ANK2

Summary

ANK2 (ankyrin 2, HGNC:493) is a protein-coding gene on chromosome 4q25-q26, encoding Ankyrin-2 (Q01484). Plays an essential role in the localization and membrane stabilization of ion transporters and ion channels in several cell types, including cardiomyocytes, as well as in striated muscle cells. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a member of the ankyrin family of proteins that link the integral membrane proteins to the underlying spectrin-actin cytoskeleton. Ankyrins play key roles in activities such as cell motility, activation, proliferation, contact and the maintenance of specialized membrane domains. Most ankyrins are typically composed of three structural domains: an amino-terminal domain containing multiple ankyrin repeats; a central region with a highly conserved spectrin binding domain; and a carboxy-terminal regulatory domain which is the least conserved and subject to variation. The protein encoded by this gene is required for targeting and stability of Na/Ca exchanger 1 in cardiomyocytes. Mutations in this gene cause long QT syndrome 4 and cardiac arrhythmia syndrome. Multiple transcript variants encoding different isoforms have been described.

Source: NCBI Gene 287 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +6 more curated relationships
• GWAS associations: 12
• Clinical variants (ClinVar): 4,210 total — 45 pathogenic, 40 likely-pathogenic
• Phenotypes (HPO): 16
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001148

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:493
Approved symbol	ANK2
Name	ankyrin 2
Location	4q25-q26
Locus type	gene with protein product
Status	Approved
Aliases	FAP87, CFAP87
Ensembl gene	ENSG00000145362
Ensembl biotype	protein_coding
OMIM	106410
Entrez	287

Gene structure

Transcript identifiers

Ensembl transcripts: 132 — 86 protein_coding, 37 retained_intron, 7 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000264366, ENST00000357077, ENST00000394537, ENST00000502701, ENST00000503271, ENST00000503423, ENST00000504415, ENST00000504454, ENST00000504887, ENST00000505342, ENST00000506344, ENST00000506722, ENST00000508007, ENST00000509550, ENST00000510275, ENST00000512298, ENST00000512999, ENST00000514160, ENST00000514167, ENST00000514246, ENST00000514960, ENST00000515034, ENST00000515644, ENST00000612754, ENST00000634436, ENST00000671704, ENST00000671727, ENST00000671756, ENST00000671762, ENST00000671793, ENST00000671809, ENST00000671825, ENST00000671854, ENST00000671863, ENST00000671882, ENST00000671893, ENST00000671906, ENST00000671951, ENST00000671971, ENST00000672045, ENST00000672068, ENST00000672088, ENST00000672090, ENST00000672177, ENST00000672209, ENST00000672221, ENST00000672240, ENST00000672246, ENST00000672251, ENST00000672312, ENST00000672315, ENST00000672350, ENST00000672356, ENST00000672362, ENST00000672366, ENST00000672402, ENST00000672411, ENST00000672502, ENST00000672684, ENST00000672696, ENST00000672731, ENST00000672759, ENST00000672779, ENST00000672793, ENST00000672830, ENST00000672854, ENST00000672880, ENST00000672915, ENST00000672930, ENST00000672934, ENST00000672955, ENST00000672965, ENST00000672986, ENST00000672990, ENST00000673044, ENST00000673048, ENST00000673109, ENST00000673231, ENST00000673240, ENST00000673255, ENST00000673298, ENST00000673334, ENST00000673353, ENST00000673363, ENST00000673430, ENST00000673453, ENST00000673536, ENST00000673538, ENST00000673546, ENST00000673555, ENST00000673573, ENST00000673778, ENST00000673943, ENST00000681990, ENST00000682049, ENST00000682189, ENST00000682198, ENST00000682211, ENST00000682346, ENST00000682678, ENST00000682900, ENST00000682959, ENST00000683070, ENST00000683089, ENST00000683180, ENST00000683310, ENST00000683354, ENST00000683360, ENST00000683389, ENST00000683464, ENST00000683568, ENST00000683595, ENST00000683662, ENST00000683723, ENST00000683777, ENST00000683826, ENST00000683893, ENST00000683908, ENST00000683972, ENST00000684225, ENST00000684230, ENST00000684378, ENST00000684470, ENST00000684591, ENST00000684653, ENST00000684681, ENST00000684727, ENST00000684730, ENST00000705785, ENST00000908425, ENST00000967538, ENST00000967539

RefSeq mRNA: 73 — MANE Select: NM_001148 NM_001127493, NM_001148, NM_001354225, NM_001354228, NM_001354230, NM_001354231, NM_001354232, NM_001354235, NM_001354236, NM_001354237, NM_001354239, NM_001354240, NM_001354241, NM_001354242, NM_001354243, NM_001354244, NM_001354245, NM_001354246, NM_001354249, NM_001354252, NM_001354253, NM_001354254, NM_001354255, NM_001354256, NM_001354257, NM_001354258, NM_001354260, NM_001354261, NM_001354262, NM_001354264, NM_001354265, NM_001354266, NM_001354267, NM_001354268, NM_001354269, NM_001354270, NM_001354271, NM_001354272, NM_001354273, NM_001354274, NM_001354275, NM_001354276, NM_001354277, NM_001354278, NM_001354279, NM_001354280, NM_001354281, NM_001354282, NM_001386142, NM_001386143, NM_001386144, NM_001386146, NM_001386147, NM_001386148, NM_001386149, NM_001386150, NM_001386151, NM_001386152, NM_001386153, NM_001386154, NM_001386156, NM_001386157, NM_001386158, NM_001386160, NM_001386161, NM_001386162, NM_001386166, NM_001386167, NM_001386174, NM_001386175, NM_001386186, NM_001386187, NM_020977

CCDS: CCDS3702, CCDS43261, CCDS54796, CCDS87250, CCDS93572, CCDS93573, CCDS93574, CCDS93575, CCDS93576, CCDS93577, CCDS93578, CCDS93579, CCDS93580, CCDS93581, CCDS93582, CCDS93583, CCDS93584, CCDS93585, CCDS93586, CCDS93587, CCDS93588, CCDS93589, CCDS93590, CCDS93591, CCDS93592, CCDS93593, CCDS93594, CCDS93595, CCDS93596, CCDS93597, CCDS93598, CCDS93599, CCDS93600

