AHNAK

Summary

AHNAK (AHNAK nucleoprotein, HGNC:347) is a protein-coding gene on chromosome 11q12.3, encoding Neuroblast differentiation-associated protein AHNAK (Q09666). May be required for neuronal cell differentiation.

The protein encoded by this gene is a large (700 kDa) structural scaffold protein consisting of a central domain with 128 aa repeats. The encoded protein may play a role in such diverse processes as blood-brain barrier formation, cell structure and migration, cardiac calcium channel regulation, and tumor metastasis. A much shorter variant encoding a 17 kDa isoform exists for this gene, and the shorter isoform initiates a feedback loop that regulates alternative splicing of this gene.

Source: NCBI Gene 79026 — RefSeq curated summary.

At a glance

• GWAS associations: 35
• Clinical variants (ClinVar): 1,111 total — 3 pathogenic, 3 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_001620

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:347
Approved symbol	AHNAK
Name	AHNAK nucleoprotein
Location	11q12.3
Locus type	gene with protein product
Status	Approved
Aliases	MGC5395, AHNAK1
Ensembl gene	ENSG00000124942
Ensembl biotype	protein_coding
OMIM	103390
Entrez	79026

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 7 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000257247, ENST00000378024, ENST00000525875, ENST00000528508, ENST00000530124, ENST00000530285, ENST00000531324, ENST00000533365

RefSeq mRNA: 4 — MANE Select: NM_001620 NM_001346445, NM_001346446, NM_001620, NM_024060

CCDS: CCDS31584, CCDS44625

Canonical transcript exons

ENST00000378024 — 5 exons

Exon	Start	End
ENSE00001286818	62536469	62536567
ENSE00001286844	62535945	62536098
ENSE00001475929	62515902	62534074
ENSE00002160470	62546660	62546806
ENSE00003253763	62535003	62535190

Expression profiles

Bgee: expression breadth ubiquitous, 297 present calls, max score 99.87.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 212.4783 / max 4852.2669, expressed in 1809 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
120117	172.3369	1799
120118	24.5205	1749
120114	6.2586	1478
206311	3.0212	1388
206309	1.9715	1056
206310	1.1619	678
206308	1.0084	623
206307	0.5851	354
120130	0.5604	309
120116	0.5294	261

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
olfactory bulb	UBERON:0002264	99.87	gold quality
calcaneal tendon	UBERON:0003701	99.75	gold quality
tendon of biceps brachii	UBERON:0008188	99.68	gold quality
tendon	UBERON:0000043	99.65	gold quality
trigeminal ganglion	UBERON:0001675	99.63	gold quality
pharyngeal mucosa	UBERON:0000355	99.62	gold quality
saphenous vein	UBERON:0007318	99.62	gold quality
nipple	UBERON:0002030	99.61	gold quality
endometrium epithelium	UBERON:0004811	99.61	gold quality
colonic epithelium	UBERON:0000397	99.60	gold quality
urethra	UBERON:0000057	99.58	gold quality
skin of hip	UBERON:0001554	99.57	gold quality
upper leg skin	UBERON:0004262	99.57	gold quality
synovial joint	UBERON:0002217	99.55	gold quality
dorsal root ganglion	UBERON:0000044	99.54	gold quality
tibial nerve	UBERON:0001323	99.54	gold quality
vena cava	UBERON:0004087	99.54	gold quality
oviduct epithelium	UBERON:0004804	99.50	gold quality
penis	UBERON:0000989	99.49	gold quality
sural nerve	UBERON:0015488	99.47	gold quality
trachea	UBERON:0003126	99.41	gold quality
cervix epithelium	UBERON:0004801	99.32	gold quality
mammalian vulva	UBERON:0000997	99.31	gold quality
skin of leg	UBERON:0001511	99.29	gold quality
mammary duct	UBERON:0001765	99.28	gold quality
skin of abdomen	UBERON:0001416	99.26	gold quality
body of tongue	UBERON:0011876	99.26	gold quality
pylorus	UBERON:0001166	99.23	gold quality
tongue squamous epithelium	UBERON:0006919	99.22	gold quality
mucosa of stomach	UBERON:0001199	99.20	gold quality

Single-cell (SCXA)

