ABCC6

Summary

ABCC6 (ATP binding cassette subfamily C member 6, HGNC:57) is a protein-coding gene on chromosome 16p13.11, encoding ATP-binding cassette sub-family C member 6 (O95255). 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). The encoded protein, a member of the MRP subfamily, is involved in multi-drug resistance. Mutations in this gene cause pseudoxanthoma elasticum. Alternatively spliced transcript variants that encode different proteins have been described for this gene.

Source: NCBI Gene 368 — RefSeq curated summary.

At a glance

• Gene–disease (curated): inherited pseudoxanthoma elasticum (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 2,010 total — 147 pathogenic, 138 likely-pathogenic (top 1% of genes corpus-wide)
• Regional missense constraint (gnomAD): 2 of 5 regions constrained (≈7% of expected missense variation)
• GTEx eGene: eQTL in 45 tissues, sQTL in 1 (q < 0.05)
• Phenotypes (HPO): 136
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.92 (unconstrained)
• MANE Select transcript: NM_001171

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:57
Approved symbol	ABCC6
Name	ATP binding cassette subfamily C member 6
Location	16p13.11
Locus type	gene with protein product
Status	Approved
Aliases	MRP6, EST349056, MLP1, URG7
Ensembl gene	ENSG00000091262
Ensembl biotype	protein_coding
OMIM	603234
Entrez	368

Gene structure

Transcript identifiers

Ensembl transcripts: 33 — 24 protein_coding, 7 nonsense_mediated_decay, 2 retained_intron

MANE Select: ENST00000205557

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 1, TSL 3: 1, TSL 5: 4

ENST00000205557, ENST00000456970, ENST00000574094, ENST00000575728, ENST00000576204, ENST00000576683, ENST00000577103, ENST00000622290, ENST00000909083, ENST00000909084, ENST00000909085, ENST00000909086, ENST00000909087, ENST00000909088, ENST00000909089, ENST00000909090, ENST00000909091, ENST00000909092, ENST00000909093, ENST00000909094, ENST00000909095, ENST00000909096, ENST00000909097, ENST00000946282, ENST00000946283, ENST00000946284, ENST00000946285, ENST00001008033, ENST00001008034, ENST00001008035, ENST00001008036, ENST00001096934, ENST00001107712

RefSeq mRNA: 5 — MANE Select: NM_001171 NM_001079528, NM_001171, NM_001351800, NM_001440309, NM_001440310

CCDS: CCDS10568, CCDS58430

Canonical transcript exons

ENST00000205557 — 31 exons

Exon	Start	End
ENSE00000670407	16182412	16182588
ENSE00000670409	16182804	16182930
ENSE00000670437	16221649	16221831
ENSE00001293454	16177452	16177626
ENSE00001318656	16178798	16178965
ENSE00001639528	16162993	16163192
ENSE00001851325	16223399	16223494
ENSE00002649611	16149565	16150241
ENSE00003477682	16150578	16150772
ENSE00003489767	16219554	16219682
ENSE00003498108	16219822	16219947
ENSE00003501018	16198021	16198182
ENSE00003506921	16208728	16208859
ENSE00003510061	16173284	16173404
ENSE00003531168	16187124	16187211
ENSE00003537315	16212185	16212246
ENSE00003555988	16190164	16190367
ENSE00003562953	16159482	16159583
ENSE00003585806	16165623	16165933
ENSE00003592923	16188831	16188974
ENSE00003602896	16175911	16175986
ENSE00003603055	16202001	16202178
ENSE00003618310	16192830	16192922
ENSE00003627359	16203410	16203613
ENSE00003629160	16154873	16155031
ENSE00003632719	16157663	16157809
ENSE00003639087	16154628	16154794
ENSE00003662846	16184959	16185034
ENSE00003669940	16214324	16214449
ENSE00003675149	16169646	16169853
ENSE00003675165	16161438	16161564

Expression profiles

Bgee: expression breadth ubiquitous, 136 present calls, max score 96.89.

Highest expression (Bgee): lobe of liver, liver, duodenum, adult mammalian kidney, body of pancreas.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ABCC6 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 45 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 46 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Nerve Tibial	eqtl	1.7e-109	+1.36	16:16223561:G:A
Muscle Skeletal	eqtl	6.2e-105	+1.10	16:16223561:G:A
Artery Tibial	eqtl	4.8e-79	+1.20	16:16223561:G:A
Thyroid	eqtl	3.2e-65	+1.04	16:16223561:G:A
Artery Aorta	eqtl	4.8e-55	+1.46	16:16223561:G:A
Skin Sun Exposed Lower leg	eqtl	6.1e-45	+0.76	16:16223561:G:A
Heart Atrial Appendage	eqtl	4.7e-40	+0.96	16:16223561:G:A
Lung	eqtl	1.1e-36	+0.45	16:16223561:G:A
Stomach	eqtl	3.8e-36	+0.92	16:16223561:G:A
Esophagus Muscularis	eqtl	5.1e-36	+0.99	16:16223561:G:A
Colon Transverse	eqtl	2.8e-35	+0.47	16:16223561:G:A
Pituitary	eqtl	6.1e-35	+1.01	16:16223561:G:A
Esophagus Gastroesophageal Junction	eqtl	6.6e-35	+1.07	16:16223561:G:A
Prostate	eqtl	1.7e-34	+1.11	16:16223561:G:A
Skin Not Sun Exposed Suprapubic	eqtl	7.9e-34	+0.68	16:16223561:G:A
Adrenal Gland	eqtl	2.5e-26	+0.92	16:16223561:G:A
Ovary	eqtl	5.0e-26	+1.59	16:16223561:G:A
Heart Left Ventricle	eqtl	6.7e-26	+1.12	16:16223561:G:A
Esophagus Mucosa	eqtl	6.3e-22	+0.71	16:16223561:G:A
Colon Sigmoid	eqtl	1.9e-18	+0.67	16:16223561:G:A

