ANKH

Summary

ANKH (ANKH inorganic pyrophosphate transport regulator, HGNC:15492) is a protein-coding gene on chromosome 5p15.2, encoding Mineralization regulator ANKH (Q9HCJ1). Transports adenosine triphosphate (ATP) and possibly other nucleoside triphosphates (NTPs) from cytosol to the extracellular space.

This gene encodes a multipass transmembrane protein that is expressed in joints and other tissues and controls pyrophosphate levels in cultured cells. Progressive ankylosis-mediated control of pyrophosphate levels has been suggested as a possible mechanism regulating tissue calcification and susceptibility to arthritis in higher animals. Mutations in this gene have been associated with autosomal dominant craniometaphyseal dysplasia.

Source: NCBI Gene 56172 — RefSeq curated summary.

At a glance

• Gene–disease (curated): chondrocalcinosis 2 (Definitive, GenCC) — +3 more curated relationships
• GWAS associations: 25
• Clinical variants (ClinVar): 529 total — 11 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 89
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_054027

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15492
Approved symbol	ANKH
Name	ANKH inorganic pyrophosphate transport regulator
Location	5p15.2
Locus type	gene with protein product
Status	Approved
Aliases	HANK, ANK, CPPDD, SLC62A1
Ensembl gene	ENSG00000154122
Ensembl biotype	protein_coding
OMIM	605145
Entrez	56172

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 7 protein_coding, 4 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000284268, ENST00000502585, ENST00000503389, ENST00000503939, ENST00000505140, ENST00000513115, ENST00000515517, ENST00000646501, ENST00000647541, ENST00000887636, ENST00000887637, ENST00000887638, ENST00000887639, ENST00000964374

RefSeq mRNA: 1 — MANE Select: NM_054027 NM_054027

CCDS: CCDS3885

Canonical transcript exons

ENST00000284268 — 12 exons

Exon	Start	End
ENSE00001014139	14716706	14716835
ENSE00001014140	14755861	14755944
ENSE00001014145	14768975	14769191
ENSE00001014146	14758480	14758598
ENSE00001262580	14871352	14871778
ENSE00001323311	14704800	14711310
ENSE00003466281	14745870	14745962
ENSE00003522016	14749172	14749306
ENSE00003523359	14713544	14713667
ENSE00003546082	14741827	14741922
ENSE00003546680	14712874	14712973
ENSE00003603984	14751069	14751239

Expression profiles

Bgee: expression breadth ubiquitous, 273 present calls, max score 99.18.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.7491 / max 217.0966, expressed in 1675 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
60984	8.3643	1553
60983	1.8327	657
60980	1.3911	554
60987	1.2364	398
60985	1.0994	625
60982	0.8930	403
60981	0.6318	330
60986	0.3004	133

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibia	UBERON:0000979	99.18	gold quality
parotid gland	UBERON:0001831	98.36	gold quality
inferior vagus X ganglion	UBERON:0005363	98.05	gold quality
pons	UBERON:0000988	98.04	gold quality
heart right ventricle	UBERON:0002080	97.92	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.77	gold quality
subthalamic nucleus	UBERON:0001906	97.76	gold quality
synovial joint	UBERON:0002217	97.63	gold quality
biceps brachii	UBERON:0001507	97.61	gold quality
superior vestibular nucleus	UBERON:0007227	97.51	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.25	gold quality
trigeminal ganglion	UBERON:0001675	97.12	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.09	gold quality
middle temporal gyrus	UBERON:0002771	97.06	gold quality
trabecular bone tissue	UBERON:0002483	97.05	gold quality
ventral tegmental area	UBERON:0002691	96.99	gold quality
descending thoracic aorta	UBERON:0002345	96.98	gold quality
thoracic aorta	UBERON:0001515	96.82	gold quality
ascending aorta	UBERON:0001496	96.77	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.73	gold quality
lateral nuclear group of thalamus	UBERON:0002736	96.70	gold quality
prefrontal cortex	UBERON:0000451	96.64	gold quality
substantia nigra pars reticulata	UBERON:0001966	96.53	gold quality
apex of heart	UBERON:0002098	96.46	gold quality
spinal cord	UBERON:0002240	96.46	gold quality
right coronary artery	UBERON:0001625	96.40	gold quality
substantia nigra pars compacta	UBERON:0001965	96.37	gold quality
saphenous vein	UBERON:0007318	96.12	gold quality
body of tongue	UBERON:0011876	96.07	gold quality
tendon of biceps brachii	UBERON:0008188	96.01	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	13.17
E-GEOD-99795	no	109.17
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FGF2, TGFB1