Detected in 15 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	2184.31
E-CURD-11	yes	1029.78
E-CURD-122	yes	41.54
E-HCAD-10	yes	34.54
E-MTAB-9543	yes	21.99
E-MTAB-9067	yes	18.73
E-MTAB-9801	yes	7.91
E-HCAD-13	yes	7.56
E-GEOD-130148	yes	5.42
E-GEOD-150728	no	4122.24
E-CURD-85	no	2826.89
E-MTAB-10596	no	821.58
E-MTAB-7249	no	328.50
E-MTAB-5061	no	3.74
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

18 targeting AHNAK, 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-767-5P	99.95	70.85	993
HSA-MIR-3663-3P	99.84	70.39	798
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-3934-5P	99.67	64.04	846
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-501-3P	99.33	66.12	651
HSA-MIR-502-3P	99.33	66.12	651
HSA-MIR-1261	98.62	68.10	896
HSA-MIR-3158-3P	98.45	64.25	560
HSA-MIR-3665	97.73	65.08	975
HSA-MIR-509-3-5P	97.21	67.74	1517
HSA-MIR-509-5P	97.21	67.90	1512
HSA-MIR-3622A-3P	97.06	66.43	1000
HSA-MIR-4418	97.04	67.16	1372
HSA-MIR-3622B-3P	96.82	66.36	988
HSA-MIR-4633-3P	93.85	63.56	534
HSA-MIR-6500-5P	93.85	63.64	522

Literature-anchored findings (GeneRIF, showing 40)