Canonical transcript exons

ENST00000357077 — 46 exons

Exon	Start	End
ENSE00001003852	113353045	113359299
ENSE00001608117	113367566	113367851
ENSE00001640477	113373090	113373173
ENSE00001641185	113369514	113369805
ENSE00001644280	113348276	113348308
ENSE00001677892	113341688	113341916
ENSE00001680003	113331972	113332070
ENSE00001686568	113365039	113365182
ENSE00001695957	113330246	113330470
ENSE00001703836	113373285	113373449
ENSE00001734750	113343017	113343142
ENSE00001757323	113345900	113346022
ENSE00001770853	113333054	113333208
ENSE00002429935	113240485	113240583
ENSE00002443400	113237599	113237622
ENSE00002444664	113278460	113278558
ENSE00002446359	113288388	113288486
ENSE00002448541	113264897	113264995
ENSE00002449934	113258313	113258411
ENSE00002460998	113282675	113282872
ENSE00002466185	113255735	113255932
ENSE00002472969	113287605	113287703
ENSE00002478532	113236987	113237172
ENSE00002480651	113274452	113274649
ENSE00002484226	113277837	113277935
ENSE00002498329	113293440	113293538
ENSE00002502454	113292416	113292514
ENSE00002506406	113258050	113258148
ENSE00002527325	113249764	113249862
ENSE00002531541	113242111	113242209
ENSE00003464198	113360823	113360897
ENSE00003486355	113335846	113336057
ENSE00003486999	113318517	113318620
ENSE00003506631	113174416	113174517
ENSE00003517727	113311255	113311399
ENSE00003519087	113363338	113363469
ENSE00003552016	113339226	113339322
ENSE00003581650	113199011	113199109
ENSE00003588817	113302767	113302839
ENSE00003626097	113350228	113350249
ENSE00003645016	113232161	113232259
ENSE00003662880	113336577	113336781
ENSE00003688183	113317707	113317809
ENSE00003789136	113196368	113196466
ENSE00003841240	113049653	113049812
ENSE00003849642	113381457	113383736

Expression profiles

Bgee: expression breadth ubiquitous, 281 present calls, max score 99.39.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 34.2398 / max 2497.5289, expressed in 1314 samples.

FANTOM5 promoters (48 alternative TSS)

Promoter ID	TPM avg	Samples expressed
49306	10.1636	1117
49319	10.1249	340
49345	3.1261	389
49307	2.0186	687
49329	1.6345	131
49369	1.2703	364
49305	0.8708	238
49331	0.4307	81
49367	0.4298	135
49333	0.4049	141

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
substantia nigra pars compacta	UBERON:0001965	99.39	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.39	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.28	gold quality
Brodmann (1909) area 46	UBERON:0006483	99.21	gold quality
postcentral gyrus	UBERON:0002581	99.18	gold quality
parietal lobe	UBERON:0001872	99.16	gold quality
orbitofrontal cortex	UBERON:0004167	99.16	gold quality
pons	UBERON:0000988	99.00	gold quality
lateral globus pallidus	UBERON:0002476	98.98	gold quality
superior vestibular nucleus	UBERON:0007227	98.96	gold quality
calcaneal tendon	UBERON:0003701	98.90	gold quality
superior frontal gyrus	UBERON:0002661	98.74	gold quality
CA1 field of hippocampus	UBERON:0003881	98.74	gold quality
cranial nerve II	UBERON:0000941	98.71	gold quality
medulla oblongata	UBERON:0001896	98.59	gold quality
corpus callosum	UBERON:0002336	98.59	gold quality
cortical plate	UBERON:0005343	98.56	gold quality
inferior olivary complex	UBERON:0002127	98.45	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	98.36	gold quality
entorhinal cortex	UBERON:0002728	98.20	gold quality
middle temporal gyrus	UBERON:0002771	98.20	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.09	gold quality
ventricular zone	UBERON:0003053	98.07	gold quality
ventral tegmental area	UBERON:0002691	98.02	gold quality
dorsal plus ventral thalamus	UBERON:0001897	97.92	gold quality
cerebellar hemisphere	UBERON:0002245	97.89	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.89	gold quality
cerebellar cortex	UBERON:0002129	97.88	gold quality
subthalamic nucleus	UBERON:0001906	97.68	gold quality
cerebellum	UBERON:0002037	97.63	gold quality

Single-cell (SCXA)

Detected in 15 experiment(s), a significant marker in 12.

Experiment	Marker?	Max mean expression
E-ANND-2	yes	1857.65
E-MTAB-11121	yes	1202.91
E-GEOD-83139	yes	395.63
E-MTAB-8142	yes	96.52
E-MTAB-8060	yes	95.29
E-CURD-88	yes	41.33
E-MTAB-8410	yes	22.10
E-GEOD-81547	yes	19.33
E-GEOD-137537	yes	16.72
E-CURD-46	yes	12.33
E-CURD-114	yes	10.09
E-ENAD-20	no	422.27
E-HCAD-4	no	19.66
E-GEOD-81608	no	14.63
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): KLF1, NKX2-5

miRNA regulators (miRDB)

126 targeting ANK2, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-545-3P	99.95	70.74	2783
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-4493	99.90	66.48	977
HSA-LET-7A-2-3P	99.87	70.53	1921