miRNA regulators (miRDB)

232 targeting ANKH, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• ANKH is upregulated by androgen in the LNCaP prostate cell line. (PMID:12185249)
• Mutations in ANKH cause chondrocalcinosis (PMID:12297987)
• Autosomal dominant familial calcium pyrophosphate dihydrate deposition disease is caused by mutation in the transmembrane protein ANKH. (PMID:12297989)
• ANKH-OR and ANKH-TR are novel genetic markers that are significantly associated with ankylosing spondylitis. (PMID:12632434)
• ANKH gene is found in patients with familial calcium pyrophosphate deposition disease. (PMID:12707589)
• haplotypes among the 3 families with P5 mutations suggest the mutations arose independently and the evolutionarily conserved P5 position of ANKH may be a hot spot for mutation in families with autosomal-dominant calcium pyrophosphate deposition disease. (PMID:13130483)
• ANKH is not significantly involved in susceptibility to or clinical manifestations of ankylosing spondylitis. (PMID:14558096)
• ANKH is associated with infantile epilepsy in a large family showing complete co-segregation of seizures and chondrocalcinosis. (PMID:15461680)
• Numerous ANKH gene mutations cause familial calcium pyrophosphate dihydrate deposition disease; they enhance ANKH protein activity, elevating extracellular pyrophosphate levels and promoting formation of pyrophosphate crystals. Review. (PMID:15474385)
• ANKH may be a candidate gene affecting bone size and geometry variation, and thus may be relevant for osteoporosis fracture risk. (PMID:15780964)
• Some cases of apparently sporadic chondrocalcinosis are caused by polymorphisms of the ankh gene. (PMID:15818664)
• Data showed significant associations of ANKH gene polymorphisms with body weight and height, limb length. (PMID:16724232)
• ANKH genetic polymorphisms in the area between SNP rs2291943 and rs2288474 are strongly associated with OPG plasma levels. (PMID:17147692)
• mutations in ANKH cause human skeletal disease (PMID:17186460)
• examined whether nine single nucleotide polymorphisms (SNPs) in ANKH-one of the key genetic factors involved in bone mineralization-can be associated with PTH and BGP levels (PMID:17403715)
• Cuff tear arthropathy is associated with variants in ANKH and TNAP that alter extracellular inorganic pyrophosphate concentrations causing calcium crystal deposition. (PMID:17563703)
• These results revealed a novel function of ANKH in the promotion of early erythroid differentiation and that ank/ank mice have lower serum levels of Epo than the normal littermates, and this is the likely cause of microcytosis in these mutant mice. (PMID:17950726)
• The present study examines the possible phenotype-haplotype specificity of the associations in osteoprotegerin and parathyroid hormone gene regions. (PMID:18821330)
• Our results suggested that there is a coordinated interrelationship between 2 key participants of Pi and PPi metabolism, ANKH and PiT-1. (PMID:19369455)
• ANK expression and function in vitro and in vivo are repressed in hypoxic environments and that the effect is regulated by HIF-1. (PMID:19419319)
• Craniometaphyseal dysplasia and chondrocalcinosis cosegregating in a family with an ANKH mutation are reported. (PMID:19449425)
• in a cohort study of candidate genes and BMD, a few modest associations were observed between SNPs in or near ALPL and several bone traits, but no association was observed with ANKH (PMID:19888898)