• Multiple titin antibodies, particularly those recognizing the PEVK region, cross-react with AHNAK. (PMID:11746675)
• he carboxyl-terminal region of ahnak provides a link between cardiac L-type Ca2+ channels and the actin-based cytoskeleton (PMID:12153988)
• The carboxyl-terminal ahnak domain exerts a stabilizing effect on muscle contractility via its interaction with actin of thin filaments. (PMID:15001564)
• AHNAK mediates activation of phospholipase C-gamma1 through protein kinase C (PMID:15033986)
• Ahnak has a critical role in cardiac Ca(V)1.2 calcium channel function and its beta-adrenergic regulation (PMID:16319140)
• A study demonstrating that Annexin2 is required for strong binding of S100A10 to the C-terminal domain of the protein Ahnak. (PMID:16984913)
• AHNAK accumulates when calpain 3 is defective in skeletal muscle of calpainopathy patients; moreover, AHNAK fragments cleaved by CAPN3 have lost their affinity for dysferlin. (PMID:18334579)
• AHNAK constitutes a novel mechanism in post-transcriptional control of gene expression. (PMID:21940993)
• these results define ahnak1 in muscle connective tissue as a novel feature of two genetically distinct muscular dystrophies that might contribute to disease pathology. (PMID:22057634)
• The AHNAK peptide adopts a coil conformation that arches across the heterotetramer contacting both annexin A2 and S100A10 protomers with tight affinity. (PMID:22940583)
• While the structure-based consensus sequence allows interactions with various stretches of the AHNAK C-terminal domain, comparison with other S100 structures reveals that the sequence has been optimized for binding to S100A10. (PMID:23275167)
• novel strategies for an accurate prognosis in larynx carcinoma and suggest potential mechanisms of inflammation-mediated tumor progression (PMID:23409183)
• Authors show here that AnxA2, p11 and AHNAK are required for type 3 secretion system-mediated Salmonella invasion of cultured epithelial cells. (PMID:23931152)
• High AHNAK expression is asociated with mesothelioma. (PMID:24253341)
• inhibition of Ahnak can promote generation of induced pluripotent stem cells (iPSC) via up-regulation of endogenous c-Myc. (PMID:26598518)
• tetrandrine may inhibit the growth of Hep-2 cells by decreasing the intracellular concentration of Ca2+ and upregulating the expressions of Brg1 and AHNAK (PMID:26642721)
• Examination of Gene Expression Omnibus database data sets suggests that downregulation of AHNAK mRNA and mutation of the AHNAK gene are common in metastatic melanoma and correlates to a poor outcome. (PMID:26672724)
• AHNAK enables mammary carcinoma cells to produce and release extracellular vesicles that cause disruption of the stroma by surrounding fibroblasts (PMID:27374178)
• our results suggest that AHNAK acts as a tumor suppressor that negatively regulates TNBC cell proliferation, TNBC xenograft growth and metastasis via different signaling pathways. (PMID:28494797)
• Based on the findings, the authors designate the Chlamydia trachomatis gene product corresponding to ct694-ctl0063translocated membrane-associated effector A (TmeA). Overall, the data reveal a role of TmeA during chlamydial invasion that manifests independently of effects on AHNAK. (PMID:28970272)
• These findings confirm that AHNAK functions in the chemotherapeutic response of breast cancer cells while also emphasizing the need for further investigation into potential implications for AHNAK in terms of predicting and modulating treatment response. (PMID:29309757)
• this study identified a new biomarker, AHNAK, applicable to discrimination between bladder urothelial carcinoma and benign urothelial lesion by liquid-based cytology. (PMID:29950347)
• Results showed that AHNAK methylation level in PBMC decreases with the exacerbation of HBV related liver disease, suggesting a certain correlation between AHNAK methylation and the progression of liver disease providing a potential differential diagnostic method for HBV-related hepatopathies, and an early detective tool for liver cancer. (PMID:30259695)
• Data show that AHNAK is a direct substrate of UBE3C, which elevated levels controlled the basal turnover of AHNAK by ubiquitin-mediated proteolysis. Elevated AHNAK levels and lower UBE3C levels predict better patient survival and might represent a prognostic marker in non-small-cell lung cancer (NSCLC). AHNAK is required for p53 binding to the promoter regions of stemness- related genes, thereby controlling cell stemness. (PMID:30503554)
• AHNAK interference restored the hepatocellular carcinoma (HCC) cell invasion and metastasis deprived by RNF38 downregulation. Clinically, elevated RNF38 and transforming growth factor beta receptor 1 (TGFBR1) expression was related to short overall survival (OS) and high cumulative recurrence rates in HCC patients. (PMID:30836988)
• High AHNAK expression is associated with metastasis in Castration-Resistant Prostate Cancer. (PMID:31110158)
• CircAHNAK1 inhibits proliferation and metastasis of triple-negative breast cancer by modulating miR-421 and RASA1. (PMID:31857500)
• SORBS1 serves a metastatic role via suppression of AHNAK in colorectal cancer cell lines. (PMID:32319594)
• MiR-222-5p promotes the growth and migration of trophoblasts by targeting AHNAK. (PMID:33215408)
• Identification of pannexin 1-regulated genes, interactome, and pathways in rhabdomyosarcoma and its tumor inhibitory interaction with AHNAK. (PMID:33564071)
• Peptide Derived from AHNAK Inhibits Cell Migration and Proliferation in Hirschsprung’s Disease by Targeting the ERK1/2 Pathway. (PMID:33853325)
• AHNAK controls 53BP1-mediated p53 response by restraining 53BP1 oligomerization and phase separation. (PMID:33961796)
• AHNAK suppresses ovarian cancer progression through the Wnt/beta-catenin signaling pathway. (PMID:34689136)
• Interaction between TMEFF1 and AHNAK proteins in ovarian cancer cells: Implications for clinical prognosis. (PMID:35338959)
• Annexin A2 and Ahnak control cortical NuMA-dynein localization and mitotic spindle orientation. (PMID:35362526)
• Identification of distinct genomic features reveals frequent somatic AHNAK and PTEN mutations predominantly in primary malignant melanoma presenting in the ureter. (PMID:35578896)
• CircAHNAK upregulates EIF2B5 expression to inhibit the progression of ovarian cancer by modulating the JAK2/STAT3 signaling pathway. (PMID:35710311)
• Downregulation of Circ_0088196 Contributes to the Development of Trophoblastic Cells through miR-133b Sponging Function to Affect the AHNAK Expression. (PMID:36198257)
• Diagnostic and prognostic value of STAP1 and AHNAK methylation in peripheral blood immune cells for HBV-related hepatopathy. (PMID:36713363)
• Silencing AHNAK promotes nasopharyngeal carcinoma progression by upregulating the ANXA2 protein. (PMID:37962808)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ahnak	ENSMUSG00000069833
rattus_norvegicus	Ahnak	ENSRNOG00000057569

Paralogs (2): PRX (ENSG00000105227), AHNAK2 (ENSG00000185567)

Protein

Protein identifiers

Neuroblast differentiation-associated protein AHNAK — Q09666 (reviewed: Q09666)

Alternative names: Desmoyokin

All UniProt accessions (6): Q09666, E9PJC6, E9PJZ0, E9PKR9, E9PLK4, E9PQE3

UniProt curated annotations — full annotation on UniProt →

Function. May be required for neuronal cell differentiation.

Subunit / interactions. Interacts with DYSF; the interaction is direct and Ca(2+)-independent.

Subcellular location. Nucleus.