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• The ankyrin-B C-terminal domain determines activity of ankyrin-B/G chimeras (PMID:11781319)
• Loss-of-function (E1425G) mutation in ankyrin-B (also known as ankyrin 2), a member of a family of versatile membrane adapters, causes dominantly inherited type 4 long-QT cardiac arrhythmia in humans (PMID:12571597)
• Data show that L1-cell adhesion molecule interactions with ankyrinB (but not with ankyrinG) are involved in the initial formation of neurites. (PMID:14657231)
• An amphipathic alpha-helix in the divergent regulatory domain of ankyrin-b interacts with the molecular co-chaperone Hdj1/Hsp40. (PMID:15075330)
• interaction between members of the ankyrin and beta-spectrin families previously established in erythrocytes and axon initial segments also occurs in neonatal cardiomyocytes with ankyrin-B and beta(2)-spectrin (PMID:15262991)
• Quantitative analysis of erythrocyte membrane proteins revealed increase in ankyrin from patients with homozygous and heterozygous forms of beta-thalassemia. (PMID:15310273)
• Genotype-negative LQTS patients with a single ANK2 variant displayed nonexertional syncope, U waves, sinus bradycardia, and extracardiac findings. (PMID:16253912)
• study identified T to A transition mutation at position 4,603 in exon 40 resulting in substitution of arginine for tryptophan at amino acid residue 1,535 in regulatory domain of ankyrin-B; this novel mutation may be a cause of type 4 long QT syndrome (PMID:16864073)
• Six novel mutations–4 in ANK2, 1 in KCNQ1, and 1 in SCN5A–were found in the patients with torsades de pointes. (PMID:17161064)
• role of ankyrin-B-dependent protein interactions in regulating cardiac electrogenesis (PMID:17242276)
• Ankyrin-B has a role in cardiac function, cardiac death and premature senescence (PMID:17940615)
• ANK2 mutations were not found to directly cause long QT syndrome. (PMID:18052691)
• the ankyrin-binding site is located on the cytoplasmic face of the InsP(3) receptor, thus validating the feasibility of in vivo ankyrin-InsP(3) receptor interactions. (PMID:18275062)
• Ankyrin B modulates the function of Na,K-ATPase/inositol 1,4,5-trisphosphate receptor signaling microdomain (PMID:18303017)
• ANK2 is subject to alternative splicing that gives rise to unique polypeptides with diverse roles in cardiac function. (PMID:18782775)
• Exon organization and novel alternative splicing of the human ANK2 gene: implications for cardiac function and human cardiac disease (PMID:18790697)
• dysfunction in AnkB-based trafficking pathways causes abnormal sinoatrial node (SAN) electrical activity and sinus node dysfunction. (PMID:18832177)
• The common genetic variation in the ANK2 gene is modified the physiological variability of the QT interval in the general population. (PMID:20031550)
• This protein has been found differentially expressed in thalami from patients with schizophrenia. (PMID:20471030)
• Data show that DAnk2-binding is critical for beta spectrin function in vivo. (PMID:20573981)
• Reduced ankyrin-B expression or mutations in ankyrin 2 are associated with atrial fibrillation. (PMID:21859974)
• Ankyrin-B protein in heart failure: identification of a new component of metazoan cardioprotection. (PMID:22778271)
• Residues 63-73 of cdB3 is also essential for ankyrin binding. (PMID:22861190)
• Gankyrin plays an essential role in estrogen-driven and GPR30-mediated endometrial carcinoma cell proliferation via the PTEN/PI3K/AKT signaling pathway. (PMID:23142288)
• ankyrin-B linker suppresses activity of the ANK repeat domain through an intramolecular interaction, likely with a groove on the surface of the ANK repeat solenoid, thereby regulating the affinities between ankyrin-B and its binding partners (PMID:23569209)
• the structures of ANK repeats in complex with an inhibitory segment from the C-terminal regulatory domain and with a sodium channel Nav1.2 peptide, are reported. (PMID:25383926)
• The identification and characterization of two functionally distinct ankyrin-B isoforms in heart provide compelling evidence that alternative splicing of the ANK2 gene regulates the fidelity of ankyrin-B interactions with proteins (PMID:26109584)
• Clinical manifestations of ANK2 variants may include QT prolongation and torsades de pointes, often precipitated by strenuous exercise or stress. (PMID:27005929)
• we support classification of Ankyrin-B p.L1622I as a “mild” loss-of-function variant that may confer arrhythmia susceptibility in the context of secondary risk factors including environment, medication, and/or additional genetic variation. (PMID:27298202)
• VariousANK2mutations are associated with a wide range of phenotypes, including aLQTS, especially with ventricular fibrillation, representing “ankyrin-B” syndrome. (PMID:27784853)
• Rare Variants in ANK2 Associated With Various Inherited Arrhythmia Syndromes. (PMID:27818464)
• Report disease-causing ANK2 variant localized to the membrane-binding domain resulting in reduced ankyrin-B expression and abnormal localization in a First Nations population with a high rate of long QT syndrome. (PMID:28196901)
• The authors discovered that the entire 24 ankyrin repeats are inhibited by combinatorial and quasi-independent bindings of multiple disordered segments located in the ankyrin-B/G linkers and tails, suggesting a mechanistic basis for differential regulations of membrane target bindings by ankyrins. (PMID:28841137)
• Disruption of Ankyrin B and Caveolin-1 Interaction Sites Alters Na(+),K(+)-ATPase Membrane Diffusion (PMID:28988699)
• Cell-autonomous adiposity results from increased cell surface GLUT4 due to ankyrin-B deficiency in humans and mice. (PMID:29133412)
• ANK2 functionally interacts with KCNH2 leading to a stronger current suppression and marked aggravation of long QT syndrome in the patient carrying variants in both proteins. (PMID:30929919)
• findings introduce what we believe to be a new pathway for Arrhythmogenic cardiomyopathy, a role of ankyrin-B in cardiac structure and signaling, a molecular link between ankyrin-B and beta-catenin, and evidence for targeted activation of the WNT/beta-catenin pathway as a potential treatment for this disease. (PMID:31264976)
• Gain of axon branching due to giant ankB deficiency/mutation is a candidate cellular mechanism to explain aberrant structural connectivity and penetrant behavioral consequences in mice as well as humans bearing autism spectrum disorder-related ANK2 mutations. (PMID:31285321)
• These novel findings have important implications for understanding the role of AnkB and Cav2.1 in the regulation of neuronal function in health and disease. (PMID:31477143)
• Mechanisms and Alterations of Cardiac Ion Channels Leading to Disease: Role of Ankyrin-B in Cardiac Function. (PMID:32023981)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ank2a	ENSDARG00000009026
mus_musculus	Ank2	ENSMUSG00000032826
rattus_norvegicus	Ank2	ENSRNOG00000011076

Paralogs (3): ANK1 (ENSG00000029534), ANK3 (ENSG00000151150), ASB7 (ENSG00000183475)

Protein

Protein identifiers

Ankyrin-2 — Q01484 (reviewed: Q01484)

Alternative names: Ankyrin-B, Brain ankyrin, Non-erythroid ankyrin

All UniProt accessions (79): A0A087WZU3, A0A0U1RQN6, A0A5F9ZGS5, A0A5F9ZGS7, A0A5F9ZGX3, A0A5F9ZGX8, A0A5F9ZGY1, A0A5F9ZGY3, A0A5F9ZGY4, A0A5F9ZGZ1, A0A5F9ZGZ5, A0A5F9ZH03, A0A5F9ZH10, A0A5F9ZH17, A0A5F9ZH18, A0A5F9ZH19, A0A5F9ZH30, A0A5F9ZH34, A0A5F9ZH35, A0A5F9ZH38, A0A5F9ZH39, A0A5F9ZH58, A0A5F9ZH70, A0A5F9ZH99, A0A5F9ZHA1, A0A5F9ZHC9, A0A5F9ZHD2, A0A5F9ZHE2, A0A5F9ZHE4, A0A5F9ZHF7, A0A5F9ZHG3, A0A5F9ZHJ4, A0A5F9ZHJ6, A0A5F9ZHL3, A0A5F9ZHL5, A0A5F9ZHL9, A0A5F9ZHM6, A0A5F9ZHN0, A0A5F9ZHN5, A0A5F9ZHQ3, A0A5F9ZHQ5, A0A5F9ZHR2, A0A5F9ZHR8, A0A5F9ZHS1, A0A5F9ZHT4, A0A5F9ZHT8, A0A5F9ZHV4, A0A5F9ZHY6, A0A5F9ZI08, A0A5F9ZI15, A0A5F9ZI16, A0A5F9ZI18, A0A5F9ZI30, A0A5F9ZI36, A0A5F9ZI40, A0A5F9ZI41, A0A5F9ZI45, A0A5F9ZI46, A0A5F9ZI53, A0A5F9ZI56, A0A5F9ZI65, A0A5F9ZI69, A0A5F9ZI73, A0A5F9ZI81, A0A5K1VW73, A0A669KB19, A0A669KBJ6, A0A994J7V8, B7Z651, D6RHE1, E9PCH6, E9PHW9, Q01484, H0Y8X8, H0Y8Y2, H0Y931, H0Y933, H0YAG3, I6L894