• The ANKH gene was associated with all four studied obesity-related traits, body mass index (BMI), the waist-hip ratio (WHR), the epidermal growth factor receptor (EGFR), and leptin (P<0.0184), and its effects were modulated by sex. (PMID:20231843)
• Three novel mutations in ANKH in simplex patients with craniometaphyseal dysplasia, are reported. (PMID:20358596)
• Following the degeneration of cartilaginous endplate, the intervertebral disc degeneration worsened and the expression level of ANK decreased in vertebral endplate chondrocytes. (PMID:20646567)
• We describe the first human progressive ankylosis phenotype and our results indicate that ANK influences articular soft tissues commonly involved in degenerative joint disorders. also, we provide the first direct evidence for a role of ANK in the CNS. (PMID:20943778)
• Phe377del mutation in ANK causes impaired osteoblastogenesis and osteoclastogenesis resulting in hypomineralization and a high bone mass phenotype. (PMID:21149338)
• Neither ANKH nor ENPP1 mutations are the cause of chondrocalcinosis in these Slovakian families. (PMID:21811784)
• the relationship between the type of temporomandibular disorders (TMD) and ANKH polymorphisms (PMID:22003394)
• These results confirm data in white Europeans that ANKH is probably not a major determinant of susceptibility to ankylosing spondylitis. (PMID:22089454)
• Two novel 18 and 12 base pair in-frame deletions are the largest ANKH mutations causing craniometaphyseal dysplasia identified to date. (PMID:22150416)
• TNF-activated NF-kappaB promotes inflammation-accelerated vascular calcification by inhibiting ankylosis protein homolog expression and consequent pyrophosphate secretion. (PMID:22437419)
• We report a novel mutation, not previously described, in ANKH exon 1, wherein serine replaces proline, in a case of early-onset severe calcium pyrophosphate disease associated with metabolic abnormalities, with similar findings in the proband’s father (PMID:22647861)
• Analysis of the present CMD family suggested the presence of a maternal mosaicism in an ANKH mutation, and the mother who was mosaic for the ANKH mutation had no apparent clinical or radiological features of CMD. (PMID:23421944)
• The aim of this study was to investigate two mineralization-related genes TNAP and ANKH polymorphisms associated with ankylosing spondylitis (AS) in the North Chinese Han population. (PMID:23612078)
• Exploratory tympanotomy might improve the hearing outcome in patients with this syndrome and therefore surgery has a limited audiometric benefit in general (PMID:23726953)
• expression levels of type II collagen, aggrecan, and ANK in endplate chondrocytes of experimental group were lower than that of control group and phosphorylation level of JNK in the experimental group which was higher than that in the control group (PMID:23769559)
• ANK was concentrated around crystal deposits and correlated with markers of chondrocyte hypertrophy. These findings support a role for ANK in CPPD crystal formation in cartilage. (PMID:24293574)
• This study validates the association between a functional polymorphism in the 5’ UTR of ANKH and Chondrocalcinosis (PMID:24467728)
• Polymorphisms in ALP, ENPP1 and ANKH are important genetic risk factors contributing to Pseudoxanthoma elasticum (PMID:25025693)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ankhb	ENSDARG00000014969
danio_rerio	ankha	ENSDARG00000071724
mus_musculus	Ank	ENSMUSG00000022265
rattus_norvegicus	Ankh	ENSRNOG00000010960