Isoforms (2)

UniProt ID	Names	Canonical?
Q09666-1	1	yes
Q09666-2	2

RefSeq proteins (4): NP_001333374, NP_001333375, NP_001611, NP_076965 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001478	PDZ	Domain
IPR036034	PDZ_sf	Homologous_superfamily
IPR052082	Myelin_sheath_structural	Family

UniProt features (252 total): modified residue 146, cross-link 33, region of interest 23, sequence conflict 15, sequence variant 13, compositionally biased region 13, short sequence motif 5, splice variant 2, chain 1, domain 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
4HRG	X-RAY DIFFRACTION	2
4FTG	X-RAY DIFFRACTION	2.51
4DRW	X-RAY DIFFRACTION	3.5

Predicted structure (AlphaFold)

No AlphaFold model available for Q09666 — 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 (179): 2600, 2670, 2708, 2728, 2798, 2832, 2845, 3054, 3092, 3182, 3220, 3362, 3409, 3412, 3426, 3544, 3716, 3746, 3766, 3836 …

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 0 (showing top):

GO Biological Process (3): regulation of RNA splicing (GO:0043484), positive regulation of plasma membrane repair (GO:1905686), regulation of voltage-gated calcium channel activity (GO:1901385)

GO Molecular Function (6): RNA binding (GO:0003723), identical protein binding (GO:0042802), S100 protein binding (GO:0044548), cadherin binding (GO:0045296), structural molecule activity conferring elasticity (GO:0097493), protein binding (GO:0005515)

GO Cellular Component (16): nucleus (GO:0005634), cytoplasm (GO:0005737), lysosomal membrane (GO:0005765), cytosol (GO:0005829), plasma membrane (GO:0005886), focal adhesion (GO:0005925), actin cytoskeleton (GO:0015629), membrane (GO:0016020), T-tubule (GO:0030315), vesicle (GO:0031982), sarcolemma (GO:0042383), costamere (GO:0043034), cell-cell contact zone (GO:0044291), extracellular exosome (GO:0070062), plasma membrane protein complex (GO:0098797), membrane raft (GO:0045121)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
protein binding	2
plasma membrane	2
RNA splicing	1
regulation of gene expression	1
regulation of primary metabolic process	1
plasma membrane repair	1
positive regulation of cellular component organization	1
regulation of plasma membrane repair	1
voltage-gated calcium channel activity	1
regulation of transmembrane transporter activity	1
nucleic acid binding	1
cell adhesion molecule binding	1
structural molecule activity	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
lysosome	1
lytic vacuole membrane	1
cytoplasm	1
membrane	1
cell periphery	1
cell-substrate junction	1
cytoskeleton	1
sarcolemma	1
membrane-bounded organelle	1
myofibril	1
cell-cell junction	1
extracellular vesicle	1
membrane protein complex	1
membrane microdomain	1

Protein interactions and networks

STRING

2918 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AHNAK	DYSF	O75923	982
AHNAK	S100A10	P08206	972
AHNAK	ANXA2	P07355	966
AHNAK	PPL	O60437	955
AHNAK	PRX	Q9BXM0	938
AHNAK	EZR	P15311	927
AHNAK	MYOF	Q9NZM1	813
AHNAK	CAPN1	P07384	791
AHNAK	CAPN3	P20807	786
AHNAK	PLCB3	Q01970	782
AHNAK	FKBP2	P26885	778
AHNAK	FTH1	P02794	777
AHNAK	SCGB1A1	P11684	770
AHNAK	MAP3K11	Q16584	769
AHNAK	FOSL1	P15407	769
AHNAK	SF1	Q15637	769

IntAct

640 interactions, top by confidence:

A	B	Type	Score
MED4	MED19	psi-mi:“MI:2364”(proximity)	0.900
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
EGFR	AHNAK	psi-mi:“MI:0915”(physical association)	0.670
NCBP2	KPNA3	psi-mi:“MI:0914”(association)	0.640
NCBP1	KPNA3	psi-mi:“MI:0914”(association)	0.640
ITK	AHNAK	psi-mi:“MI:0915”(physical association)	0.610
AHNAK	S100A10	psi-mi:“MI:0915”(physical association)	0.610
AHNAK	NS	psi-mi:“MI:0915”(physical association)	0.540
MAPT	KIF2A	psi-mi:“MI:0914”(association)	0.530
GALK2	POTEF	psi-mi:“MI:0914”(association)	0.530
GJB7	PALM3	psi-mi:“MI:0914”(association)	0.530
GPR141	STXBP3	psi-mi:“MI:0914”(association)	0.530
ZNF517	GGPS1	psi-mi:“MI:0914”(association)	0.530
ALPG	ALPP	psi-mi:“MI:0914”(association)	0.530
GRK7	HSP90AA1	psi-mi:“MI:0914”(association)	0.530
PLOD3	PLOD2	psi-mi:“MI:0914”(association)	0.530
Cdk1	PHGDH	psi-mi:“MI:0914”(association)	0.500
rep	AHNAK	psi-mi:“MI:0915”(physical association)	0.490
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
FAM20C	AHNAK	psi-mi:“MI:0217”(phosphorylation reaction)	0.440

