophil count
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0007989	monocyte percentage of leukocytes
EFO:0004833	neutrophil count
EFO:0007985	platelet crit
EFO:0007984	platelet component distribution width
EFO:0009188	Red cell distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2046258 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 94,362 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

3 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL932	DIPYRIDAMOLE	4	52,091
CHEMBL192	SILDENAFIL	4	42,240
CHEMBL285913	TREQUINSIN	2	31

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB clinical annotations

2 annotations by evidence level (1 strongest → 4):

Variant	Association	Level	Drugs	Phenotypes
rs10937158	Toxicity	3	fluorouracil;irinotecan;leucovorin	Colorectal Neoplasms
rs3749438	Toxicity	3	fluorouracil;irinotecan;leucovorin	Colorectal Neoplasms

PharmGKB variants

3 variants:

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2292997	ABCC5	3	2.50	1	fluorouracil;irinotecan;leucovorin
rs3749438	ABCC5	3	3.25	1	fluorouracil;irinotecan;leucovorin
rs10937158	ABCC5	3	3.25	1	fluorouracil;irinotecan;leucovorin

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

15 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs10937158	fluorouracil, irinotecan, leucovorin	Toxicity	Allele T is associated with decreased risk of Diarrhea when treated with fluorouracil, irinotecan and leucovorin in people with Colorectal Neoplasms as compared to genotype CC.	PMID:26352872
rs3749438	fluorouracil, irinotecan, leucovorin	Toxicity	Allele A is associated with increased risk of Diarrhea when treated with fluorouracil, irinotecan and leucovorin in people with Colorectal Neoplasms as compared to genotype GG.	PMID:26352872
rs939338	cisplatin, doxorubicin	Efficacy	Allele G is associated with decreased progression-free survival when treated with cisplatin and doxorubicin in people with Osteosarcoma as compared to allele A.	PMID:25829401
rs1533682	doxorubicin	Metabolism/PK	Genotype TT is associated with increased clearance of doxorubicin in women with Breast Neoplasms as compared to genotypes CC + CT.	PMID:26975227
rs3749442	glyburide	Efficacy	Allele A is associated with increased response to glibenclamide in people with as compared to allele G.	PMID:27403931
rs3749442	cannabidiol	Efficacy	Genotypes AA + AG are associated with decreased response to cannabidiol in people with Epilepsy as compared to genotype GG.	PMID:34464454
rs3749442	cannabidiol	Toxicity	Genotypes AA + AG are associated with increased likelihood of sedation when treated with cannabidiol in people with Epilepsy as compared to genotype GG.	PMID:34464454
rs939338	Antineoplastic And Immunomodulating Agents	Toxicity	Genotype AA is associated with increased severity of Neutropenia, Leukopenia, Thrombocytopenia or Anemia when treated with Antineoplastic And Immunomodulating Agents in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to genotypes AG + GG.	PMID:38269022
rs1132776	Antineoplastic And Immunomodulating Agents	Toxicity	Genotype GG is associated with increased severity of Neutropenia, Leukopenia, Thrombocytopenia or Anemia when treated with Antineoplastic And Immunomodulating Agents in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to genotypes AA + AG.	PMID:38269022
rs3749442	Antineoplastic And Immunomodulating Agents	Toxicity	Genotype AA is associated with increased severity of Neutropenia, Leukopenia, Thrombocytopenia or Anemia when treated with Antineoplastic And Immunomodulating Agents in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to genotypes AG + GG.	PMID:38269022
rs4148575	Antineoplastic And Immunomodulating Agents	Toxicity	Genotype GG is associated with increased severity of Neutropenia, Leukopenia, Thrombocytopenia or Anemia when treated with Antineoplastic And Immunomodulating Agents in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to genotypes AA + AG.	PMID:38269022
rs4148579	Antineoplastic And Immunomodulating Agents	Toxicity	Genotype CC is associated with increased severity of Neutropenia, Leukopenia, Thrombocytopenia or Anemia when treated with Antineoplastic And Immunomodulating Agents in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to genotypes CT + TT.	PMID:38269022
rs4148580	Antineoplastic And Immunomodulating Agents	Toxicity	Genotype CC is associated with increased severity of Neutropenia, Leukopenia, Thrombocytopenia or Anemia when treated with Antineoplastic And Immunomodulating Agents in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma.	PMID:38269022
rs7627754	daunorubicin, doxorubicin	Toxicity	Genotypes AA + AT is associated with decreased likelihood of Cardiotoxicity when treated with daunorubicin or doxorubicin in children with Neoplasms as compared to genotype TT.	PMID:40741000
rs562	irinotecan	Toxicity	Genotype CC is associated with increased likelihood of Drug Toxicity when treated with irinotecan in people with Colorectal Neoplasms as compared to genotypes CT + TT.	PMID:21892003

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — ABCC subfamily

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
compound 2 [PMID: 22380603]	Inhibition	7.19	pKi
sildenafil	Inhibition	5.92	pKi