Protein

Protein identifiers

Mineralization regulator ANKH — Q9HCJ1 (reviewed: Q9HCJ1)

Alternative names: ATP carrier protein ANKH, Progressive ankylosis protein homolog

All UniProt accessions (3): Q9HCJ1, A0A2R8Y5E7, D6RGI5

UniProt curated annotations — full annotation on UniProt →

Function. Transports adenosine triphosphate (ATP) and possibly other nucleoside triphosphates (NTPs) from cytosol to the extracellular space. Mainly regulates their levels locally in peripheral tissues while playing a minor systemic role. Prevents abnormal ectopic mineralization of the joints by regulating the extracellular levels of the calcification inhibitor inorganic pyrophosphate (PPi), which originates from the conversion of extracellular NTPs to NMPs and PPis by ENPP1. Regulates the release of the TCA cycle intermediates to the extracellular space, in particular citrate, succinate and malate. Extracellular citrate mostly present in bone tissue is required for osteogenic differentiation of mesenchymal stem cells, stabilization of hydroxyapatite structure and overall bone strength. The transport mechanism remains to be elucidated.

Subcellular location. Cell membrane.

Tissue specificity. Found in osteoblasts from mandibular bone and from iliac bone; not detected in osteoclastic cells.

Disease relevance. Chondrocalcinosis 2 (CCAL2) [MIM:118600] Chondrocalcinosis is a common cause of joint pain and arthritis caused by calcium deposition in articular cartilage and the presence of calcium hypophosphate crystals in synovial fluid, cartilage and periarticular soft tissue. CCAL2 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry. Craniometaphyseal dysplasia, autosomal dominant (CMDD) [MIM:123000] An osteochondrodysplasia characterized by hyperostosis and sclerosis of the craniofacial bones associated with abnormal modeling of the metaphyses. Sclerosis of the skull may lead to asymmetry of the mandible, as well as to cranial nerve compression, that may finally result in hearing loss and facial palsy. The disease is caused by variants affecting the gene represented in this entry. A missense variant of ANKH cosegregates with a complex phenotype according to an autosomal recessive pattern. Affected homozygous individuals from a large consanguinous family show sensorineural and conductive hearing loss, intellectual disability, spinal ankylosis, and periarticular calcification of small joints. Only a mild arthropathy is observed in heterozygous individuals.

Similarity. Belongs to the ANKH family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9HCJ1-1	1	yes
Q9HCJ1-2	2

RefSeq proteins (1): NP_473368* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009887	ANKH	Family

Pfam: PF07260

Catalyzed reactions (Rhea), 2 shown:

• citrate(in) = citrate(out) (RHEA:33183)
• ATP(in) = ATP(out) (RHEA:75687)

UniProt features (33 total): sequence variant 12, topological domain 9, transmembrane region 8, chain 1, region of interest 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HCJ1-F1	84.57	0.44

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5223345	Miscellaneous transport and binding events
R-HSA-382551	Transport of small molecules

MSigDB gene sets: 462 (showing top): GOBP_BEHAVIOR, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOLDRATH_IMMUNE_MEMORY, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_INORGANIC_ANION_TRANSPORT, CHANDRAN_METASTASIS_DN, GOBP_NUCLEOTIDE_TRANSPORT, GOBP_ORGANOPHOSPHATE_ESTER_TRANSPORT, NKX62_Q2, GOBP_BONE_MINERALIZATION, BILD_E2F3_ONCOGENIC_SIGNATURE, MCBRYAN_PUBERTAL_BREAST_3_4WK_UP, INGRAM_SHH_TARGETS_UP, GOMF_NUCLEOBASE_CONTAINING_COMPOUND_TRANSMEMBRANE_TRANSPORTER_ACTIVITY, GOBP_PHOSPHATE_ION_TRANSPORT

GO Biological Process (16): skeletal system development (GO:0001501), locomotory behavior (GO:0007626), gene expression (GO:0010467), bone mineralization (GO:0030282), regulation of bone mineralization (GO:0030500), phosphate ion transmembrane transport (GO:0035435), muscle cell cellular homeostasis (GO:0046716), phosphate ion homeostasis (GO:0055062), calcium ion homeostasis (GO:0055074), transmembrane transport (GO:0055085), diphosphate metabolic process (GO:0071344), cementum mineralization (GO:0071529), inhibition of non-skeletal tissue mineralization (GO:0140928), response to sodium phosphate (GO:1904383), ATP export (GO:1904669), inorganic diphosphate transport (GO:0030505)

GO Molecular Function (3): phosphate transmembrane transporter activity (GO:0005315), ATP transmembrane transporter activity (GO:0005347), obsolete inorganic diphosphate transmembrane transporter activity (GO:0030504)