BioGRID (448): AHNAK (Two-hybrid), NOL9 (Two-hybrid), AHNAK (Affinity Capture-RNA), AHNAK (Affinity Capture-MS), AHNAK (Affinity Capture-MS), AHNAK (Affinity Capture-MS), AHNAK (Reconstituted Complex), AHNAK (Affinity Capture-MS), AHNAK (Affinity Capture-MS), AHNAK (Affinity Capture-Western), ACTN4 (Co-fractionation), AHNAK (Co-fractionation), AHNAK (Co-fractionation), AHNAK (Co-fractionation), AHNAK (Co-fractionation)

ESM2 similar proteins: A0A8I5ZN27, A6NNT2, D3ZEN0, E1AZ71, E1BM58, O15061, O15446, O55103, O88737, O88778, P08855, P0C671, P10636, P10637, P12036, P16884, P19246, P19332, P27816, P34926, P36225, P53814, P62521, P78559, Q06002, Q09666, Q0VA45, Q28181, Q3TN34, Q3UH66, Q4R729, Q5S6V2, Q5STT6, Q5T0Z8, Q5YCV9, Q5YCW0, Q5YCW1, Q63425, Q76KJ5, Q7Z2K8

Diamond homologs: E1BM58, O55103, Q09666, Q63425, Q8IVF2, Q9BXM0

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
MAPK1	unknown	AHNAK	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 231 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
Dengue Virus-Host Interactions	14	4.2×	6e-03
Metabolism of RNA	14	3.8×	6e-03
Viral Infection Pathways	16	3.2×	9e-03
Infectious disease	19	3.1×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1111 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	3
Uncertain significance	913
Likely benign	111
Benign	50

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
149385	GRCh38/hg38 11q12.3(chr11:62249520-62946093)x3	Pathogenic
59754	GRCh38/hg38 11q12.3(chr11:62433886-63096003)x3	Pathogenic
59755	GRCh38/hg38 11q12.3(chr11:62452571-62862781)x3	Pathogenic
3063189	GRCh37/hg19 11p11.12-q13.1(chr11:50398499-63924462)x3	Likely pathogenic
394819	GRCh37/hg19 11q12.3(chr11:61840997-62987330)x1	Likely pathogenic
974739	NC_000011.10:g.62483829_62531399dup	Likely pathogenic

SpliceAI

928 predictions. Top by Δscore:

Variant	Effect	Δscore
11:62534997:ACTC:A	donor_loss	1.0000
11:62534999:TCACC:T	donor_loss	1.0000
11:62535000:CA:C	donor_loss	1.0000
11:62535001:A:AC	donor_gain	1.0000
11:62535001:A:T	donor_loss	1.0000
11:62535002:C:CA	donor_loss	1.0000
11:62535002:C:CT	donor_gain	1.0000
11:62535187:TCCC:T	acceptor_gain	1.0000
11:62535188:CCC:C	acceptor_gain	1.0000
11:62535188:CCCC:C	acceptor_gain	1.0000
11:62535189:CC:C	acceptor_gain	1.0000
11:62535189:CCC:C	acceptor_gain	1.0000
11:62535190:CC:C	acceptor_gain	1.0000
11:62535191:C:CC	acceptor_gain	1.0000
11:62535191:C:T	acceptor_gain	1.0000
11:62535192:T:A	acceptor_loss	1.0000
11:62535196:C:CT	acceptor_gain	1.0000
11:62535197:A:T	acceptor_gain	1.0000
11:62535938:GACTC:G	donor_loss	1.0000
11:62535939:ACTC:A	donor_loss	1.0000
11:62535940:CTCA:C	donor_loss	1.0000
11:62535941:TCA:T	donor_loss	1.0000
11:62535942:CA:C	donor_loss	1.0000
11:62535943:A:AC	donor_gain	1.0000
11:62535943:AC:A	donor_gain	1.0000
11:62535943:ACCCT:A	donor_gain	1.0000
11:62535944:C:CC	donor_gain	1.0000
11:62535944:C:T	donor_loss	1.0000
11:62535944:CC:C	donor_gain	1.0000
11:62535944:CCCT:C	donor_gain	1.0000