Binding affinities (BindingDB)

6 measured of 7 human assays (8 total across all organisms); most potent 6 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
5-[4-Ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-benzenesulfonyla mino]-2-hydroxy-benzoic acid	KI	65.3 nM
CHEMBL2047880	KI	75.3 nM
3-(((3-(2-(7-chloroquinoline-2-yl)ethenyl)phenyl)((3-dimethylamino-3-oxopropyl)thio)methyl)thio)propanoic acid	IC50	4000 nM
9,10-Dimethoxy-3-methyl-2-(2,4,6-trimethyl-phenylimino)-2,3,6,7-tetrahydro-pyrimido[6,1-a]isoquinolin-4-one	IC50	10000 nM
SILDENAFIL CITRATE	IC50	20000 nM
dilazep	IC50	20000 nM

ChEMBL bioactivities

3 potent at pChembl≥5 of 7 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.18	Ki	65.3	nM	CHEMBL1338248
7.12	Ki	75.3	nM	CHEMBL2047880
5.92	Ki	1200	nM	SILDENAFIL

PubChem BioAssay actives

3 with measured affinity, of 49 total; 3 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
5-[[4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6H-pyrazolo[4,5-d]pyrimidin-5-yl)phenyl]sulfonylamino]-2-hydroxybenzoic acid	668995: Inhibition of ABCC5 in human erythrocytes assessed as inhibition of ATP-mediated [3H]cGMP uptake in inside-out vesicles after 60 mins by liquid scintillation counting	ki	0.0653	uM
5-[[3-(3-tert-butyl-1-methyl-7-oxo-6H-pyrazolo[4,5-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonylamino]-2-hydroxybenzoic acid	668995: Inhibition of ABCC5 in human erythrocytes assessed as inhibition of ATP-mediated [3H]cGMP uptake in inside-out vesicles after 60 mins by liquid scintillation counting	ki	0.0753	uM
Sildenafil	668995: Inhibition of ABCC5 in human erythrocytes assessed as inhibition of ATP-mediated [3H]cGMP uptake in inside-out vesicles after 60 mins by liquid scintillation counting	ki	1.2000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cisplatin	increases expression, decreases response to substance, affects cotreatment	4
Estradiol	affects cotreatment, decreases expression, increases expression	4
bisphenol A	increases expression, decreases expression	3
Zidovudine	increases export, increases expression	3
afimoxifene	decreases expression, decreases reaction, increases expression	2
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
perfluorooctanoic acid	decreases expression	2
potassium chromate(VI)	increases expression, affects cotreatment, decreases expression	2
chrysin	affects reaction, increases transport, decreases expression	2
5(6)-carboxy-2’,7’-dichlorofluorescein	increases transport, increases uptake, decreases reaction	2
Oxaliplatin	affects response to substance, decreases response to substance	2
Acetaminophen	affects expression, increases expression	2
Benzo(a)pyrene	decreases methylation, increases expression	2
Fluorouracil	decreases reaction, decreases response to substance, increases export	2
Glutathione	increases transport, affects transport, affects reaction	2
Methotrexate	decreases response to substance, decreases expression	2
Thioguanine	decreases reaction, decreases response to substance	2
Valproic Acid	affects expression, increases expression	2
Particulate Matter	increases expression, decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
4’-methoxy-1-naphthylfenoterol	decreases expression	1
FR900359	decreases phosphorylation	1
ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate	decreases expression	1
dicrotophos	increases expression	1
5-fluorouridine	increases export	1
daidzein	decreases reaction, decreases response to substance, increases export	1
naringenin	decreases reaction, decreases response to substance, increases export	1
2’-deoxyuridylic acid	increases export	1
2-butenal	decreases expression	1
hesperetin	increases export, decreases reaction, decreases response to substance	1

ChEMBL screening assays

24 unique, capped per target: 17 functional, 4 admet, 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2049558	Binding	Inhibition of ABCC5 in human erythrocytes assessed as inhibition of ATP-mediated [3H]cGMP uptake in inside-out vesicles at 32 uM after 60 mins by liquid scintillation counting	Novel cGMP efflux inhibitors identified by virtual ligand screening (VLS) and confirmed by experimental studies. — *J Med Chem*
CHEMBL2075979	Functional	TP_TRANSPORTER: uptake in membrane vesicles from MRP5-expressing V79 cells	The multidrug resistance protein 5 functions as an ATP-dependent export pump for cyclic nucleotides. — *J Biol Chem*
CHEMBL3532855	ADMET	Activity at MRP5 in human Colo-357 cells assessed as decrease of drug accumulation after 2 hrs relative to wild type cells	Drug efflux transporter multidrug resistance-associated protein 5 affects sensitivity of pancreatic cancer cell lines to the nucleoside anticancer drug 5-fluorouracil. — *Drug Metab Dispos*

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B5ZZ	C2BBe1 MRP5 KO	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for ABCC5 across ~30M SureChEMBL compounds — explore on Sugi Predict.