GO Cellular Component (4): extracellular region (GO:0005576), plasma membrane (GO:0005886), membrane (GO:0016020), outer membrane (GO:0019867)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
inorganic ion homeostasis	2
ATP transport	2
cellular anatomical structure	2
membrane	2
system development	1
behavior	1
macromolecule biosynthetic process	1
ossification	1
biomineral tissue development	1
regulation of ossification	1
bone mineralization	1
regulation of biomineral tissue development	1
phosphate ion transport	1
transmembrane transport	1
cellular homeostasis	1
monoatomic cation homeostasis	1
transport	1
cellular process	1
phosphorus metabolic process	1
oxoacid metabolic process	1
tooth mineralization	1
tissue homeostasis	1
response to salt	1
inorganic anion transport	1
secondary active transmembrane transporter activity	1
adenine nucleotide transmembrane transporter activity	1
purine ribonucleotide transmembrane transporter activity	1
cell periphery	1

Protein interactions and networks

STRING

710 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ANKH	ENPP1	P22413	796
ANKH	ALPL	P05186	713
ANKH	GHR	P10912	666
ANKH	ABCC6	P78420	590
ANKH	IBSP	P21815	582
ANKH	PHOSPHO1	Q8TCT1	526
ANKH	CD274	Q9NZQ7	519
ANKH	FCGR3A	P08637	496
ANKH	MGP	P08493	461
ANKH	TMEM247	A6NEH6	458
ANKH	SPP1	P10451	456
ANKH	LARP7	Q4G0J3	451
ANKH	ZNF532	Q9HCE3	448
ANKH	ATP12A	P54707	442
ANKH	ATP4A	P20648	441

IntAct

8 interactions, top by confidence:

A	B	Type	Score
TRDN	TMEM223	psi-mi:“MI:0914”(association)	0.640
ABCD4	ABCD4	psi-mi:“MI:0914”(association)	0.640
FAM234B	ABCD4	psi-mi:“MI:0914”(association)	0.620
ANKH	FAM234B	psi-mi:“MI:0914”(association)	0.530
RPSA	ANKH	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (132): ANKH (Affinity Capture-RNA), ANKH (Affinity Capture-RNA), ANKH (Proximity Label-MS), ANKH (Proximity Label-MS), ANKH (Proximity Label-MS), ANKH (Proximity Label-MS), SELENBP1 (Affinity Capture-MS), KIAA1467 (Affinity Capture-MS), GAPDHS (Affinity Capture-MS), ENPP4 (Affinity Capture-MS), DUSP14 (Affinity Capture-MS), DSG4 (Affinity Capture-MS), ANKH (Affinity Capture-MS), ANKH (Affinity Capture-MS), ANKH (Negative Genetic)

ESM2 similar proteins: A1C5W7, A1DG37, A1DI95, A2QFJ9, A2X8A7, A2Y8U6, A6S3R7, A6SSM3, A7E7N1, A7EXE6, A7KAM9, A7KAN0, B8AT51, B8BDK8, B9FMX4, E9EFH8, G2WS43, G4N553, I1RE72, P58355, P58366, P58368, P58369, P78746, Q0CL24, Q0JAW2, Q0U103, Q1E8Z0, Q28CE7, Q2HFE0, Q2QNK7, Q2UD74, Q2UMJ2, Q2V4F9, Q4LE88, Q4WH97, Q4WZY1, Q51IZ9, Q5AVT9, Q5AW93

Diamond homologs: P58366, P58367, P58368, P58369, Q9HCJ1, Q9JHZ2

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
FGF2	“up-regulates quantity by expression”	ANKH	“transcriptional regulation”
TGFB1	“up-regulates quantity by expression”	ANKH	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	11
Likely pathogenic	5
Uncertain significance	227
Likely benign	135
Benign	100

Top pathogenic / likely-pathogenic (16)