AlphaMissense

39420 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:62535953:A:T	V49D	0.996
11:62535094:A:G	L84P	0.995
11:62536031:A:G	L23P	0.995
11:62535127:A:G	L73P	0.994
11:62535160:A:G	F62S	0.994
11:62536025:A:T	I25N	0.994
11:62536054:C:A	W15C	0.994
11:62536054:C:G	W15C	0.994
11:62535181:A:C	I55S	0.993
11:62536056:A:G	W15R	0.993
11:62536056:A:T	W15R	0.993
11:62533965:A:T	I151N	0.992
11:62535181:A:T	I55N	0.992
11:62533965:A:C	I151S	0.991
11:62535159:A:C	F62L	0.991
11:62535159:A:T	F62L	0.991
11:62535161:A:G	F62L	0.991
11:62535166:A:T	I60N	0.991
11:62535173:C:G	A58P	0.990
11:62536070:A:G	L10P	0.990
11:62533939:A:C	Y160D	0.989
11:62535124:A:G	L74P	0.989
11:62536064:A:G	L12P	0.989
11:62535166:A:C	I60S	0.988
11:62535187:T:C	D53G	0.988
11:62535998:A:T	V34E	0.988
11:62535181:A:G	I55T	0.987
11:62533965:A:G	I151T	0.986
11:62535088:A:G	L86P	0.986
11:62535160:A:C	F62C	0.986

dbSNP variants (sampled 300 via entrez): RS1000023135 (11:62456845 C>T), RS1000026997 (11:62498612 A>G), RS1000034819 (11:62543972 CTCTG>C), RS1000104652 (11:62493549 G>A,T), RS1000111761 (11:62458022 T>C), RS1000126528 (11:62450121 A>T), RS1000135507 (11:62479366 C>A), RS1000168163 (11:62501840 A>G), RS1000171803 (11:62434206 TC>T), RS1000210074 (11:62463710 T>G), RS1000213539 (11:62476392 CAA>C,CA,CAAA), RS1000258606 (11:62545438 C>T), RS1000259424 (11:62505077 C>T), RS1000307868 (11:62434508 G>A), RS1000309331 (11:62498355 T>A)

Disease associations

OMIM: gene MIM:103390 | disease phenotypes: MIM:142623, MIM:612840

GenCC curated gene-disease

Mondo (3): Hirschsprung disease, susceptibility to, 1 (MONDO:0007723), leukocyte adhesion deficiency 3 (MONDO:0013016), megacolon (MONDO:0001273)

Orphanet (3): Hirschsprung disease (Orphanet:388), Leukocyte adhesion deficiency (Orphanet:2968), Leukocyte adhesion deficiency type III (Orphanet:99844)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

35 associations (top):

Study	Trait	p-value
GCST001737_2	Chronic obstructive pulmonary disease-related biomarkers	1.000000e-09
GCST001737_22	Chronic obstructive pulmonary disease-related biomarkers	2.000000e-14
GCST002449_6	Plasma omega-6 polyunsaturated fatty acid levels (arachidonic acid)	0.000000e+00
GCST002449_8	Plasma omega-6 polyunsaturated fatty acid levels (arachidonic acid)	7.000000e-147
GCST004183_19	Lung function (FEV1)	1.000000e-13
GCST005549_12	Alzheimer’s disease (late onset)	2.000000e-07
GCST005956_12	Waist-to-hip ratio adjusted for BMI	2.000000e-06
GCST005956_2	Waist-to-hip ratio adjusted for BMI	1.000000e-08
GCST005962_37	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	5.000000e-07
GCST005962_51	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	1.000000e-07
GCST006019_36	Gamma glutamyl transferase levels	3.000000e-17
GCST006288_181	Heel bone mineral density	6.000000e-15
GCST006288_39	Heel bone mineral density	2.000000e-27
GCST006288_732	Heel bone mineral density	1.000000e-15
GCST006979_797	Heel bone mineral density	2.000000e-96
GCST006979_798	Heel bone mineral density	2.000000e-14
GCST006988_106	Blond vs. brown/black hair color	7.000000e-23
GCST009652_3	Serum alkaline phosphatase levels	3.000000e-07
GCST010242_311	HDL cholesterol levels	3.000000e-14
GCST010244_196	Triglyceride levels	3.000000e-08
GCST010302_38	Cutaneous melanoma or hair colour	2.000000e-33
GCST011349_17	Gamma glutamyl transferase levels	1.000000e-17
GCST90002394_470	Monocyte percentage of white cells	1.000000e-10
GCST90011898_2	Alanine aminotransferase levels	8.000000e-12
GCST90013405_131	Liver enzyme levels (alanine transaminase)	1.000000e-16
GCST90013406_200	Liver enzyme levels (alkaline phosphatase)	2.000000e-18
GCST90013407_181	Liver enzyme levels (gamma-glutamyl transferase)	1.000000e-74
GCST90020024_379	A body shape index	7.000000e-25
GCST90020025_941	Waist-to-hip ratio adjusted for BMI	4.000000e-09
GCST90020025_942	Waist-to-hip ratio adjusted for BMI	4.000000e-10