Top tissues by expression

showing 100 of 138 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	96.89	gold quality
liver	UBERON:0002107	96.47	gold quality
duodenum	UBERON:0002114	90.91	gold quality
adult mammalian kidney	UBERON:0000082	89.68	gold quality
body of pancreas	UBERON:0001150	87.37	gold quality
kidney	UBERON:0002113	86.55	gold quality
mucosa of transverse colon	UBERON:0004991	85.19	gold quality
cortex of kidney	UBERON:0001225	82.67	gold quality
pancreas	UBERON:0001264	80.68	gold quality
upper lobe of left lung	UBERON:0008952	79.25	gold quality
metanephros cortex	UBERON:0010533	79.22	gold quality
body of stomach	UBERON:0001161	79.11	gold quality
lung	UBERON:0002048	78.66	gold quality
right lung	UBERON:0002167	78.49	gold quality
right adrenal gland cortex	UBERON:0035827	78.08	gold quality
stomach	UBERON:0000945	77.83	gold quality
small intestine	UBERON:0002108	77.80	gold quality
transverse colon	UBERON:0001157	77.41	gold quality
small intestine Peyer’s patch	UBERON:0003454	77.31	gold quality
rectum	UBERON:0001052	77.11	gold quality
monocyte	CL:0000576	76.86	gold quality
leukocyte	CL:0000738	76.80	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	76.78	gold quality
right lobe of thyroid gland	UBERON:0001119	76.67	gold quality
right adrenal gland	UBERON:0001233	76.47	gold quality
thyroid gland	UBERON:0002046	76.11	gold quality
left lobe of thyroid gland	UBERON:0001120	75.84	gold quality
fundus of stomach	UBERON:0001160	75.80	gold quality
gall bladder	UBERON:0002110	75.74	gold quality
right uterine tube	UBERON:0001302	75.31	gold quality
colonic epithelium	UBERON:0000397	75.27	gold quality
granulocyte	CL:0000094	75.15	gold quality
blood	UBERON:0000178	75.08	gold quality
skeletal muscle tissue	UBERON:0001134	75.02	gold quality
intestine	UBERON:0000160	73.37	gold quality
muscle tissue	UBERON:0002385	72.42	gold quality
left adrenal gland	UBERON:0001234	72.40	gold quality
skeletal muscle organ	UBERON:0014892	72.03	gold quality
left adrenal gland cortex	UBERON:0035825	71.95	gold quality
muscle of leg	UBERON:0001383	71.92	gold quality
omental fat pad	UBERON:0010414	71.72	gold quality
adrenal gland	UBERON:0002369	71.46	gold quality
colon	UBERON:0001155	71.44	gold quality
adipose tissue	UBERON:0001013	71.19	gold quality
gastrocnemius	UBERON:0001388	70.84	gold quality
subcutaneous adipose tissue	UBERON:0002190	70.57	gold quality
thoracic mammary gland	UBERON:0005200	70.17	gold quality
apex of heart	UBERON:0002098	69.98	gold quality
saliva-secreting gland	UBERON:0001044	69.57	gold quality
adrenal tissue	UBERON:0018303	68.73	gold quality
right atrium auricular region	UBERON:0006631	68.63	gold quality
bone marrow cell	CL:0002092	68.52	gold quality
prostate gland	UBERON:0002367	68.06	gold quality
bone marrow	UBERON:0002371	68.02	gold quality
islet of Langerhans	UBERON:0000006	67.74	gold quality
minor salivary gland	UBERON:0001830	67.73	gold quality
popliteal artery	UBERON:0002250	67.23	gold quality
tibial artery	UBERON:0007610	67.17	gold quality
hindlimb stylopod muscle	UBERON:0004252	66.83	gold quality
tonsil	UBERON:0002372	65.85	gold quality
material anatomical entity	UBERON:0000465	64.54	gold quality
multicellular organism	UBERON:0000468	64.54	gold quality
anatomical system	UBERON:0000467	64.46	gold quality
left coronary artery	UBERON:0001626	64.15	gold quality
lower esophagus mucosa	UBERON:0035834	63.96	gold quality
sural nerve	UBERON:0015488	63.93	gold quality
vermiform appendix	UBERON:0001154	63.75	gold quality
muscle layer of sigmoid colon	UBERON:0035805	63.47	gold quality
heart	UBERON:0000948	63.23	gold quality
endocervix	UBERON:0000458	62.62	gold quality
spinal cord	UBERON:0002240	62.38	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	62.38	gold quality
fallopian tube	UBERON:0003889	62.35	gold quality
right coronary artery	UBERON:0001625	62.21	gold quality
substantia nigra	UBERON:0002038	61.75	gold quality
descending thoracic aorta	UBERON:0002345	61.42	gold quality
thoracic aorta	UBERON:0001515	61.16	gold quality
ascending aorta	UBERON:0001496	61.02	gold quality
caudate nucleus	UBERON:0001873	60.91	gold quality
hypothalamus	UBERON:0001898	60.67	gold quality
endometrium	UBERON:0001295	60.66	gold quality
mucosa of stomach	UBERON:0001199	60.21	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	60.04	gold quality
Ammon’s horn	UBERON:0001954	59.81	gold quality
amygdala	UBERON:0001876	59.78	gold quality
putamen	UBERON:0001874	59.70	gold quality
temporal lobe	UBERON:0001871	59.64	gold quality
heart left ventricle	UBERON:0002084	59.62	gold quality
lower esophagus	UBERON:0013473	59.46	gold quality
lower esophagus muscularis layer	UBERON:0035833	59.39	gold quality
superior frontal gyrus	UBERON:0002661	59.06	gold quality
spleen	UBERON:0002106	58.83	gold quality
right ovary	UBERON:0002118	58.44	gold quality
stromal cell of endometrium	CL:0002255	58.32	gold quality
uterine cervix	UBERON:0000002	58.10	gold quality
prefrontal cortex	UBERON:0000451	57.99	gold quality
ovary	UBERON:0000992	57.99	gold quality
adenohypophysis	UBERON:0002196	57.96	gold quality
smooth muscle tissue	UBERON:0001135	57.94	gold quality
telencephalon	UBERON:0001893	57.88	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.14

HPA expression

RNA tissue specificity: Tissue enhanced

51 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Liver	tissue	40.3
Kidney	tissue	21.7
Duodenum	tissue	13.9
Salivary gland	tissue	11.3
Small intestine	tissue	8.0
Pancreas	tissue	6.5
Lung	tissue	5.8
Colon	tissue	5.1
Rectum	tissue	5.0
Thyroid gland	tissue	4.7
Adipose tissue	tissue	4.5
Gallbladder	tissue	3.9
Stomach 1	tissue	3.7
Skeletal muscle	tissue	3.6
Parathyroid gland	tissue	2.4
Prostate	tissue	2.1
Breast	tissue	1.7
Epididymis	tissue	1.5
Choroid plexus	tissue	1.5
Cervix	tissue	1.4
Heart muscle	tissue	1.4
Fallopian tube	tissue	1.2
Seminal vesicle	tissue	1.1
Ovary	tissue	1.0
Locus coeruleus	tissue	1.0
Adrenal gland	tissue	1.0
Pituitary gland	tissue	0.8
Retina	tissue	0.8
Appendix	tissue	0.8
Postcentral gyrus	tissue	0.7
Hippocampus	tissue	0.6
Bone marrow	tissue	0.6
Vagina	tissue	0.5
Nucleus accumbens	tissue	0.5
Esophagus	tissue	0.4
Smooth muscle	tissue	0.4
Frontal cortex	tissue	0.4
Caudate putamen	tissue	0.4
Endometrium 1	tissue	0.3
Lymph node	tissue	0.2
Testis	tissue	0.2
Tongue	tissue	0.2
Placenta	tissue	0.2
Spleen	tissue	0.2
Urinary bladder	tissue	0.1
Medulla oblongata	tissue	0.1
Thalamus	tissue	0.1
Superior colliculi	tissue	0.1
Spinal cord	tissue	0.1
Tonsil	tissue	0.1
Olfactory bulb	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 184; highest nTPM — Periaquaductal grey, lateral (1.7), Nucleus tractus solitarii (1.5), Blood vessel (1.4), Cervical spinal cord, central gray (1.3), Dorsal raphe nucleus (1.3).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HNF4A, ID4, NFE2, NR1I3, PLAG1, PLAGL1, SOX2, SP1

miRNA regulators (miRDB)