Variant ID	HGVS	Classification
146802	GRCh38/hg38 5p15.2-15.1(chr5:12572563-17965988)x1	Pathogenic
147752	GRCh38/hg38 5p15.2-15.1(chr5:10212880-16770474)x3	Pathogenic
1807840	GRCh37/hg19 5p15.31-14.3(chr5:8081005-22210970)x1	Pathogenic
2446724	GRCh37/hg19 5p15.2-15.1(chr5:10165922-18156739)x3	Pathogenic
3340533	NM_054027.6(ANKH):c.1261dup (p.Leu421fs)	Pathogenic
5191	NM_054027.6(ANKH):c.1126TTC[1] (p.Phe377del)	Pathogenic
5195	NM_054027.6(ANKH):c.143T>C (p.Met48Thr)	Pathogenic
5197	NM_054027.6(ANKH):c.1465GAG[1] (p.Glu490del)	Pathogenic
5200	NM_054027.6(ANKH):c.1015T>C (p.Cys339Arg)	Pathogenic
5201	NM_054027.6(ANKH):c.1172T>C (p.Leu391Pro)	Pathogenic
5202	NM_054027.6(ANKH):c.1001T>G (p.Leu334Arg)	Pathogenic
2627751	NM_054027.6(ANKH):c.314-2A>T	Likely pathogenic
5192	NM_054027.6(ANKH):c.1165G>A (p.Gly389Arg)	Likely pathogenic
5196	NM_054027.6(ANKH):c.-11C>T	Likely pathogenic
5198	NM_054027.6(ANKH):c.14C>T (p.Pro5Leu)	Likely pathogenic
563040	GRCh37/hg19 5p15.2(chr5:13167440-14733954)x1	Likely pathogenic

SpliceAI

2830 predictions. Top by Δscore:

Variant	Effect	Δscore
5:14712868:TCTCA:T	donor_loss	1.0000
5:14712869:CTCA:C	donor_loss	1.0000
5:14712870:TCA:T	donor_loss	1.0000
5:14712871:CACCT:C	donor_loss	1.0000
5:14712872:A:AT	donor_loss	1.0000
5:14712873:C:CA	donor_loss	1.0000
5:14712969:GCACC:G	acceptor_gain	1.0000
5:14712970:CACC:C	acceptor_gain	1.0000
5:14712970:CACCC:C	acceptor_gain	1.0000
5:14712971:ACC:A	acceptor_gain	1.0000
5:14712971:ACCC:A	acceptor_loss	1.0000
5:14712972:CC:C	acceptor_gain	1.0000
5:14712972:CCC:C	acceptor_gain	1.0000
5:14712973:CC:C	acceptor_gain	1.0000
5:14712973:CCTG:C	acceptor_loss	1.0000
5:14712974:C:CC	acceptor_gain	1.0000
5:14712974:C:T	acceptor_gain	1.0000
5:14712975:T:C	acceptor_loss	1.0000
5:14712977:CAGA:C	acceptor_gain	1.0000
5:14712978:A:T	acceptor_gain	1.0000
5:14712980:A:AC	acceptor_gain	1.0000
5:14712980:A:C	acceptor_gain	1.0000
5:14713530:C:CA	donor_gain	1.0000
5:14713539:CATA:C	donor_loss	1.0000
5:14713540:ATAC:A	donor_loss	1.0000
5:14713541:TACCC:T	donor_loss	1.0000
5:14713542:A:AC	donor_gain	1.0000
5:14713542:A:C	donor_loss	1.0000
5:14713542:AC:A	donor_gain	1.0000
5:14713542:ACC:A	donor_gain	1.0000

