UNC45A

Summary

UNC45A (unc-45 myosin chaperone A, HGNC:30594) is a protein-coding gene on chromosome 15q26.1, encoding Protein unc-45 homolog A (Q9H3U1). Acts as a co-chaperone for HSP90. It is a selective cancer dependency (DepMap: 19.2% of cell lines).

This gene encodes a regulatory component of the progesterone receptor/heat shock protein 90 chaperoning complex, which functions in the assembly and folding of the progesterone receptor. The encoded protein is thought to be essential for normal cell proliferation, and for the accumulation of myosin during development of muscle cells.

Source: NCBI Gene 55898 — RefSeq curated summary.

At a glance

• Gene–disease (curated): osteootohepatoenteric syndrome (Strong, GenCC)
• Clinical variants (ClinVar): 635 total — 5 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 32
• Cancer dependency (DepMap): dependent in 19.2% of screened cell lines
• MANE Select transcript: NM_018671

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30594
Approved symbol	UNC45A
Name	unc-45 myosin chaperone A
Location	15q26.1
Locus type	gene with protein product
Status	Approved
Aliases	SMAP-1, GC-UNC45
Ensembl gene	ENSG00000140553
Ensembl biotype	protein_coding
OMIM	611219
Entrez	55898

Gene structure

Transcript identifiers

Ensembl transcripts: 36 — 23 protein_coding, 9 retained_intron, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000418476, ENST00000461266, ENST00000471780, ENST00000480470, ENST00000486253, ENST00000487875, ENST00000495068, ENST00000497152, ENST00000553671, ENST00000554481, ENST00000556319, ENST00000556482, ENST00000556704, ENST00000557212, ENST00000639885, ENST00000672480, ENST00000895387, ENST00000895388, ENST00000895389, ENST00000895390, ENST00000895391, ENST00000895392, ENST00000895393, ENST00000895394, ENST00000895395, ENST00000895396, ENST00000895397, ENST00000895398, ENST00000936141, ENST00000936142, ENST00000971437, ENST00000971438, ENST00000971439, ENST00000971440, ENST00000971441, ENST00000971442

RefSeq mRNA: 5 — MANE Select: NM_018671 NM_001039675, NM_001323619, NM_001323620, NM_001323621, NM_018671

CCDS: CCDS10367

Canonical transcript exons

ENST00000418476 — 20 exons

Exon	Start	End
ENSE00000943755	90944892	90945063
ENSE00000943756	90946614	90946914
ENSE00001108262	90948654	90948794
ENSE00001108269	90948142	90948283
ENSE00001307423	90942437	90942605
ENSE00001313350	90942912	90943082
ENSE00003464662	90935285	90935375
ENSE00003555199	90950154	90950267
ENSE00003562898	90940306	90940473
ENSE00003569062	90936285	90936460
ENSE00003570330	90949316	90949443
ENSE00003581338	90953459	90954093
ENSE00003606474	90950500	90950615
ENSE00003623244	90935946	90935982
ENSE00003650599	90947796	90947890
ENSE00003662197	90949654	90949720
ENSE00003662314	90939731	90939823
ENSE00003676577	90935544	90935705
ENSE00003680191	90953155	90953310
ENSE00003692253	90952929	90953046

Expression profiles

Bgee: expression breadth ubiquitous, 263 present calls, max score 96.27.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 36.9075 / max 223.1221, expressed in 1825 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
148528	36.2663	1824
148527	0.5578	209
148529	0.0833	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
esophagogastric junction muscularis propria	UBERON:0035841	96.27	gold quality
lower esophagus muscularis layer	UBERON:0035833	96.24	gold quality
lower esophagus	UBERON:0013473	96.23	gold quality
popliteal artery	UBERON:0002250	95.94	gold quality
tibial artery	UBERON:0007610	95.93	gold quality
aorta	UBERON:0000947	95.68	gold quality
muscle layer of sigmoid colon	UBERON:0035805	95.61	gold quality
descending thoracic aorta	UBERON:0002345	95.46	gold quality
thoracic aorta	UBERON:0001515	95.45	gold quality
ascending aorta	UBERON:0001496	95.44	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.32	gold quality
cerebellar hemisphere	UBERON:0002245	95.22	gold quality
body of uterus	UBERON:0009853	95.20	gold quality
skin of leg	UBERON:0001511	95.10	gold quality
mucosa of stomach	UBERON:0001199	95.06	gold quality
cerebellar cortex	UBERON:0002129	95.05	gold quality
stromal cell of endometrium	CL:0002255	94.99	gold quality
right coronary artery	UBERON:0001625	94.97	gold quality
left coronary artery	UBERON:0001626	94.95	gold quality
ectocervix	UBERON:0012249	94.92	gold quality
endocervix	UBERON:0000458	94.60	gold quality
coronary artery	UBERON:0001621	94.60	gold quality
skin of abdomen	UBERON:0001416	94.59	gold quality
lower esophagus mucosa	UBERON:0035834	94.55	gold quality
esophagus	UBERON:0001043	94.52	gold quality
mucosa of transverse colon	UBERON:0004991	93.95	gold quality
right adrenal gland cortex	UBERON:0035827	93.86	gold quality
right adrenal gland	UBERON:0001233	93.83	gold quality
right ovary	UBERON:0002118	93.82	gold quality
cerebellum	UBERON:0002037	93.61	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.70