Targeting ABCC6 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 35 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-548AG	99.77	69.25	1492
HSA-MIR-548AI	99.69	69.24	1494
HSA-MIR-548BA	99.69	69.14	1514
HSA-MIR-570-5P	99.69	69.24	1494
HSA-MIR-5700	99.64	69.88	2280
HSA-MIR-567	99.63	68.57	1219
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-199A-5P	99.51	69.71	1107
HSA-MIR-199B-5P	99.51	69.74	1098
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-3614-5P	99.30	65.25	837
HSA-MIR-625-5P	99.02	68.64	2031
HSA-MIR-181A-2-3P	98.91	67.60	1168
HSA-MIR-887-5P	98.82	65.90	1347
HSA-MIR-5006-5P	98.79	66.92	1246
HSA-MIR-603	98.58	68.28	1603
HSA-MIR-6509-3P	98.32	67.33	1343
HSA-MIR-5088-3P	98.29	66.63	1310
HSA-MIR-5691	98.23	67.02	1335
HSA-MIR-6805-3P	98.23	67.02	1334
HSA-MIR-5007-5P	97.95	64.71	614
HSA-MIR-4665-5P	97.91	67.69	1536
HSA-MIR-676-3P	97.86	65.70	668
HSA-MIR-30C-1-3P	97.80	66.36	1499
HSA-MIR-30C-2-3P	97.80	66.45	1499
HSA-MIR-6788-5P	97.80	66.41	1532

Functional genomics

gnomAD constraint: pLI 1.24e-33, LOEUF 0.917, missense Z 1.03 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000205557 splits into 5 regions with different missense tolerance; 2 are missense-constrained (≈7% 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
16:16,150,136–16,208,816	1601 / 1635.5	0.98	no
16:16,208,817–16,214,449	49 / 85.8	0.57	no
16:16,219,554–16,219,947	17 / 108.1	0.16	yes (p 1.9e-18)
16:16,221,649–16,221,807	66 / 69.5	0.95	no
16:16,221,808–16,223,434	0 / 28.3	0.00	yes (p 1.1e-07)

Literature-anchored findings (GeneRIF, showing 40)

• point mutations in Pseudoxanthoma elasticum (PMID:11439001)
• mutations cause pseudoxanthoma elasticum (PMID:11536079)
• Loss of ATP-dependent transport activity in pseudoxanthoma elasticum-associated mutants of human ABCC6 (MRP6). (PMID:11880368)
• Presence of the R1141X mutation in the ABCC6 gene is associated with a sharply increased risk of premature coronary artery disease (PMID:12176944)
• We suggest that the severity of the Pseudoxanthoma elasticum phenotype is not directly correlated with the level of ABCC6/MRP6 activity. (PMID:12673275)
• A specific founder effect for the R1141X mutation exists in Dutch patients with PXE (pseudoxanthoma elasticum). (PMID:12714611)
• Using linkage analysis and mutation detection techniques, mutations in the ABCC6 gene were recently implicated in the etiology of pseudoxanthoma elasticum. (PMID:12850230)
• Asn15, which is located in the extracellular N-terminal region of human ABCC6, is the only N-glycosylation site in this protein. (PMID:12901863)
• Twenty-three different mutations were identified, among which 11 were new, in Italian patients with pseudoxanthoma elasticum (PMID:15459974)
• first report of missense mutation identification in the ABCC6 gene in Japanese pseudoxanthoma elasticum patients. (PMID:15645653)
• ABCC6 gene mutations is associated with German pseudoxanthoma elasticum patients (PMID:15723264)
• there is a DNA methylation-dependent activator sequence in the ABCC6 promoter (PMID:15760889)
• The widespread tissue distribution of ABCC6 suggests that ABCC6 fulfills multiple functions in different tissues. (PMID:15889270)
• ABCC6 mutations may have roles in Pseudoxanthoma elasticum (PMID:15894595)
• mutations in ABCC6 may have a role in pseudoxanthoma elasticum (PMID:16086317)
• alterations in ABCC6 are not a genetic risk factor for abdominal aortic aneurysm (PMID:16127278)
• Human ABCC6 displays tissue-specific gene expression, which can be modulated by proinflammatory cytokines. (PMID:16374464)
• Finds 16 PXE causing mutations and 11 neutral polymorphisms or sequence variations in particular ABCC6 exons of German patients and their relatives. (PMID:16392638)
• ABCC6 deficiency in Pseudoxanthoma elasticum (PXE) patients induces a persistent imbalance in circulating metabolite(s), which may impair the synthetic abilities of normal elastoblasts or specifically alter elastic fiber assembly. (PMID:16543900)
• 10 novel mutations within the ABCC6 gene are associated with pseudoxanthoma elasticum. (PMID:16835894)
• This suggests ABCC6 gene expression and the first identification of a transcription factor which is relevant to regulation of ABCC6 level in tissues and in some PXE patients. (PMID:17045963)
• heterozygote carriers had changes in dermal elastic fibre organization, morphology & labelling midway between those seen in pseudoxanthoma elasticum & normal skin; having a single mutation in the ABCC6 gene seems enough to modify dermal elastic fibres (PMID:17309461)
• ABCC6 mutations have a role in the pathogenesis of pseudoxanthoma elasticum (PMID:17617515)
• The mechanism underlying retinal dysfunction is unknown but may result from metabolic disturbance leading to retinal toxicity with a possible role of modifying genetic or environmental factors rather than specific ABCC6 mutations. (PMID:17724214)
• ABCC6 genomic rearrangements may have a role in pseudoxanthoma elasticum in French patients (PMID:17823974)
• This study shows elastic fibers like in the lesional skin of patients with a variety of inflammatory skin diseases in the absence of clinical evidence of pseudoxanthoma elasticum; and some of these patients harbor changes in ABCC6. (PMID:17880583)
• Compound heterozygosity for a novel and a recurrent ABCC6 gene mutation in an Italian family with Pseudoxanthoma elasticum. (PMID:18029147)
• ABCC6 is the most important, and probably only, causative gene of pseudoxanthoma elasticum(PXE). In total, 188 different ABCC6 mutations have now been reported in PXE in the literature. (PMID:18253096)
• ABCC6 is unlikely to be a modifier gene for familial Mediterranean fever severity. (PMID:18305351)
• study to illustrate phenotypic overlap consisting of usual, but limited, or atypical manifestations of PXE between heterozygous carriers of single ABCC6 mutation & patients diagnosed with PXE, carriers of homozygous or compound heterozygous mutations (PMID:18347285)
• Expression and localization MRP6 were significantly higher in hepatoid than in control adenocarcinoma (PMID:18439156)
• Study demonstrates that partial duplication of PKD1 and ABCC6 has many consequences: pseudogenes give rise to new transcripts and mediate gene conversion, which results in disease-causing mutations and also serves as a reservoir for sequence variation. (PMID:18791038)
• analysis of GGCX and ABCC6 mutations in a family with pseudoxanthoma elasticum-like phenotypes [case report] (PMID:18800149)
• identified ABCC6 as a target gene for transcriptional induction by PLAG1 and PLAGL1, transcription factors from the PLAG family of cell cycle progression-related DNA-binding proteins (PMID:18850323)
• These data provide a genetic proof of the importance of these domain-domain interactions in the ABCC6 transporter. (PMID:19133228)
• Very recently, the ABCC6 gene on chromosome 16p13.1 was found to be associated with the disease. (PMID:19298904)
• Delineation of the ABCC6 mutation profile in South African PXE patients will be used as a guide for molecular genetic testing in a clinical setting and for genetic counselling. (PMID:19339160)
• novel sequence determinants of liver-specific transcription of the ABCC6 gene with direct relevance for at least some pseudoxanthoma elasticum patients were identified. (PMID:19341707)
• Studies show that individuals homozygous for the c.3775delT mutation in the ABCC6 gene can have a highly variable phenotype. (PMID:19904211)
• The R1141X loss-of-function mutation of the ABCC6 gene is a strong genetic risk factor for coronary artery disease. (PMID:19929409)

Cross-species orthologs

15 orthologs

Organism	Symbol	Gene ID
danio_rerio	abcc2	ENSDARG00000014031
danio_rerio	abcc13	ENSDARG00000062519
mus_musculus	Abcc6	ENSMUSG00000030834
rattus_norvegicus	Abcc6	ENSRNOG00000028781
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), ABCC1 (ENSG00000103222), ABCC3 (ENSG00000108846), ABCC5 (ENSG00000114770), ABCC11 (ENSG00000121270), ABCC10 (ENSG00000124574), ABCC4 (ENSG00000125257), ABCC12 (ENSG00000140798)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1351634) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 13 distinct phenotype terms.