UniProt curated annotations — full annotation on UniProt →

Function. Plays an essential role in the localization and membrane stabilization of ion transporters and ion channels in several cell types, including cardiomyocytes, as well as in striated muscle cells. In skeletal muscle, required for proper localization of DMD and DCTN4 and for the formation and/or stability of a special subset of microtubules associated with costameres and neuromuscular junctions. In cardiomyocytes, required for coordinate assembly of Na/Ca exchanger, SLC8A1/NCX1, Na/K ATPases ATP1A1 and ATP1A2 and inositol 1,4,5-trisphosphate (InsP3) receptors at sarcoplasmic reticulum/sarcolemma sites. Required for expression and targeting of SPTBN1 in neonatal cardiomyocytes and for the regulation of neonatal cardiomyocyte contraction rate. In the inner segment of rod photoreceptors, required for the coordinated expression of the Na/K ATPase, Na/Ca exchanger and beta-2-spectrin (SPTBN1). Plays a role in endocytosis and intracellular protein transport. Associates with phosphatidylinositol 3-phosphate (PI3P)-positive organelles and binds dynactin to promote long-range motility of cells. Recruits RABGAP1L to (PI3P)-positive early endosomes, where RABGAP1L inactivates RAB22A, and promotes polarized trafficking to the leading edge of the migrating cells. Part of the ANK2/RABGAP1L complex which is required for the polarized recycling of fibronectin receptor ITGA5 ITGB1 to the plasma membrane that enables continuous directional cell migration.

Subunit / interactions. Interacts with RHBG and SPTBN1. Colocalizes with Na/K ATPase, Na/Ca exchanger and SPTBN1. Directly interacts with DMD; this interaction is necessary for DMD localization at the sarcolemma. Interacts with DCTN4; this interaction is required for DCTN4 retention at costameres. Identified in complexes that contain VIM, EZR, AHNAK, BFSP1, BFSP2, ANK2, PLEC, PRX and spectrin. Interacts (via death domain) with RABGAP1L (via Rab-GAP TBC domain).

Subcellular location. Cytoplasm. Cytoskeleton. Membrane. Myofibril. Sarcomere. M line. Apical cell membrane. Cell membrane. Postsynaptic cell membrane. Early endosome. Recycling endosome. Lysosome. Mitochondrion. Z line. Sarcolemma. T-tubule.

Tissue specificity. Present in plasma membrane of neurons as well as glial cells throughout the brain. Expressed in fetal brain and in temporal cortex of adult brain. Also expressed in the inner segments of rod photoreceptors in retina.

Post-translational modifications. Phosphorylated at multiple sites by different protein kinases and each phosphorylation event regulates the protein’s structure and function.

Disease relevance. Long QT syndrome 4 (LQT4) [MIM:600919] A heart disorder characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias. They cause syncope and sudden death in response to exercise or emotional stress, and can present with a sentinel event of sudden cardiac death in infancy. Long QT syndrome type 4 shows many atypical features compared to classical long QT syndromes, including pronounced sinus bradycardia, polyphasic T waves and atrial fibrillation. Cardiac repolarization defects may be not as severe as in classical LQT syndromes and prolonged QT interval on EKG is not a consistent feature. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The tandem configuration of the two ZU5 and the UPA domains forms a structural supramodule termed ZZU. ZU5-1 mediates interaction with beta-spectrin, and the ZU5-1/UPA interface is required for ankyrin’s function other than binding to spectrin.

Isoforms (4)

UniProt ID	Names	Canonical?
Q01484-4	3	yes
Q01484-2	2
Q01484-5	4
Q01484-7	5

RefSeq proteins (73): NP_001120965, NP_001139, NP_001341154, NP_001341157, NP_001341159, NP_001341160, NP_001341161, NP_001341164, NP_001341165, NP_001341166, NP_001341168, NP_001341169, NP_001341170, NP_001341171, NP_001341172, NP_001341173, NP_001341174, NP_001341175, NP_001341178, NP_001341181, NP_001341182, NP_001341183, NP_001341184, NP_001341185, NP_001341186, NP_001341187, NP_001341189, NP_001341190, NP_001341191, NP_001341193, NP_001341194, NP_001341195, NP_001341196, NP_001341197, NP_001341198, NP_001341199, NP_001341200, NP_001341201, NP_001341202, NP_001341203, NP_001341204, NP_001341205, NP_001341206, NP_001341207, NP_001341208, NP_001341209, NP_001341210, NP_001341211, NP_001373071, NP_001373072, NP_001373073, NP_001373075, NP_001373076, NP_001373077, NP_001373078, NP_001373079, NP_001373080, NP_001373081, NP_001373082, NP_001373083, NP_001373085, NP_001373086, NP_001373087, NP_001373089, NP_001373090, NP_001373091, NP_001373095, NP_001373096, NP_001373103, NP_001373104, NP_001373115, NP_001373116, NP_066187 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000488	Death_dom	Domain
IPR000906	ZU5_dom	Domain
IPR002110	Ankyrin_rpt	Repeat
IPR011029	DEATH-like_dom_sf	Homologous_superfamily
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR040745	Ankyrin_UPA	Domain
IPR051165	Multifunctional_ANK_Repeat	Family

Pfam: PF00023, PF00531, PF00791, PF12796, PF13637, PF17809

UniProt features (289 total): helix 71, modified residue 50, strand 40, repeat 39, compositionally biased region 35, region of interest 16, sequence variant 11, sequence conflict 9, splice variant 5, turn 5, domain 4, mutagenesis site 3, chain 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
6KZJ	X-RAY DIFFRACTION	1.5
5Y4F	X-RAY DIFFRACTION	1.95
8ZE8	X-RAY DIFFRACTION	2.07
5YIS	X-RAY DIFFRACTION	2.2
4D8O	X-RAY DIFFRACTION	2.2
5Y4E	X-RAY DIFFRACTION	2.34
4RLY	X-RAY DIFFRACTION	2.5
5YIR	X-RAY DIFFRACTION	2.75
5Y4D	X-RAY DIFFRACTION	3.3
6M3Q	X-RAY DIFFRACTION	3.44
4RLV	X-RAY DIFFRACTION	3.49

Predicted structure (AlphaFold)

No AlphaFold model available for Q01484 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Functional residue map

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

Post-translational modifications (50): 853, 874, 1382, 1459, 1461, 1473, 1500, 1596, 1732, 1733, 1736, 1855, 1858, 1929, 2127, 2239, 2243, 2269, 2275, 2405 …

Mutagenesis-validated functional residues (3):

Position	Phenotype
975–977	prevents binding to sptbn1.
1000	prevents binding to sptbn1.
1100–1103	weak binding to sptbn1.