EFO canonical traits (15, from GWAS)

EFO ID	Trait name
EFO:0005080	CC16 measurement
EFO:0005680	omega-6 polyunsaturated fatty acid measurement
EFO:0004314	forced expiratory volume
EFO:1001870	late-onset Alzheimers disease
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0004532	serum gamma-glutamyl transferase measurement
EFO:0009270	heel bone mineral density
EFO:0003924	hair color
EFO:0004533	alkaline phosphatase measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004530	triglyceride measurement
EFO:0007989	monocyte percentage of leukocytes
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008531	Megacolon	C06.405.469.158.701
C567555	Leukocyte Adhesion Deficiency, Type III (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4296008 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.96	Kd	109.9	nM	CHEMBL5653589
6.96	ED50	109.9	nM	CHEMBL5653589
5.32	Kd	4794	nM	CHEMBL3752910
5.32	ED50	4794	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 5 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147821: Binding affinity to human AHNAK incubated for 45 mins by Kinobead based pull down assay	kd	0.1099	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147821: Binding affinity to human AHNAK incubated for 45 mins by Kinobead based pull down assay	kd	4.7938	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, increases expression, decreases expression, affects cotreatment	5
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation, increases expression, increases mutagenesis	5
Tretinoin	decreases expression, increases expression	4
bisphenol F	decreases expression, increases expression, affects cotreatment	3
trichostatin A	affects cotreatment, increases expression	3
bisphenol S	decreases expression, increases methylation, affects cotreatment	3
Air Pollutants	increases expression, affects cotreatment, decreases expression, increases abundance	3
Cisplatin	affects expression, decreases expression, decreases response to substance	3
Estradiol	increases expression, affects expression	3
Tobacco Smoke Pollution	affects expression, decreases expression	3
arsenite	decreases reaction, increases reaction, affects expression, affects binding	2
Panobinostat	affects cotreatment, increases expression	2
Mustard Gas	decreases expression, increases phosphorylation	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Valproic Acid	decreases expression, increases expression	2
Cadmium Chloride	increases abundance, increases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
TAK-243	affects sumoylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
deoxynivalenol	decreases expression	1
sodium arsenate	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression, affects localization	1
kojic acid	decreases expression	1
beta-lapachone	increases expression	1
methylparaben	decreases expression	1
afimoxifene	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118579	Binding	Binding affinity to AHNAK in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02343562	PHASE4	UNKNOWN	Probiotics for Prophylaxis of Postoperative Hirschsprungs Associated Enterocolitis
NCT07186647	PHASE4	COMPLETED	Laparoscopic-Assisted Transanal Pull-Through for Hirschsprung Disease in Pediatric:Short and Intermediate Outcomes of Two Different Techniques
NCT04904081	PHASE3	UNKNOWN	Feasibility of Use of Indocyanine Green in Pediatric Colorectal Surgery
NCT00630838	PHASE2	COMPLETED	Probiotic Prophylaxis of Hirschprung’s Disease Associated Enterocolitis (HAEC)
NCT01985646	EARLY_PHASE1	COMPLETED	A Trial on Conservative Treatment for Infants’ Hirschsprung Disease
NCT00478712	Not specified	RECRUITING	Hirschsprung Disease Genetic Study
NCT01515501	Not specified	COMPLETED	Endoscopic Mucosal Resection for the Diagnosis of a-Ganglionosis, a Controlled Prospective Trial (EDGE Trial)
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01927809	Not specified	UNKNOWN	Genetic Mosaicism in Hirschsprung’s Disease