AlphaMissense

3226 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:14712924:C:G	G439R	1.000
5:14712924:C:T	G439R	1.000
5:14712928:A:C	F437L	1.000
5:14712928:A:T	F437L	1.000
5:14712930:A:G	F437L	1.000
5:14712941:A:G	L433P	1.000
5:14713600:G:C	S403R	1.000
5:14713600:G:T	S403R	1.000
5:14713602:T:G	S403R	1.000
5:14713610:A:G	L400P	1.000
5:14713610:A:T	L400H	1.000
5:14713637:A:G	L391P	1.000
5:14713643:C:T	G389E	1.000
5:14713644:C:A	G389W	1.000
5:14713644:C:G	G389R	1.000
5:14713644:C:T	G389R	1.000
5:14713658:C:A	R384M	1.000
5:14745876:G:C	F303L	1.000
5:14745876:G:T	F303L	1.000
5:14745878:A:G	F303L	1.000
5:14745911:A:G	W292R	1.000
5:14745911:A:T	W292R	1.000
5:14749209:A:T	V262D	1.000
5:14749227:G:C	P256R	1.000
5:14749227:G:T	P256H	1.000
5:14749232:A:C	S254R	1.000
5:14749232:A:T	S254R	1.000
5:14749234:T:G	S254R	1.000
5:14749263:A:C	L244W	1.000
5:14749273:A:G	W241R	1.000

dbSNP variants (sampled 300 via entrez): RS1000001167 (5:14827426 G>A), RS1000006613 (5:14704935 C>T), RS1000038732 (5:14862287 G>A,T), RS1000109888 (5:14778697 G>A), RS1000111547 (5:14802059 G>A,C), RS1000113870 (5:14864770 C>G), RS1000138106 (5:14738915 G>C), RS1000145098 (5:14868095 A>G), RS1000166637 (5:14843234 G>A,T), RS1000170080 (5:14765476 T>A), RS1000179551 (5:14711655 C>T), RS1000199784 (5:14765252 A>G), RS1000209860 (5:14852209 G>C), RS1000212819 (5:14719075 C>A,T), RS1000218362 (5:14724044 G>A)

Disease associations

OMIM: gene MIM:605145 | disease phenotypes: MIM:123000, MIM:118600, MIM:618825, MIM:601764

GenCC curated gene-disease

Disease	Classification	Inheritance
chondrocalcinosis 2	Definitive	Autosomal dominant
craniometaphyseal dysplasia, autosomal dominant	Definitive	Autosomal dominant
skeletal dysplasia	Moderate	Autosomal dominant
craniometaphyseal dysplasia	Supportive	Autosomal dominant

Mondo (7): craniometaphyseal dysplasia, autosomal dominant (MONDO:0007397), chondrocalcinosis 2 (MONDO:0007319), intellectual developmental disorder, autosomal dominant 63, with macrocephaly (MONDO:0032939), intellectual disability (MONDO:0001071), benign familial infantile epilepsy (MONDO:0017615), skeletal dysplasia (MONDO:0018230), craniometaphyseal dysplasia (MONDO:0015465)

Orphanet (5): Craniometaphyseal dysplasia (Orphanet:1522), Familial calcium pyrophosphate deposition (Orphanet:1416), Rare epilepsy (Orphanet:101998), Self-limited infantile epilepsy (Orphanet:306), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

89 total (30 of 89 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000212	Gingival overgrowth
HP:0000238	Hydrocephalus
HP:0000256	Macrocephaly
HP:0000276	Long face
HP:0000303	Mandibular prognathia
HP:0000316	Hypertelorism
HP:0000337	Broad forehead
HP:0000358	Posteriorly rotated ears
HP:0000360	Tinnitus
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000410	Mixed hearing impairment
HP:0000426	Prominent nasal bridge
HP:0000431	Wide nasal bridge
HP:0000452	Choanal stenosis
HP:0000505	Visual impairment
HP:0000506	Telecanthus
HP:0000577	Exotropia
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000678	Dental crowding
HP:0000680	Delayed eruption of primary teeth
HP:0000689	Dental malocclusion
HP:0000692	Tooth malposition
HP:0000696	Delayed eruption of permanent teeth
HP:0000867	Secondary hyperparathyroidism
HP:0000925	Abnormality of the vertebral column

GWAS associations

25 associations (top):