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-445095	Interaction between L1 and Ankyrins
R-HSA-6807878	COPI-mediated anterograde transport
R-HSA-1266738	Developmental Biology
R-HSA-199977	ER to Golgi Anterograde Transport
R-HSA-199991	Membrane Trafficking
R-HSA-373760	L1CAM interactions
R-HSA-392499	Metabolism of proteins
R-HSA-422475	Axon guidance
R-HSA-446203	Asparagine N-linked glycosylation
R-HSA-5653656	Vesicle-mediated transport
R-HSA-597592	Post-translational protein modification
R-HSA-948021	Transport to the Golgi and subsequent modification
R-HSA-9675108	Nervous system development

MSigDB gene sets: 419 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_POTASSIUM_ION_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_CALCIUM_ION_TRANSPORT, GNF2_RTN1, chr4q25, GOBP_MEMBRANE_DEPOLARIZATION, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, GOBP_CIRCULATORY_SYSTEM_PROCESS, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GCANCTGNY_MYOD_Q6, GOBP_MEMBRANE_DEPOLARIZATION_DURING_ACTION_POTENTIAL, GOBP_PLASMA_MEMBRANE_ORGANIZATION, GTTAAAG_MIR302B, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING

GO Biological Process (40): regulation of heart rate (GO:0002027), atrial septum development (GO:0003283), intracellular calcium ion homeostasis (GO:0006874), endocytosis (GO:0006897), intracellular protein localization (GO:0008104), positive regulation of gene expression (GO:0010628), regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion (GO:0010881), regulation of cardiac muscle contraction by calcium ion signaling (GO:0010882), protein transport (GO:0015031), paranodal junction assembly (GO:0030913), regulation of protein stability (GO:0031647), T-tubule organization (GO:0033292), protein localization to cell surface (GO:0034394), protein localization to M-band (GO:0036309), protein localization to T-tubule (GO:0036371), protein stabilization (GO:0050821), regulation of release of sequestered calcium ion into cytosol (GO:0051279), response to methylmercury (GO:0051597), regulation of calcium ion transport (GO:0051924), positive regulation of calcium ion transport (GO:0051928), regulation of cardiac muscle contraction (GO:0055117), regulation of ventricular cardiac muscle cell membrane repolarization (GO:0060307), sarcoplasmic reticulum calcium ion transport (GO:0070296), protein localization to endoplasmic reticulum (GO:0070972), protein localization to plasma membrane (GO:0072659), regulation of cardiac muscle cell contraction (GO:0086004), ventricular cardiac muscle cell action potential (GO:0086005), atrial cardiac muscle cell action potential (GO:0086014), SA node cell action potential (GO:0086015), membrane depolarization during SA node cell action potential (GO:0086046), atrial cardiac muscle cell to AV node cell communication (GO:0086066), SA node cell to atrial cardiac muscle cell communication (GO:0086070), regulation of heart rate by cardiac conduction (GO:0086091), regulation of SA node cell action potential (GO:0098907), regulation of atrial cardiac muscle cell action potential (GO:0098910), positive regulation of potassium ion import across plasma membrane (GO:1903288), cytoskeleton organization (GO:0007010), signal transduction (GO:0007165), nervous system development (GO:0007399), Golgi vesicle transport (GO:0048193)

GO Molecular Function (12): structural constituent of cytoskeleton (GO:0005200), cytoskeletal adaptor activity (GO:0008093), enzyme binding (GO:0019899), protein kinase binding (GO:0019901), spectrin binding (GO:0030507), protein-macromolecule adaptor activity (GO:0030674), transmembrane transporter binding (GO:0044325), ATPase binding (GO:0051117), channel activator activity (GO:0099103), potassium channel activator activity (GO:0099104), phosphorylation-dependent protein binding (GO:0140031), protein binding (GO:0005515)

GO Cellular Component (23): mitochondrion (GO:0005739), lysosome (GO:0005764), early endosome (GO:0005769), cytosol (GO:0005829), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), intercalated disc (GO:0014704), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324), Z disc (GO:0030018), T-tubule (GO:0030315), M band (GO:0031430), A band (GO:0031672), sarcolemma (GO:0042383), neuron projection (GO:0043005), costamere (GO:0043034), postsynaptic membrane (GO:0045211), recycling endosome (GO:0055037), cytoplasm (GO:0005737), endosome (GO:0005768), membrane (GO:0016020), organelle (GO:0043226), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
L1CAM interactions	1
ER to Golgi Anterograde Transport	1
Membrane Trafficking	1
Transport to the Golgi and subsequent modification	1
Vesicle-mediated transport	1
Axon guidance	1
Nervous system development	1
Post-translational protein modification	1
Metabolism of proteins	1
Asparagine N-linked glycosylation	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	7
protein binding	3
regulation of biological quality	2
intracellular protein localization	2
calcium ion transport	2
cytoskeletal protein binding	2
cytoplasm	2
endosome	2
plasma membrane region	2
regulation of heart contraction	1
cardiac atrium development	1
cardiac septum development	1
intracellular monoatomic cation homeostasis	1
calcium ion homeostasis	1
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
macromolecule localization	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1
regulation of cardiac muscle contraction by calcium ion signaling	1
calcium-mediated signaling	1
regulation of cardiac muscle contraction	1
cardiac muscle contraction	1
transport	1
establishment of protein localization	1
cell-cell junction assembly	1
cellular component assembly involved in morphogenesis	1
myelin assembly	1
plasma membrane organization	1
muscle cell development	1
membrane organization	1
protein localization to organelle	1
protein localization to plasma membrane	1
regulation of protein stability	1
release of sequestered calcium ion into cytosol	1
regulation of calcium ion transmembrane transport	1

Protein interactions and networks

STRING

6016 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ANK2	EPB41	P11171	996
ANK2	SPTBN1	Q01082	991
ANK2	SPTAN1	Q13813	990
ANK2	ADD1	P35611	988
ANK2	ADD3	Q9UEY8	986
ANK2	L1CAM	P32004	980
ANK2	ADD2	P35612	977
ANK2	ITPR3	Q14573	952
ANK2	OBSCN	Q5VST9	944
ANK2	TTN	Q8WZ42	932
ANK2	NFASC	O94856	920
ANK2	SLC4A1	P02730	909
ANK2	SKP1	P34991	889
ANK2	MAML1	Q92585	868
ANK2	RBPJ	Q06330	865

IntAct

94 interactions, top by confidence:

A	B	Type	Score
MAPK8IP1	MAPK8	psi-mi:“MI:0914”(association)	0.770
GABARAPL2	IPO5	psi-mi:“MI:0914”(association)	0.690
HIF1AN	GMDS	psi-mi:“MI:0914”(association)	0.640
KCNJ11	ANK2	psi-mi:“MI:0407”(direct interaction)	0.590
KCNJ11	ANK2	psi-mi:“MI:0915”(physical association)	0.590
KCNJ11	ANK2	psi-mi:“MI:0914”(association)	0.590
ANK2	RRBP1	psi-mi:“MI:0915”(physical association)	0.560
NUFIP1	PDE2A	psi-mi:“MI:0914”(association)	0.530
CHL1	LGALS1	psi-mi:“MI:0914”(association)	0.530
ANK2	EHD3	psi-mi:“MI:0915”(physical association)	0.510
ANK2	ACOT7	psi-mi:“MI:0914”(association)	0.500
ACOT7	ANK2	psi-mi:“MI:0915”(physical association)	0.500
ANK2	DYNC1H1	psi-mi:“MI:0915”(physical association)	0.500
CEP120	ANK2	psi-mi:“MI:0915”(physical association)	0.470
ANK2	EPS15	psi-mi:“MI:0407”(direct interaction)	0.440
ANK2	EHD1	psi-mi:“MI:0915”(physical association)	0.400
EHD2	ANK2	psi-mi:“MI:0915”(physical association)	0.400
ANK2	EHD4	psi-mi:“MI:0915”(physical association)	0.400
GRB2	ANK2	psi-mi:“MI:0915”(physical association)	0.400
NCK1	ANK2	psi-mi:“MI:0915”(physical association)	0.400
ANK2	H1-2	psi-mi:“MI:0915”(physical association)	0.400
ANK2	DMD	psi-mi:“MI:0915”(physical association)	0.400
DCTN4	ANK2	psi-mi:“MI:0915”(physical association)	0.400
DMD	ANK2	psi-mi:“MI:0915”(physical association)	0.400
ANK2	CTNNB1	psi-mi:“MI:0915”(physical association)	0.400
ANK2	CVC2	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (313): ANK2 (Affinity Capture-MS), ANK2 (Affinity Capture-MS), ANK2 (Affinity Capture-MS), ANK2 (Affinity Capture-MS), ANK2 (Affinity Capture-MS), ANK2 (Affinity Capture-MS), ANK2 (Affinity Capture-MS), ANK2 (Affinity Capture-MS), ANK2 (Affinity Capture-MS), CEP120 (Affinity Capture-Western), ANK2 (Proximity Label-MS), ANK2 (Affinity Capture-MS), ANK2 (Affinity Capture-MS), ANK2 (Affinity Capture-MS), ANK2 (Affinity Capture-MS)

ESM2 similar proteins: A0PJZ0, A6NGH8, A7E2S9, B2RR83, B7U179, B9DHT4, C7B178, D3J162, D3J163, F4IDQ6, G5E8K5, O22161, O44997, O70511, P16157, P53355, Q01484, Q02357, Q05921, Q08E43, Q12955, Q3EC11, Q4R3S3, Q4R544, Q52T38, Q5R6D7, Q5RCK5, Q5TYM7, Q5VYY1, Q60772, Q641X1, Q7T163, Q80YE7, Q8C8R3, Q91ZT9, Q91ZU0, Q92527, Q94B55, Q9BGT9, Q9CQM6

Diamond homologs: G5E8K5, O70511, P16157, Q01484, Q02357, Q12955, Q8C8R3, Q8IV45

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
OBSCN	“up-regulates quantity”	ANK2	relocalization
ANK2	“up-regulates quantity”	PPP2R5A	relocalization
ANK2	“up-regulates quantity”	CACNA1A	binding
ANK2	“up-regulates quantity”	CACNA1B	binding
ANK2	“up-regulates quantity”	DMD	relocalization
ANK2	“up-regulates quantity”	DCTN4	relocalization
NFASC	“up-regulates quantity”	ANK2	relocalization
NRCAM	“up-regulates quantity”	ANK2	relocalization
CHL1	“up-regulates quantity”	ANK2	relocalization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 98 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.

GO biological processes:

GO term	Partners	Fold	FDR
cellular response to cAMP	6	19.8×	3e-04
learning or memory	6	16.4×	6e-04
mitotic spindle organization	5	15.4×	4e-03
endocytic recycling	5	15.2×	4e-03
endocytosis	10	10.8×	3e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

4210 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	45
Likely pathogenic	40
Uncertain significance	2179
Likely benign	1298
Benign	138

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1208780	NM_001148.6(ANK2):c.10367dup (p.Thr3457fs)	Pathogenic
1342783	NM_001148.6(ANK2):c.10367del (p.Gly3456fs)	Pathogenic
1483377	NM_001148.6(ANK2):c.10480_10481dup (p.Gln3494fs)	Pathogenic
1729746	NM_001148.6(ANK2):c.3281dup (p.Val1095fs)	Pathogenic
2029441	NM_001148.6(ANK2):c.9817del (p.Ser3273fs)	Pathogenic
2228433	NM_001148.6(ANK2):c.11437C>T (p.Gln3813Ter)	Pathogenic
2430081	NM_001148.6(ANK2):c.9184G>T (p.Glu3062Ter)	Pathogenic
2506786	NM_001148.6(ANK2):c.1036G>T (p.Glu346Ter)	Pathogenic
2544521	NM_001148.6(ANK2):c.2282_2289del (p.Gly761fs)	Pathogenic
2565317	NM_001148.6(ANK2):c.11760_11761delinsTT (p.Gln3921Ter)	Pathogenic
2575852	NM_001148.6(ANK2):c.2954_2955del (p.Arg985fs)	Pathogenic
2576605	NM_001148.6(ANK2):c.3262C>T (p.Arg1088Ter)	Pathogenic
2861152	NM_001148.6(ANK2):c.9162del (p.Phe3055fs)	Pathogenic
3068471	NM_001148.6(ANK2):c.10768G>T (p.Glu3590Ter)	Pathogenic
3119609	NM_001148.6(ANK2):c.9115del (p.Asp3039fs)	Pathogenic
3338732	NM_001148.6(ANK2):c.4279C>T (p.Arg1427Ter)	Pathogenic
3340753	NM_001148.6(ANK2):c.4248+1G>T	Pathogenic
3376711	NM_001148.6(ANK2):c.5635_5638del (p.Ser1879fs)	Pathogenic
3376712	NM_001148.6(ANK2):c.3913C>T (p.Arg1305Ter)	Pathogenic
3376713	NM_001148.6(ANK2):c.6245dup (p.Gly2083fs)	Pathogenic
3376714	NM_001148.6(ANK2):c.9539_9545delinsTGGATGATGAG (p.Asp3180fs)	Pathogenic
3377103	NM_001148.6(ANK2):c.10313_10316del (p.Leu3438fs)	Pathogenic
3390615	NM_001148.6(ANK2):c.3412C>T (p.Arg1138Ter)	Pathogenic
3540979	NM_001148.6(ANK2):c.2929C>T (p.Arg977Ter)	Pathogenic
3540989	NM_001148.6(ANK2):c.4755_4756del (p.Gly1586fs)	Pathogenic
3632705	NM_001148.6(ANK2):c.2784del (p.Ser930fs)	Pathogenic
3654249	NM_001148.6(ANK2):c.9323del (p.Leu3108fs)	Pathogenic
3729667	NM_001148.6(ANK2):c.9240del (p.Asp3081fs)	Pathogenic
3898990	NM_001148.6(ANK2):c.2796+1G>A	Pathogenic
3906496	NM_001148.6(ANK2):c.8062C>T (p.Arg2688Ter)	Pathogenic

SpliceAI

5399 predictions. Top by Δscore:

Variant	Effect	Δscore
4:113049809:GAAG:G	donor_gain	1.0000
4:113174411:C:CA	acceptor_gain	1.0000
4:113174411:CGCAG:C	acceptor_gain	1.0000
4:113174414:A:AG	acceptor_gain	1.0000
4:113174414:AGTCT:A	acceptor_gain	1.0000
4:113174415:G:GA	acceptor_gain	1.0000
4:113174415:GT:G	acceptor_gain	1.0000
4:113174415:GTC:G	acceptor_gain	1.0000
4:113174415:GTCT:G	acceptor_gain	1.0000
4:113174415:GTCTG:G	acceptor_gain	1.0000
4:113174515:CAGGT:C	donor_loss	1.0000
4:113174516:AGGT:A	donor_loss	1.0000
4:113174517:GGTA:G	donor_loss	1.0000
4:113174518:G:GC	donor_loss	1.0000
4:113174519:T:A	donor_loss	1.0000
4:113196364:TCA:T	acceptor_loss	1.0000
4:113196366:A:AG	acceptor_gain	1.0000
4:113196366:AGAAT:A	acceptor_gain	1.0000
4:113196367:G:GC	acceptor_gain	1.0000
4:113196367:GA:G	acceptor_gain	1.0000
4:113196367:GAA:G	acceptor_gain	1.0000
4:113196367:GAAT:G	acceptor_gain	1.0000
4:113196367:GAATG:G	acceptor_gain	1.0000
4:113196465:AG:A	donor_loss	1.0000
4:113199004:A:AG	acceptor_gain	1.0000
4:113199005:A:G	acceptor_gain	1.0000
4:113199008:CAGAA:C	acceptor_loss	1.0000
4:113199009:A:AG	acceptor_gain	1.0000
4:113199009:A:C	acceptor_loss	1.0000
4:113199009:AGAAG:A	acceptor_gain	1.0000

AlphaMissense

25966 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:113174438:T:C	L36P	1.000
4:113174447:C:A	A39D	1.000
4:113196371:G:A	G64R	1.000
4:113196371:G:C	G64R	1.000
4:113196372:G:A	G64E	1.000
4:113196375:T:C	L65P	1.000
4:113196381:C:A	A67D	1.000
4:113196390:T:C	L70P	1.000
4:113196393:C:A	A71D	1.000
4:113196395:G:C	A72P	1.000
4:113196396:C:A	A72D	1.000
4:113196400:G:C	K73N	1.000
4:113196400:G:T	K73N	1.000
4:113196429:T:C	L83P	1.000
4:113199014:G:A	G97R	1.000
4:113199014:G:C	G97R	1.000
4:113199015:G:A	G97E	1.000
4:113199015:G:T	G97V	1.000
4:113199019:T:A	N98K	1.000
4:113199019:T:G	N98K	1.000
4:113199024:C:A	A100D	1.000
4:113199027:T:A	L101H	1.000
4:113199027:T:C	L101P	1.000
4:113199030:A:G	H102R	1.000
4:113199033:T:A	I103N	1.000
4:113199072:T:C	L116P	1.000
4:113232167:T:C	F131L	1.000
4:113232168:T:C	F131S	1.000
4:113232168:T:G	F131C	1.000
4:113232169:T:A	F131L	1.000

dbSNP variants (sampled 300 via entrez): RS1000000028 (4:113263823 A>G), RS1000005431 (4:113138376 G>A,C), RS1000017395 (4:112720232 C>T), RS1000023152 (4:113045067 A>T), RS1000036068 (4:112902886 T>C), RS1000049225 (4:113229362 G>A), RS1000058373 (4:113220208 G>A), RS1000070082 (4:113031490 G>A), RS1000074513 (4:113145774 T>G), RS1000079011 (4:113362862 G>C), RS1000083439 (4:113308861 G>A), RS1000084134 (4:112823510 C>T), RS1000085293 (4:112738999 T>C), RS1000087227 (4:113051542 G>A), RS1000091622 (4:112910132 A>T)

Disease associations

OMIM: gene MIM:106410 | disease phenotypes: MIM:600919, MIM:601144, MIM:156000, MIM:192500, MIM:600996, MIM:604772, MIM:228900, MIM:258150, MIM:115080, MIM:194200

GenCC curated gene-disease

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Strong	Autosomal dominant
cardiac arrhythmia, ankyrin-B-related	Limited	Autosomal dominant
Brugada syndrome	Limited	Autosomal dominant
catecholaminergic polymorphic ventricular tachycardia	Limited	Autosomal dominant
heart conduction disease	Limited	Autosomal dominant
neurodevelopmental disorder	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (4)

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

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AD
Brugada syndrome	Disputed	AD
catecholaminergic polymorphic ventricular tachycardia	Disputed	AD
long QT syndrome	Disputed	AD

Mondo (30): long QT syndrome (MONDO:0002442), cardiac arrhythmia, ankyrin-B-related (MONDO:0010958), Brugada syndrome (MONDO:0015263), neurodevelopmental disorder (MONDO:0700092), Meniere disease (MONDO:0007972), familial long QT syndrome (MONDO:0019171), long QT syndrome 4 (MONDO:0800323), cardiac rhythm disease (MONDO:0007263), cardiomyopathy (MONDO:0004994), ventricular fibrillation (MONDO:0000190), complex neurodevelopmental disorder (MONDO:0100038), atrial fibrillation (MONDO:0004981), dilated cardiomyopathy (MONDO:0005021), ventricular tachycardia (MONDO:0005477), autism spectrum disorder (MONDO:0005258)

Orphanet (15): Romano-Ward syndrome (Orphanet:101016), Congenital long QT syndrome (Orphanet:768), Brugada syndrome (Orphanet:130), Rare cardiomyopathy (Orphanet:167848), Non-specific syndromic intellectual disability (Orphanet:528084), Dilated cardiomyopathy (Orphanet:217604), Catecholaminergic polymorphic ventricular tachycardia (Orphanet:3286), Inherited arrhythmogenic cardiomyopathy (Orphanet:247), Rare hypertrophic cardiomyopathy (Orphanet:217569), Fibular aplasia-complex brachydactyly syndrome (Orphanet:2639), Hereditary progressive cardiac conduction defect (Orphanet:871), NON RARE IN EUROPE: Menière disease (Orphanet:45360), NON RARE IN EUROPE: Autism (Orphanet:106), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Wolff-Parkinson-White syndrome (Orphanet:907)

HPO phenotypes

16 total (21 of 16 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000365	Hearing impairment
HP:0001197	Abnormality of prenatal development or birth
HP:0001250	Seizure
HP:0001279	Syncope
HP:0001645	Sudden cardiac death
HP:0001657	Prolonged QT interval
HP:0001664	Torsade de pointes
HP:0001688	Sinus bradycardia
HP:0002900	Hypokalemia
HP:0004308	Ventricular arrhythmia
HP:0005110	Atrial fibrillation
HP:0005135	Abnormal T-wave
HP:0005184	Prolonged QTc interval
HP:0012332	Abnormal autonomic nervous system physiology
HP:0500018	Abnormal cardiac exercise stress test
HP:0001663	Ventricular fibrillation
HP:0001644	Dilated cardiomyopathy
HP:0001635	Congestive heart failure
HP:0001639	Hypertrophic cardiomyopathy
HP:0001716	Wolff-Parkinson-White syndrome