NCT02193685	Not specified	UNKNOWN	Identification Genetic, Immunologic and Microbial Markers of Hirschsprung Associated Enterocolitis in Children With Hirschsprung Disease
NCT02216994	Not specified	UNKNOWN	A New Scoring System Improves Diagnostic Accuracy of Intestinal Dysganglionosis –a Prospective Study
NCT02296008	Not specified	COMPLETED	3D High Resolution Anorectal Manometry in Children After Surgery for Anorectal Disorders
NCT02776176	Not specified	UNKNOWN	Enhanced Recovery After Surgery In Hirschsprung Disease
NCT02857205	Not specified	COMPLETED	MICROPRUNG : Intestinal Microbiota Analysis in Patients With or Without Hirschsprung’s Associated EnteroColitis
NCT03269812	Not specified	UNKNOWN	Laparoscopic Assisted Pull-through Versus Other Surgical Procedures for Treatment of Hirschsprung Disease
NCT03666767	Not specified	COMPLETED	Management and Outcomes of Congenital Anomalies in Low-, Middle- and High-Income Countries
NCT04020939	Not specified	COMPLETED	The Role of Indocyanine Green Angiography Fluorescence on Intestinal Resections in Pediatric Surgery.
NCT04106947	Not specified	UNKNOWN	Transition of Care for Patients With Hirschsprung Disease and Anorectal Malformations
NCT04149093	Not specified	UNKNOWN	The Association Between Calretinin and the Function of Ganglion Cells in Hirschsprung Disease
NCT04150120	Not specified	COMPLETED	eHealth as an Aid for Facilitating and Supporting Self-management in Families With Long-term Childhood Illness
NCT04213976	Not specified	UNKNOWN	Ostomy in Continuity or Conventional Ileostomy: a Retrospective Multicentric Analysis
NCT04476225	Not specified	COMPLETED	Induced Pluripotent Stem Cells for Disease Research
NCT04598841	Not specified	COMPLETED	Nutrition Support for Hirschsprung Disease
NCT04622410	Not specified	RECRUITING	Registry for Hirschsprung Disease of the BELAPS
NCT04624334	Not specified	TERMINATED	Non-invasive Assessment of Colonic Motility
NCT04730128	Not specified	COMPLETED	Translation and Validation of a Disease-specific Questionnaire for Hirschsprung’s Disease in Danish Patients
NCT04837963	Not specified	COMPLETED	Does Hirschsprung Disease Increase the Risk of Febrile Urinary Tract Infection in Children
NCT04957667	Not specified	COMPLETED	Scintigraphic Defecography for Evaluation of Functional Outcome in an Adult Hirschsprung Population
NCT05038345	Not specified	TERMINATED	Hirschsprung Disease Trends in the United States: Analysis of the National Inpatient Sample
NCT05044741	Not specified	COMPLETED	Risk Factors of Perforated HSCR in Neonates
NCT05293353	Not specified	UNKNOWN	Neokare Safety and Tolerability Assessment in Neonates With GI Problems
NCT05307419	Not specified	UNKNOWN	Full Thickness vs. Rectal Suction Biopsy in the Diagnosis of Hirschsprungs Disease
NCT05450991	Not specified	RECRUITING	Long-term Qualitative and Quantitative Outcomes of Children With Hirschsprung’s Disease and Anorectal Malformations
NCT05655845	Not specified	UNKNOWN	Risk Factors for Bowel Dysfunction at Preschool and Early Childhood Age in Children With Hirschsprung Disease
NCT06072976	Not specified	RECRUITING	The Influence of Feeding Source on the Gut Microbiome and Time to Full Feeds in Neonates With Congenital Gastrointestinal Pathologies
NCT06197061	Not specified	UNKNOWN	Comparison of Robot-assisted With Laparoscopic-assisted Modified Soave Procedure for Classical Hirschsprung Disease
NCT06573723	Not specified	RECRUITING	Institutional Registry of Rare Diseases
NCT06590142	Not specified	RECRUITING	Hirschsprung’s Advances; Working Towards Autologous tIssue therapIes
NCT06592534	Not specified	NOT_YET_RECRUITING	Babies With Enterocolitis - A Study of Faecal Calprotectin in Hirschsprung Disease (The BEACH Study)
NCT06650683	Not specified	RECRUITING	Impact of Providing Nursing Support on Parental Stress Related to Preoperative Care of a Newborn with Hirschsprung’s Disease