Mouse phenotype (MP)	Records
increased susceptibility to dystrophic cardiac calcinosis	4
calcified skin	3
decreased susceptibility to dystrophic cardiac calcinosis	2
calcinosis	2
calcified artery	2
decreased circulating HDL cholesterol level	1
abnormal kidney vasculature morphology	1
nephrocalcinosis	1
abnormal Bruch membrane morphology	1
increased circulating creatinine level	1
calcified retina	1
abnormal vibrissa follicle morphology	1
abnormal snout skin morphology	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
Bacillus subtilis subsp. subtilis str. 168	P68579	100.0%	Diamond
Bacillus phage SPBc2	P68580	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
Cryptococcus neoformans H99	J9VQH1	42.5%	Diamond
Mycosarcoma maydis	A0A0D1CZ63	41.8%	Diamond
Aspergillus versicolor	P9WEL8	41.0%	Diamond
Candida albicans SC5314	Q5A762	41.0%	Diamond
Aspergillus nidulans FGSC A4	A0A1U8QTJ9	40.6%	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
CEP20	protein-coding	123811
NOMO3	protein-coding	408050
ABCC1	protein-coding	4363
MIR3180-2	ncRNA	100422956
MIR3670-2	ncRNA	100846994
MIR3179-2	ncRNA	100422886
MIR6770-2	ncRNA	102465908
MIR6511A2	ncRNA	102466812
MYH11	protein-coding	4629

Protein

Protein identifiers

ATP-binding cassette sub-family C member 6 — O95255 (reviewed: O95255)

Alternative names: Anthracycline resistance-associated protein, Multi-specific organic anion transporter E, Multidrug resistance-associated protein 6

All UniProt accessions (4): A0A804HJ04, A0A8C8Q0G8, I3L1Z6, O95255

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 glutathione conjugates such as leukotriene-c4 (LTC4) and N-ethylmaleimide S-glutathione (NEM-GS) (in vitro), and an anionic cyclopentapeptide endothelin antagonist, BQ-123. May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier. Does not appear to actively transport drugs outside the cell. Confers low levels of cellular resistance to etoposide, teniposide, anthracyclines and cisplatin. Mediates the release of nucleoside triphosphates, predominantly ATP, into the circulation, where it is rapidly converted into AMP and the mineralization inhibitor inorganic pyrophosphate (PPi) by the ecto-enzyme ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1), therefore playing a role in PPi homeostasis. Inhibits TNF-mediated apoptosis through blocking one or more caspases.

Subcellular location. Basal cell membrane Basolateral cell membrane Endoplasmic reticulum membrane.

Tissue specificity. Expressed in kidney and liver. Very low expression in other tissues. In testis, localized to peritubular myoid cells, Leydig cells, along the basal membrane of Sertoli cells and moderately in the adluminal compartment of the seminiferous tubules.

Post-translational modifications. Glycosylated.

Disease relevance. Pseudoxanthoma elasticum (PXE) [MIM:264800] A multisystem disorder characterized by accumulation of mineralized and fragmented elastic fibers in the skin, vascular walls, and Burch membrane in the eye. Clinically, patients exhibit characteristic lesions of the posterior segment of the eye including peau d’orange, angioid streaks, and choroidal neovascularizations, of the skin including soft, ivory colored papules in a reticular pattern that predominantly affect the neck and large flexor surfaces, and of the cardiovascular system with peripheral and coronary arterial occlusive disease as well as gastrointestinal bleedings. The disease is caused by variants affecting the gene represented in this entry. Homozygous or compound heterozygous ABCC6 mutations have been found in the overwhelming majority of cases. Individuals carrying heterozygous mutations express limited manifestations of the pseudoxanthoma elasticum phenotype. Arterial calcification of infancy, generalized, 2 (GACI2) [MIM:614473] A severe autosomal recessive disorder characterized by calcification of the internal elastic lamina of muscular arteries and stenosis due to myointimal proliferation. The disorder is often fatal within the first 6 months of life because of myocardial ischemia resulting in refractory heart failure. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. LTC4 transport is completely inhibited by 1 mM orthovanadate.

Induction. Induced by HBV x antigen upon hepatitis B viral infection.

Miscellaneous. May function as a half transporter.

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

Isoforms (3)

UniProt ID	Names	Canonical?
O95255-1	1	yes
O95255-2	2, URG7
O95255-3	3, Delta19Delta24

RefSeq proteins (5): NP_001072996, NP_001162, NP_001338729, NP_001427238, NP_001427239 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003439	ABC_transporter-like_ATP-bd	Domain
IPR003593	AAA+_ATPase	Domain
IPR005292	MRP	Family
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
IPR056227	TMD0_ABC	Domain

Pfam: PF00005, PF00664, PF24357

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)

• an S-substituted glutathione(in) + ATP + H2O = an S-substituted glutathione(out) + ADP + phosphate + H(+) (RHEA:19121)
• leukotriene C4(in) + ATP + H2O = leukotriene C4(out) + ADP + phosphate + H(+) (RHEA:38963)

UniProt features (230 total): sequence variant 122, strand 25, helix 25, topological domain 18, transmembrane region 17, sequence conflict 6, domain 4, splice variant 4, turn 2, binding site 2, chain 1, region of interest 1, compositionally biased region 1, modified residue 1, glycosylation site 1

Structure

Experimental structures (PDB)

4 structures by resolution:

PDB	Title	Method	Resolution (Å)
6BZS	Human ABCC6 NBD1 in Apo state	X-RAY DIFFRACTION	2.3
6BZR	Human ABCC6 NBD2 in ADP-bound state	X-RAY DIFFRACTION	2.8
6P7F	Human ABCC6 NBD2 R1459D mutant in Apo state	X-RAY DIFFRACTION	2.85
6NLO	Human ABCC6 NBD1 H812A in Apo state	X-RAY DIFFRACTION	2.85

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95255-F1	81.32	0.29

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transporters, Primary Active Transporters, Predicted membrane proteins, Plasma proteins, Cancer-related genes, Candidate cancer biomarkers, Disease related genes, Potential drug targets, Human disease related genes, Congenital malformations, Congenital malformations of skin

Protein evidence: Evidence at protein level

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

Antibody reliability (HPA): IF supported

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
663–670	ATP
1299–1306	ATP

Post-translational modifications (1)

Type	Positions
Phosphoserine	1286

Glycosylation sites (1)

Type	Positions
N-linked (glcnac…) asparagine	15

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 6; 4 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