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST002041_4	Blood trace element (Cu levels)	1.000000e-06
GCST002304_16	Fractional exhaled nitric oxide (childhood)	5.000000e-13
GCST002304_22	Fractional exhaled nitric oxide (childhood)	8.000000e-08
GCST004902_21	Parkinson’s disease	5.000000e-11
GCST005951_145	Body mass index	4.000000e-08
GCST007576_414	Chronotype	1.000000e-08
GCST008750_4	Diastolic blood pressure	1.000000e-06
GCST010293_1	Response to levetiracetam in genetic generalized epilepsy	1.000000e-07
GCST010726_25	Periventricular white matter hyperintensities	2.000000e-06
GCST012189_4	Systolic blood pressure and diastolic blood pressure (bivariate analysis)	3.000000e-06
GCST90006993_1	Gut microbiota relative abundance (unclassified genus belonging to the order Clostridiales)	9.000000e-07
GCST90006997_4	Gut microbiota relative abundance (Coprococcus)	9.000000e-06

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0005267	serum copper measurement
EFO:0005536	nitric oxide exhalation measurement
EFO:0004340	body mass index
EFO:0008328	chronotype measurement
EFO:0006336	diastolic blood pressure
EFO:0005665	white matter hyperintensity measurement
EFO:0006335	systolic blood pressure
EFO:0007874	gut microbiome measurement

MeSH disease descriptors (18)

Descriptor	Name	Tree numbers
D019571	Arrhythmogenic Right Ventricular Dysplasia	C14.240.400.145; C14.280.238.028; C14.280.400.145; C16.131.240.400.145
D001281	Atrial Fibrillation	C14.280.067.198; C23.550.073.198
D053840	Brugada Syndrome	C14.280.067.322; C14.280.123.250; C16.320.100
D009202	Cardiomyopathies	C14.280.238
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D002312	Cardiomyopathy, Hypertrophic	C14.280.238.100; C14.280.484.048.750.070.160
D006323	Heart Arrest	C14.280.383
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
D008575	Meniere Disease	C09.218.568.217.500
D065886	Neurodevelopmental Disorders	F03.625
D017180	Tachycardia, Ventricular	C14.280.067.845.940; C14.280.123.875.940; C23.550.073.845.940
D016171	Torsades de Pointes	C14.280.067.845.940.700; C14.280.123.875.940.700; C23.550.073.845.940.700
D014693	Ventricular Fibrillation	C14.280.067.922; C23.550.073.922
D014927	Wolff-Parkinson-White Syndrome	C14.280.067.780.977; C14.280.123.750.977; C16.131.240.400.980
C563409	Arrhythmogenic Right Ventricular Dysplasia, Familial, 2 (supp.)
C537931	Fibular hypoplasia and complex brachydactyly (supp.)
C562902	Oligosynaptic Infertility (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects methylation, increases expression, affects cotreatment, increases methylation	5
Valproic Acid	affects cotreatment, decreases expression, increases expression	5
sodium arsenite	affects methylation, affects splicing, decreases expression, increases expression	3
Benzo(a)pyrene	affects methylation, decreases expression	3
Doxorubicin	decreases expression	3
Cyclosporine	decreases expression, increases expression	3
Aflatoxin B1	decreases expression, decreases methylation, increases methylation	3
entinostat	increases expression, affects cotreatment	2
Daunorubicin	decreases expression	2
Mitoxantrone	decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
methylmercuric chloride	decreases expression	1
apocarotenal	increases expression	1
methyleugenol	decreases expression	1
methylselenic acid	increases expression	1
trichostatin A	decreases expression, increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
arsenite	affects expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
sulforaphane	increases expression	1
cobaltous chloride	increases expression	1
butyraldehyde	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
benzo(e)pyrene	increases methylation	1
avobenzone	decreases expression	1
chromium hexavalent ion	increases abundance, decreases expression	1
perfluoro-n-nonanoic acid	increases expression	1
2-palmitoylglycerol	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00702117	PHASE4	COMPLETED	Ajmaline Utilization in the Diagnosis and Treatment of Cardiac Arrhythmias
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT00701077	PHASE3	TERMINATED	DAPERB 3,4-DiAminoPyridine and Electrophysiological Response in Brugada Syndrome
NCT00927732	PHASE3	TERMINATED	Hydroquinidine Versus Placebo in Patients With Brugada Syndrome
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02933437	PHASE2	UNKNOWN	The Response To Ajmaline Provocation in Healthy Subjects
NCT07146880	PHASE2	NOT_YET_RECRUITING	Empagliflozin as a Potential Therapeutic Solution for Patients With Brugada Syndrome
NCT06658899	PHASE2	RECRUITING	A Phase 2 Study of CRD-4730 in CPVT
NCT07263139	PHASE2	RECRUITING	Safety, Tolerability, and Exploratory Efficacy of AGP100 in Patients With Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT01648205	PHASE2	COMPLETED	Long-term Efficacy Study of Sodium Channel Blocker in LQT3 Patients
NCT02412709	PHASE2	UNKNOWN	Long QT Syndrome Screening in Newborns
NCT04581408	PHASE2	COMPLETED	Mutation-specific Therapy for the Long QT Syndrome
NCT07148089	PHASE1	RECRUITING	A Study of SGT-501 Gene Therapy in Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT00316459	PHASE1	COMPLETED	Study Evaluating the Effects of Multiple Oral Doses of ERB-041 on Cardiac Repolarization in Healthy Subjects
NCT01849003	PHASE1	COMPLETED	Study of the Effect of GS-6615 in Subjects With LQT-3
NCT02365532	PHASE1	COMPLETED	Effect of Oral GS-6615 on Dofetilide-Induced QT Prolongation, Safety, and Tolerability in Healthy Adults
NCT02412098	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Hepatic Function
NCT02441829	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Renal Function
NCT05759962	PHASE1	COMPLETED	Phase 1 Study of LQT-1213 in Healthy Adults
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
NCT00292032	Not specified	COMPLETED	Registry of Unexplained Cardiac Arrest
NCT02014961	Not specified	UNKNOWN	Worm Study: Modifier Genes in Sudden Cardiac Death
NCT02052765	Not specified	COMPLETED	AnalyST & Brugada Syndrome - Feasibility Study
NCT02302274	Not specified	COMPLETED	Diagnostic Value and Safety of Flecainide Infusion Test in Brugada Syndrome
NCT02344277	Not specified	COMPLETED	Evaluation of Subcutaneous Implantable Cardiac Defibrillator in Brugada Patients