Study	Trait	p-value
GCST002253_5	Homeostasis model assessment of insulin resistance (dietary factor interaction)	7.000000e-06
GCST002826_15	Urate levels (BMI interaction)	2.000000e-06
GCST003487_2	Response to fenofibrate (total cholesterol levels)	2.000000e-06
GCST006065_16	Glaucoma (primary open-angle)	7.000000e-13
GCST006394_41	Intraocular pressure	1.000000e-12
GCST006395_23	Glaucoma	4.000000e-10
GCST006395_44	Glaucoma	6.000000e-10
GCST006412_45	Intraocular pressure	5.000000e-15
GCST006867_38	Type 2 diabetes	3.000000e-09
GCST006868_3	Type 2 diabetes	4.000000e-09
GCST007515_25	Type 2 diabetes	1.000000e-07
GCST007516_7	Type 2 diabetes (adjusted for BMI)	4.000000e-07
GCST007517_8	Type 2 diabetes	2.000000e-07
GCST007518_12	Type 2 diabetes (adjusted for BMI)	1.000000e-07
GCST009379_270	Type 2 diabetes	2.000000e-11
GCST009379_271	Type 2 diabetes	8.000000e-13
GCST009379_272	Type 2 diabetes	2.000000e-11
GCST009379_273	Type 2 diabetes	2.000000e-08
GCST009379_274	Type 2 diabetes	3.000000e-10
GCST009725_37	Intraocular pressure	3.000000e-12
GCST009726_16	Glaucoma	2.000000e-08
GCST009798_56	Asthma	5.000000e-13
GCST010118_40	Type 2 diabetes	3.000000e-09
GCST010766_2	Type 2 diabetes (time to event)	4.000000e-08
GCST90011770_51	Glaucoma (primary open-angle)	8.000000e-19

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004501	HOMA-IR
EFO:0008111	diet measurement
EFO:0004340	body mass index
EFO:0004531	urate measurement
EFO:0007806	total cholesterol change measurement
EFO:0004695	intraocular pressure measurement
EFO:0004918	age at diagnosis

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C563162	Chondrocalcinosis 2 (supp.)
C565145	Craniometaphyseal Dysplasia, Autosomal Dominant (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — SLC62 Pyrophosphate transporters

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases methylation	8
trichostatin A	affects cotreatment, increases expression	3
Acetaminophen	decreases expression, increases expression	3
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation	3
Estradiol	increases expression, increases reaction	3
entinostat	increases expression, affects cotreatment	2
Panobinostat	increases expression, affects cotreatment	2
Tobacco Smoke Pollution	decreases expression	2
Tretinoin	increases expression, decreases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
triphenyl phosphate	affects expression	1
propionaldehyde	decreases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
sulforaphane	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	increases methylation	1
nickel sulfate	increases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases expression, affects cotreatment	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	decreases methylation	1
NSC 689534	affects binding, decreases expression	1
Dasatinib	increases expression	1
Fulvestrant	decreases methylation	1
Vorinostat	decreases expression	1

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D4FT	HCT116-ANKH-KO-c3	Cancer cell line	Male
CVCL_D4FU	HCT116-ANKH-KO-c7	Cancer cell line	Male
CVCL_D7G3	Ubigene HEK293T ANKH KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT00001754	Not specified	COMPLETED	Study of Skeletal Disorders and Short Stature
NCT02762318	Not specified	TERMINATED	Identification and Characterization of Bone-related Genetic Variants in Families
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT05247645	Not specified	RECRUITING	Data Collection of Patients With Rare Bone Diseases
NCT05876416	Not specified	RECRUITING	Decoding the Genetic Landscape of Skeletal Diseases
NCT05991609	Not specified	ACTIVE_NOT_RECRUITING	Extreme Morphology and Metabolic Health
NCT06002373	Not specified	UNKNOWN	Assessment of Artificial Intelligence for Treatment Decision Recommendation of Adult Skeletal Class III Patients
NCT06529848	Not specified	RECRUITING	Impact of Exercise Training on Ischemia With Non-Obstructive Coronary Arteries (INOCA): The ExINOCA Study
NCT01630460	Not specified	RECRUITING	Genetic and Functional Analysis of Craniometaphyseal Dysplasia (CMD)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)