6 pathways:

ID	Pathway	Evidence
R-HSA-5690338	Defective ABCC6 causes PXE ⚕	curated
R-HSA-382556	ABC-family protein mediated transport	curated
R-HSA-5619084	ABC transporter disorders ⚕	—
R-HSA-1643685	Disease ⚕	—
R-HSA-5619115	Disorders of transmembrane transporters ⚕	—
R-HSA-382551	Transport of small molecules	—

MSigDB gene sets: 412 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, GNF2_GSTM1, MODULE_418, GNF2_HPN, GOBP_INORGANIC_ANION_TRANSPORT, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOTIDE_TRANSPORT, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_TRANSPORT, KEGG_ABC_TRANSPORTERS, GOBP_RESPONSE_TO_METAL_ION, PATIL_LIVER_CANCER, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_ESTER_TRANSPORT

GO Biological Process (15): visual perception (GO:0007601), response to xenobiotic stimulus (GO:0009410), gene expression (GO:0010467), ATP transport (GO:0015867), inorganic diphosphate transport (GO:0030505), intracellular phosphate ion homeostasis (GO:0030643), response to magnesium ion (GO:0032026), ATP metabolic process (GO:0046034), phosphate ion homeostasis (GO:0055062), calcium ion homeostasis (GO:0055074), transmembrane transport (GO:0055085), leukotriene transport (GO:0071716), inhibition of non-skeletal tissue mineralization (GO:0140928), response to sodium phosphate (GO:1904383), carboxylic acid transport (GO:0046942)

GO Molecular Function (8): ATP binding (GO:0005524), ABC-type glutathione S-conjugate transporter activity (GO:0015431), ATP hydrolysis activity (GO:0016887), ATPase-coupled transmembrane transporter activity (GO:0042626), ABC-type transporter activity (GO:0140359), nucleotide binding (GO:0000166), protein binding (GO:0005515), transmembrane transporter activity (GO:0022857)

GO Cellular Component (6): extracellular region (GO:0005576), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), basal plasma membrane (GO:0009925), basolateral plasma membrane (GO:0016323), membrane (GO:0016020)

Reactome top-level categories

4 top-level categories:

Category	Pathways
Transport of small molecules	1
ABC transporter disorders	1
Disorders of transmembrane transporters	1
Disease	1

GO top-level categories

44 GO namespaces:

Category	Terms
inorganic ion homeostasis	2
ATP-dependent activity	2
cellular anatomical structure	2
plasma membrane region	2
sensory perception of light stimulus	1
response to chemical	1
macromolecule biosynthetic process	1
purine ribonucleotide transport	1
adenine nucleotide transport	1
inorganic anion transport	1
phosphate ion homeostasis	1
intracellular chemical homeostasis	1
response to metal ion	1
nucleoside triphosphate metabolic process	1
purine ribonucleotide metabolic process	1
purine ribonucleoside triphosphate metabolic process	1
monoatomic cation homeostasis	1
transport	1
cellular process	1
icosanoid transport	1
tissue homeostasis	1
response to salt	1
organic acid transport	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
anion binding	1
ABC-type transporter activity	1
sulfur compound transmembrane transporter activity	1
ribonucleoside triphosphate phosphatase 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
binding	1
transporter activity	1
transmembrane transport	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
basal part of cell	1
basal plasma membrane	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 13 of 29 annotations. The rest are phylogenetic / computational / electronic (IEA).

13 experimentally-supported GO terms:

GO term	NS	Evidence
ATP metabolic process	BP	direct assay
ATP transport	BP	direct assay
calcium ion homeostasis	BP	direct assay
gene expression	BP	direct assay
leukotriene transport	BP	direct assay
phosphate ion homeostasis	BP	direct assay
basal plasma membrane	CC	direct assay
basolateral plasma membrane	CC	direct assay
extracellular region	CC	direct assay
plasma membrane	CC	direct assay
ABC-type glutathione S-conjugate transporter activity	MF	direct assay
ATP binding	MF	direct assay
ATPase-coupled transmembrane transporter activity	MF	direct assay

Protein interactions and networks

IntAct

Human interaction partners of ABCC6 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 85 partners by confidence:

Partner	Interaction type	MIscore	Records
PATJ	direct interaction	0.440	9
GRIP1	direct interaction	0.440	5
GRIP2	direct interaction	0.440	5
DLG1	direct interaction	0.440	3
DLG3	direct interaction	0.440	3
FRMPD2	direct interaction	0.440	3
IL16	direct interaction	0.440	3
LNX1	direct interaction	0.440	3
MAGI2	direct interaction	0.440	3
MPDZ	direct interaction	0.440	3
SCRIB	direct interaction	0.440	3
WHRN	direct interaction	0.440	3
APBA1	direct interaction	0.440	2
APBA2	direct interaction	0.440	2
DLG2	direct interaction	0.440	2
DLG4	direct interaction	0.440	2
GRID2IP	direct interaction	0.440	2
LNX2	direct interaction	0.440	2
MAGI1	direct interaction	0.440	2
NHERF4	direct interaction	0.440	2
PDZK1	direct interaction	0.440	2
TJP1	direct interaction	0.440	2
AHNAK	direct interaction	0.440	1
APBA3	direct interaction	0.440	1
ARHGAP21	direct interaction	0.440	1
ARHGEF11	direct interaction	0.440	1
ARHGEF12	direct interaction	0.440	1
CARD11	direct interaction	0.440	1
CASK	direct interaction	0.440	1
DLG5	direct interaction	0.440	1

BioGRID (58 interactions; top human partners by supporting records): HSPA5 (Affinity Capture-MS; 2 records), A1BG (Two-hybrid), A2M (Affinity Capture-MS), ADNP (Affinity Capture-MS), AK2 (Two-hybrid), AKR1A1 (Affinity Capture-MS), ALDH1A1 (Affinity Capture-MS), ALDH1B1 (Affinity Capture-MS), C19orf10 (Affinity Capture-MS), C9orf64 (Affinity Capture-MS), CALR (Affinity Capture-MS), CLTC (Affinity Capture-MS), COPA (Affinity Capture-MS), COPB1 (Affinity Capture-MS), COPS6 (Affinity Capture-MS)

SIGNOR signaling

3 signaling interactions:

A	Effect	B	Mechanism
PLAG1	“up-regulates quantity by expression”	ABCC6	“transcriptional regulation”
PLAGL1	“up-regulates quantity by expression”	ABCC6	“transcriptional regulation”
SOX2	“up-regulates quantity by expression”	ABCC6	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 85 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
Ras activation upon Ca2+ influx through NMDA receptor	5	49.2×	2e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	46.9×	2e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	46.9×	2e-06
Assembly and cell surface presentation of NMDA receptors	10	43.8×	2e-12
Dopamine Neurotransmitter Release Cycle	5	42.8×	3e-06
Long-term potentiation	5	41.0×	3e-06
Neurexins and neuroligins	11	37.3×	1e-12
Protein-protein interactions at synapses	7	32.0×	1e-07

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	11	78.0×	3e-16
protein localization to synapse	6	56.0×	1e-07
receptor clustering	7	53.3×	1e-08
regulation of postsynaptic membrane neurotransmitter receptor levels	7	42.3×	5e-08
cell-cell adhesion	10	12.4×	7e-07
protein-containing complex assembly	8	11.1×	4e-05
regulation of small GTPase mediated signal transduction	5	8.8×	6e-03
chemical synaptic transmission	7	6.6×	3e-03