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

28 targeting UNC45A, 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-3064-3P	100.00	70.09	1254
HSA-MIR-199A-3P	99.75	70.48	929
HSA-MIR-199B-3P	99.75	70.48	929
HSA-MIR-3129-5P	99.75	70.46	914
HSA-MIR-4690-5P	99.65	66.24	813
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-5580-5P	99.38	66.96	1139
HSA-MIR-4316	99.37	65.75	1360
HSA-MIR-7974	99.24	65.48	1137
HSA-MIR-6510-5P	99.14	66.59	1081
HSA-MIR-485-5P	99.10	64.78	1889
HSA-MIR-6884-5P	99.10	64.50	1987
HSA-MIR-7977	98.65	66.18	2590
HSA-MIR-603	98.58	68.28	1603
HSA-MIR-216B-3P	98.55	67.19	1223
HSA-MIR-4436B-3P	98.25	65.26	1494
HSA-MIR-6735-5P	98.24	65.36	1488
HSA-MIR-7843-5P	98.12	65.26	1421
HSA-MIR-4632-5P	97.82	65.38	1470
HSA-MIR-6879-5P	97.77	65.52	1521
HSA-MIR-296-5P	97.61	64.02	851
HSA-MIR-9851-5P	97.57	67.49	1067
HSA-MIR-1227-3P	97.36	66.94	834
HSA-MIR-134-5P	97.11	66.52	976
HSA-MIR-3118	97.11	66.58	984
HSA-MIR-6773-5P	97.04	64.30	595
HSA-MIR-6724-5P	96.41	63.11	507

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 19.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 17)

• GCUNC-45 is a novel modulator of progesterone receptor chaperoning by hsp90. (PMID:16478993)
• elevated GC UNC-45 protein expression in ovarian carcinoma proliferation and metastasis. (PMID:17872978)
• GCUNC45 is required for the normal cellular distribution of Hsp90beta, but not Hsp90alpha. (PMID:18285346)
• The authors found that UNC-45A is alternatively expressed at the mRNA and protein levels as two isoforms and that the two isoforms differ only by a proline-rich 15-amino-acid sequence near the amino-terminus. (PMID:21802425)
• Findings identify a novel centrosomal function for UNC45A and its role in cell proliferation and tumorigenesis. (PMID:25444911)
• UNC-45A is a crucial component in regulating human NK cell cytoskeletal dynamics via promoting the formation of actomyosin complexes. (PMID:26438524)
• Results provide novel insights into the molecular mechanisms of neurite growth and define UNC-45A as a novel and master regulator of NMII-mediated cellular processes in neurons. (PMID:28356421)
• UNC-45a promotes generation of contractile actomyosin bundles through synchronized non-muscle myosin II folding and filament-assembly activities. (PMID:29055011)
• A transient induction of the human UNC45-GC, but not UNC45-SM, could rescue the defective endocytosis in these she4Delta cells at 39 degrees C, irrespective of whether they possessed Hsp90alpha or Hsp90beta. (PMID:29288355)
• Whole-exome sequencing of all affected individuals and their parents identified biallelic mutations in Unc-45 Myosin Chaperone A (UNC45A) as a likely driver for cholestasis, congenital diarrhea, impaired hearing, and bone fragility. (PMID:29429573)
• In cells, UNC-45A binds to and destabilizes mitotic spindles, and its depletion causes severe defects in chromosome congression and segregation. UNC-45A is overexpressed in human clinical specimens from chemoresistant ovarian cancer and that UNC-45A-overexpressing cells resist chromosome missegregation and aneuploidy when treated with clinically relevant concentrations of paclitaxel. (PMID:30322860)
• The co-chaperone UNC45A is essential for the expression of mitotic kinase NEK7 and tumorigenesis. (PMID:30737284)
• UNC-45A breaks the microtubule lattice independently of its effects on non-muscle myosin II. (PMID:33262310)
• A myosin chaperone, UNC-45A, is a novel regulator of intestinal epithelial barrier integrity and repair. (PMID:35344227)
• A Functional Relationship Between UNC45A and MYO5B Connects Two Rare Diseases With Shared Enteropathy. (PMID:35421597)
• UNC45A deficiency causes microvillus inclusion disease-like phenotype by impairing myosin VB-dependent apical trafficking. (PMID:35575086)
• Aagenaes syndrome/lymphedema cholestasis syndrome 1 is caused by a founder variant in the 5’-untranslated region of UNC45A. (PMID:37328071)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	unc45a	ENSDARG00000103643
mus_musculus	Unc45a	ENSMUSG00000030533
rattus_norvegicus	Unc45a	ENSRNOG00000012357
drosophila_melanogaster	unc-45	FBGN0288846
caenorhabditis_elegans		WBGENE00006781