Disease & clinical

Genetic variants

Variant evidence for ABCC6: 2,010 ClinVar records (285 pathogenic / likely pathogenic); 1 PharmGKB clinical annotation; 5 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

2,010 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	147
Likely pathogenic	138
Uncertain significance	764
Likely benign	663
Benign	58

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 285 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
6559	NM_001171.6(ABCC6):c.3421C>T (p.Arg1141Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	42
6560	NM_001171.6(ABCC6):c.2787+1G>T	Pathogenic	criteria provided, multiple submitters, no conflicts	18
30339	NM_001171.6(ABCC6):c.1552C>T (p.Arg518Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	13
6574	NM_001171.6(ABCC6):c.3736-1G>A	Pathogenic	criteria provided, multiple submitters, no conflicts	11
30337	NM_001171.6(ABCC6):c.2294G>A (p.Arg765Gln)	Pathogenic	criteria provided, multiple submitters, no conflicts	11
372294	NM_001171.6(ABCC6):c.1132C>T (p.Gln378Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	11
6576	NM_001171.6(ABCC6):c.4015C>T (p.Arg1339Cys)	Pathogenic	criteria provided, multiple submitters, no conflicts	10
6564	NM_001171.6(ABCC6):c.3940C>T (p.Arg1314Trp)	Pathogenic	criteria provided, multiple submitters, no conflicts	9
6563	NM_001171.6(ABCC6):c.3775del (p.Trp1259fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	8
6569	NM_001171.6(ABCC6):c.3389C>T (p.Thr1130Met)	Pathogenic	criteria provided, multiple submitters, no conflicts	8
433320	NM_001171.6(ABCC6):c.3662G>A (p.Arg1221His)	Pathogenic	criteria provided, multiple submitters, no conflicts	7
433330	NM_001171.6(ABCC6):c.3774dup (p.Trp1259fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	7
433350	NM_001171.6(ABCC6):c.4104del (p.Asp1368fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	6
433351	NM_001171.6(ABCC6):c.4182del (p.Lys1394fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	6
433401	NM_001171.6(ABCC6):c.3507-1G>A	Pathogenic	criteria provided, multiple submitters, no conflicts	6

Per-variant reference — Sugi Variant

Explore ABCC6’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; 30 predictions of 2,941):

Position(s)	Effect	Δscore	Sites
16:16154626–16154627	donor_loss	1.0000	5
16:16154795–16154796	acceptor_loss	1.0000	5
16:16173303	donor_gain	1.0000
16:16173308	donor_gain	1.0000
16:16173405–16173406	acceptor_loss	1.0000	3
16:16173410–16173412	acceptor_gain	1.0000	3
16:16178966–16178967	acceptor_loss	1.0000	5
16:16178973	acceptor_gain	1.0000
16:16178976	acceptor_gain	1.0000
16:16182410–16182411	donor_loss	1.0000	5

AlphaMissense

1,614 missense substitutions predicted likely pathogenic (of 9,670 scored), across 629 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
D777	8	0.897	0.959
D416	8	0.895	0.932
F568	8	0.894	0.984
D1056	8	0.875	0.939
D784	8	0.871	0.940
F551	8	0.851	0.946
N710	8	0.777	0.932
D778	7	0.869	0.900
F216	7	0.868	0.965
W218	7	0.861	0.967
W971	7	0.844	0.945
F326	7	0.839	0.945
F991	7	0.837	0.947
W701	7	0.832	0.928
W1170	7	0.822	0.968
F1021	7	0.820	0.935
F1140	7	0.818	0.953
F539	7	0.804	0.946
E1427	7	0.791	0.934
F1493	7	0.786	0.898

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Liver Hepatocellular Carcinoma)

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

2 prognostic cancer types:

Cancer	Prognostic	p-value
Uterine Corpus Endometrial Carcinoma (TCGA)	unfavorable	2.79e-05
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	0.000234

Disease associations

OMIM: gene MIM:603234 | disease phenotypes: MIM:177850, MIM:264800, MIM:614473, MIM:125853

GenCC curated gene-disease

4 curated gene-disease records:

Disease	Classification	Inheritance	Records
inherited pseudoxanthoma elasticum	Definitive	Semidominant
autosomal recessive inherited pseudoxanthoma elasticum	Definitive	Autosomal recessive	6
arterial calcification, generalized, of infancy, 2	Definitive	Autosomal recessive	2
arterial calcification of infancy	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

1 validity classifications:

Disease	Classification	Inheritance
inherited pseudoxanthoma elasticum	Definitive	SD

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (8 panels, 7 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

8 panels:

Panel	Rating
DDG2P	green
Familial cerebral small vessel disease	green
Fetal anomalies	green
Generalised arterial calcification in infancy	green
Paediatric disorders	green
Pseudoxanthoma elasticum	green
Retinal disorders	green
Rare genetic inflammatory skin disorders	amber

Mondo (10): pseudoxanthoma elasticum, forme fruste (MONDO:0008333), autosomal recessive inherited pseudoxanthoma elasticum (MONDO:0009925), arterial calcification, generalized, of infancy, 2 (MONDO:0013768), inherited retinal dystrophy (MONDO:0019118), pseudoxanthoma elasticum (inherited or acquired) (MONDO:0024308), congenital alveolar dysplasia due to TBX4 (MONDO:0100097), type 2 diabetes mellitus (MONDO:0005148), cutis laxa (MONDO:0016175), inherited pseudoxanthoma elasticum (MONDO:0100091), arterial calcification of infancy (MONDO:0018870)

Orphanet (4): Generalized arterial calcification of infancy (Orphanet:51608), Pseudoxanthoma elasticum (Orphanet:758), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Cutis laxa (Orphanet:209)

HPO phenotypes

showing 60 of 136 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000121	Nephrocalcinosis
HP:0000218	High palate
HP:0000365	Hearing impairment
HP:0000381	Stapes ankylosis
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000410	Mixed hearing impairment
HP:0000474	Thickened nuchal skin fold
HP:0000488	Retinopathy
HP:0000505	Visual impairment
HP:0000545	Myopia
HP:0000573	Retinal hemorrhage
HP:0000592	Blue sclerae
HP:0000608	Macular degeneration
HP:0000630	Abnormal retinal arterial/arteriolar morphology
HP:0000737	Irritability
HP:0000765	Abnormal thorax morphology
HP:0000766	Abnormal sternum morphology
HP:0000822	Hypertension
HP:0000951	Abnormality of the skin
HP:0000961	Cyanosis
HP:0000969	Edema
HP:0000973	Cutis laxa
HP:0000974	Hyperextensible skin
HP:0000978	Bruising susceptibility
HP:0001012	Multiple lipomas
HP:0001065	Striae distensae
HP:0001102	Angioid streaks
HP:0001250	Seizure
HP:0001297	Stroke
HP:0001342	Cerebral hemorrhage
HP:0001382	Joint hypermobility
HP:0001482	Subcutaneous nodule
HP:0001507	Growth abnormality
HP:0001531	Failure to thrive in infancy
HP:0001541	Ascites
HP:0001561	Polyhydramnios
HP:0001582	Redundant skin
HP:0001634	Mitral valve prolapse
HP:0001635	Congestive heart failure
HP:0001640	Cardiomegaly
HP:0001644	Dilated cardiomyopathy
HP:0001645	Sudden cardiac death
HP:0001650	Aortic valve stenosis
HP:0001653	Mitral regurgitation
HP:0001658	Myocardial infarction
HP:0001677	Coronary artery atherosclerosis
HP:0001681	Angina pectoris
HP:0001698	Pericardial effusion
HP:0001714	Ventricular hypertrophy
HP:0001717	Coronary artery calcification
HP:0001718	Mitral stenosis
HP:0001723	Restrictive cardiomyopathy
HP:0001789	Hydrops fetalis
HP:0001872	Abnormality of thrombocytes
HP:0001920	Renal artery stenosis
HP:0001945	Fever
HP:0002013	Vomiting

GWAS associations

5 associations:

Study	Trait	p-value
GCST90002403_686	Red blood cell count	7e-17
GCST90002384_382	Hemoglobin	3e-15
GCST90002383_212	Hematocrit	6e-14
GCST010083_319	Hemoglobin levels	9e-14
GCST003051_1	Multiple myeloma (survival)	7e-9

EFO canonical traits (from GWAS)

4 canonical traits:

EFO ID	Trait name
EFO:0000638	overall survival
EFO:0004509	hemoglobin measurement
EFO:0004348	hematocrit
EFO:0004305	erythrocyte count

MeSH disease descriptors

5 disease descriptors:

Descriptor	Name	Tree numbers
D003483	Cutis Laxa	C16.320.850.180; C17.300.230; C17.800.827.180
D003924	Diabetes Mellitus, Type 2	C18.452.394.750.149; C19.246.300
D011561	Pseudoxanthoma Elasticum	C14.907.454.530; C15.378.463.515.530; C16.131.831.766; C16.320.850.750; C17.300.766; C17.800.804.766; C17.800.827.750
D058499	Retinal Dystrophies	C11.768.585.658
C537440	Arterial calcification of infancy *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2073661 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB clinical annotations

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

Variant	Association	Level	Drugs	Phenotypes
rs2238472	Toxicity	3	docetaxel;thalidomide	Prostatic Neoplasms

PharmGKB variants

1 variants:

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2238472	ABCC6	3	2.00	1	docetaxel;thalidomide

PharmGKB variant annotations

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

2 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs9940825	cyclophosphamide	Toxicity	Genotype CT is associated with increased likelihood of Mucositis when treated with cyclophosphamide in children with Acute lymphoblastic leukemia or Lymphoma as compared to genotype CC.	PMID:41823204
rs2238472	docetaxel, thalidomide	Toxicity	Allele C is associated with increased risk of toxicity when treated with docetaxel and thalidomide in people with Prostatic Neoplasms as compared to allele T.	PMID:20038957

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — ABCC subfamily

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, affects methylation	6
Cyclosporine	decreases expression	3
Aflatoxin B1	affects expression, decreases expression, increases methylation	3
Docetaxel	affects expression, decreases response to substance, affects response to substance	2
Acetaminophen	decreases expression	2
Benzbromarone	decreases reaction, decreases activity, affects transport	2
Indomethacin	affects transport, decreases reaction, decreases activity	2
Phenobarbital	decreases expression, increases expression	2
Tobacco Smoke Pollution	decreases expression	2
Valproic Acid	decreases expression, increases expression	2
methylmercuric chloride	decreases expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	decreases expression	1
bisphenol A	affects expression	1
fluorexon	affects transport	1
senecionine	decreases expression	1
senkirkine	decreases expression	1
heliotrine	decreases expression	1
trichostatin A	decreases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
diallyl disulfide	decreases expression, increases expression	1
diallyl trisulfide	increases expression	1
N-ethylmaleimide-S-glutathione	affects transport, decreases reaction	1
di-n-butylphosphoric acid	affects expression	1
calcein AM	affects transport, increases reaction	1
belinostat	decreases expression	1
bisphenol S	decreases methylation	1
Rosiglitazone	decreases expression	1

ChEMBL screening assays

10 unique, capped per target: 9 functional, 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2075388	Functional	TP_TRANSPORTER: uptake in membrane vesicles from MRP6-expressing Sf9 cells	Loss of ATP-dependent transport activity in pseudoxanthoma elasticum-associated mutants of human ABCC6 (MRP6). — *J Biol Chem*
CHEMBL4423073	Binding	Inhibition of ABCC6 (unknown origin) expressed in HEK293 cells assessed as increase in doxorubicin efflux at 100 uM after 30 mins by fluorescence assay	The P-glycoprotein inhibitor diltiazem-like 8-(4-chlorophenyl)-5-methyl-8-[(2Z)-pent-2-en-1-yloxy]-8H-[1,2,4]oxadiazolo[3,4-c][1,4]thiazin-3-one inhibits esterase activity and H3 histone acetylation. — *Eur J Med Chem*

Cellosaurus cell lines

4 cell lines: 2 cancer cell line, 1 transformed cell line, 1 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B6A3	C2BBe1 MRP6 KO	Cancer cell line	Male
CVCL_B6AK	HepaRG MRP6 KO	Cancer cell line	Female
CVCL_LN32	HEK293/hABCC6	Transformed cell line	Female
CVCL_Y109	GM04994	Finite cell line	Male

Clinical trials (associated diseases)

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

showing 60 of 227 trials:

NCT	Phase	Status	Title
NCT01955135	Phase 4	COMPLETED	Anesthesia for Retinopathy of Prematurity
NCT07685886	Phase 4	NOT_YET_RECRUITING	MIRACLE-T2D Montelukast Intervention for Renal, Cardiovascular and Eye Health in Type 2 Diabetes
NCT00006163	Phase 4	COMPLETED	Computer-assisted Diabetes Self-management Interventions
NCT00036504	Phase 4	COMPLETED	Efficacy and Safety of Twice-Daily Insulin Lispro Low Mixture Compared to a Once-Daily Long Acting Insulin Comparator in Patients Who Have Been Using One or More Oral Antihyperglycemic Agents Without Insulin
NCT00044460	Phase 4	COMPLETED	Efficacy and Safety In Poorly Controlled Type 2 Diabetics
NCT00095446	Phase 4	COMPLETED	NovoLog Observation Trial in Subjects With Type 1 and Type 2 Diabetes
NCT00101751	Phase 4	COMPLETED	INITIATE Plus (INITiation of Insulin to Reach A1c TargEt) Study
NCT00110370	Phase 4	COMPLETED	Comparing Pre-Mixed Insulin With Insulin Glargine Combined With Rapid-Acting Insulin in Patients With Type 2 Diabetes
NCT00110448	Phase 4	COMPLETED	Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial
NCT00118950	Phase 4	COMPLETED	Effect of Metformin Versus Repaglinide Treatment in Non-Obese Type 2 Diabetic Patients Uncontrolled by Diet
NCT00118963	Phase 4	COMPLETED	Effect of Repaglinide Versus Metformin Treatment in Non-Obese Patients With Type-2-Diabetes
NCT00121966	Phase 4	COMPLETED	South Danish Diabetes Study: Evaluation of the Antidiabetic Treatment of Type 2 Diabetes Mellitus
NCT00123604	Phase 4	COMPLETED	Vascular Effects of Carvedilol Versus Metoprolol in Hypertensive Patients With Type 2 Diabetes
NCT00123643	Phase 4	COMPLETED	Vascular Effects of Rosiglitazone Versus Glyburide in Type 2 Diabetic Patients
NCT00124397	Phase 4	COMPLETED	Atorvastatin and Endothelial Function in Type 2 Diabetes Mellitus (ATTEND-Study)
NCT00129233	Phase 4	COMPLETED	Comparison of Valsartan With Amlodipine in Hypertensive Patients With Glucose Intolerance
NCT00133718	Phase 4	COMPLETED	A 2 Year Trial of Patients With Type 2 Diabetes Focusing on Cardiovascular Diagnostics and Metabolic Control
NCT00135070	Phase 4	TERMINATED	Hospital In-Patient Insulin Study
NCT00141232	Phase 4	COMPLETED	Evaluating Atorvastatin With Omega-3 Fatty Acids in Cardiovascular Risk Reduction in Patients With Type 2 Diabetes
NCT00144144	Phase 4	UNKNOWN	A Study on Ca Blocker Versus AII Antagonists in Hypertension With Type 2 Diabetes
NCT00149331	Phase 4	COMPLETED	The Effects of Two Education Strategies About Insulin on Patient Preferences and Perceptions About Insulin Therapy
NCT00162357	Phase 4	COMPLETED	Post-PCI:Cardiac Imaging in Patients With Diabetes to Detect Coronary Artery Blockages Previously Opened by Angioplasty
NCT00174681	Phase 4	COMPLETED	Tulip Study: Testing the Usefulness of Lantus When Initiated Prematurely In Patients With Type 2 Diabetes
NCT00174824	Phase 4	COMPLETED	Comparison of Insulin Glargine and NPH Human Insulin in Progression of Diabetic Retinopathy in Type 2 Diabetic Patients
NCT00177398	Phase 4	COMPLETED	Effect of Glargine Insulin on Glucose Control in Hospitalized Patients Who Receive Tube Feedings
NCT00179400	Phase 4	COMPLETED	The Role of Acute Combined PPAR Alpha and Gamma Stimulation on Insulin Action in Humans
NCT00184561	Phase 4	COMPLETED	Effectiveness and Safety of Biphasic Insulin Aspart 70/30 in Subjects With Type 2 Diabetes
NCT00184626	Phase 4	COMPLETED	Comparison of Insulin Glargine Versus Biphasic Insulin Aspart 30/70 or Biphasic Insulin Aspart 30/70 in Combination With Metformin in Subjects With Type 2 Diabetes.
NCT00191178	Phase 4	COMPLETED	Effects of Insulin in Perceived Mood Symptoms in Patients With Type 2 Diabetes
NCT00191282	Phase 4	COMPLETED	Hyperglycemia and Cardiovascular Outcomes With Type 2 Diabetes
NCT00191464	Phase 4	COMPLETED	Long-Term Effects of Insulin Plus Metformin Regimens on the Overall and Postprandial Glycemic Control of Patients With Type 2 Diabetes
NCT00192803	Phase 4	UNKNOWN	Non-Insulin Dependent Diabetes Mellitus (NIDDM) and Angiotensin Converting Enzyme 2 (ACE2): Diabetic Patients Treated With Antihypertensive Drugs
NCT00202033	Phase 4	COMPLETED	Impact of Self-Monitoring Blood Glucose Frequency on Glycemic Control in Patients With Type 2 Diabetes
NCT00205660	Phase 4	COMPLETED	Changes in Adiposity, Metabolic Measures From Atypicals to Aripiprazole
NCT00212290	Phase 4	COMPLETED	Insulin Resistance and Central Nervous System (CNS) Function in Type 2 Diabetes
NCT00212303	Phase 4	COMPLETED	Exercise Training in Type 2 Diabetes and Hypertension
NCT00225342	Phase 4	WITHDRAWN	Study Protocol for Rosiglitazone Versus Gliclazide in Diabetics With Angina
NCT00238472	Phase 4	COMPLETED	A Pilot Study to Evaluate the Effects of Nateglinide vs. Glibenclamide on Renal Hemodynamics and Albumin Excretion
NCT00239538	Phase 4	COMPLETED	SMOOTH - Blood Pressure Control in Diabetic/Obese Patients
NCT00240253	Phase 4	COMPLETED	A Study Evaluating the Efficacy and Safety of Adding Symlin® to Lantus® (Insulin Glargine) in Subjects With Type 2 Diabetes
NCT00240422	Phase 4	COMPLETED	Trial to Compare the Effects of Either Telmisartan (40-80 mg PO Once Daily) or Ramipril (5-10 mg PO Once Daily) on Renal Endothelial Dysfunction in Hypertensive Patients With Type 2 Diabetes
NCT00241085	Phase 4	COMPLETED	Effect of Valsartan on Proteinuria in Patients With Hypertension and Diabetes Mellitus
NCT00241605	Phase 4	COMPLETED	AVANDAMET Versus Metformin For Type 2 Diabetes Mellitus
NCT00254085	Phase 4	UNKNOWN	Substitution of First Phase Insulin Response in Patient With Type 2 Diabetes.
NCT00258804	Phase 4	COMPLETED	Insulin Glargine During and After the Period of Fasting in Ramadan
NCT00262548	Phase 4	COMPLETED	C-Reactive Protein (CRP) in Obese Diabetic Women
NCT00264589	Phase 4	COMPLETED	Exercise Training and Cardiovascular Function in Obesity and in Type 2 Diabetes
NCT00264901	Phase 4	COMPLETED	Comparison of Self Adjustment Versus Standard of Care Treatment in Subjects With Type 2 Diabetes
NCT00265746	Phase 4	WITHDRAWN	Prevention of Diabetes Mellitus Development in Women Who Had Already Experienced A Gestational Diabetes
NCT00268645	Phase 4	COMPLETED	Insulin Glargine in Type 2 Diabetes
NCT00272077	Phase 4	COMPLETED	Insulin Glargine in Type 2 Diabetes Mellitus
NCT00272831	Phase 4	COMPLETED	The Use of Cilostazol in Patients With Diabetic Nephropathy
NCT00274274	Phase 4	COMPLETED	Efficacy and Safety of a Fixed or a Flexible Supplementary Insulin Therapy in Type 2 Diabetes
NCT00279201	Phase 4	COMPLETED	The DURABLE Trial: Evaluating the Durability of Starter Insulin Regimens in Patients With Type 2 Diabetes (IOOV)
NCT00282360	Phase 4	COMPLETED	Effect of Metabolic Therapy in Patients With Chronic Ischemic Heart Disease
NCT00282451	Phase 4	COMPLETED	Effect of Biphasic Insulin Compared to Biphasic Insulin Combined With Insulin Aspart, With or Without Metformin in Type 2 Diabetes
NCT00283049	Phase 4	TERMINATED	Insulin Glargine Injection Treatment in Place of Thiazolidinedione (TZD), Sulfonylurea, or Metformin in Triple Agent Therapy for Type 2 Diabetes Mellitus (T2DM) Adult Subjects With Unsatisfactory Control
NCT00283777	Phase 4	COMPLETED	Chromium and Insulin Action
NCT00290394	Phase 4	COMPLETED	Ambulatory Blood Pressure Reduction After Rosiglitazone Treatment In Normotensive Type 2 Diabetic Patients
NCT00296296	Phase 4	COMPLETED	Immunosuppression Impact on the Metabolic Control of Kidney Transplant With Pre-Existing Type 2 Diabetes (DM)