Paralogs (18): RPAP3 (ENSG00000005175), TOMM34 (ENSG00000025772), ST13 (ENSG00000100380), STUB1 (ENSG00000103266), SPAG1 (ENSG00000104450), SGTA (ENSG00000104969), TTC1 (ENSG00000113312), TTC31 (ENSG00000115282), UNC45B (ENSG00000141161), SPATA16 (ENSG00000144962), TTC12 (ENSG00000149292), TOMM70 (ENSG00000154174), SUGT1 (ENSG00000165416), STIP1 (ENSG00000168439), TTC32 (ENSG00000183891), SGTB (ENSG00000197860), TTC4 (ENSG00000243725), DNAAF4 (ENSG00000256061)

Protein

Protein identifiers

Protein unc-45 homolog A — Q9H3U1 (reviewed: Q9H3U1)

Alternative names: GCUNC-45, Smooth muscle cell-associated protein 1

All UniProt accessions (4): A0A1W2PNX8, A0A5F9ZI17, A0A5F9ZI32, Q9H3U1

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a co-chaperone for HSP90. Prevents the stimulation of HSP90AB1 ATPase activity by AHSA1. Positive factor in promoting PGR function in the cell. May be necessary for proper folding of myosin (Potential). Necessary for normal cell proliferation. Necessary for normal myotube formation and myosin accumulation during muscle cell development. May play a role in erythropoiesis in stroma cells in the spleen.

Subunit / interactions. Interacts with PGR isoforms A and B as well as with NR3C1 in the absence of ligand, and with HSP90AB1. Binding to HSP90AB1 involves 2 UNC45A monomers per HSP90AB1 dimer.

Subcellular location. Cytoplasm. Perinuclear region. Nucleus.

Tissue specificity. Detected in peripheral blood leukocytes, bone marrow, adrenal gland, trachea, spinal cord, thyroid, lymph node and stomach.

Disease relevance. Osteootohepatoenteric syndrome (OOHE) [MIM:619377] An autosomal recessive disorder characterized by cholestasis, congenital diarrhea, impaired hearing, and bone fragility. Some patients also display mild developmental delay and intellectual disability. The disease may be caused by variants affecting the gene represented in this entry.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9H3U1-1	1, 2, SMAP-1b	yes
Q9H3U1-2	2, 3
Q9H3U1-3	3

RefSeq proteins (5): NP_001034764, NP_001310548, NP_001310549, NP_001310550, NP_061141* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011989	ARM-like	Homologous_superfamily
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR019734	TPR_rpt	Repeat
IPR024660	UCS_central_dom	Domain

Pfam: PF11701, PF13181, PF13432

UniProt features (31 total): sequence variant 8, helix 7, mutagenesis site 4, repeat 3, modified residue 3, splice variant 2, chain 1, sequence conflict 1, turn 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2DBA	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H3U1-F1	86.36	0.49

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 (3): 15, 70, 483

Mutagenesis-validated functional residues (4):

Position	Phenotype
33	abolishes interaction with hsp90ab1; when associated with d-40. no effect on interaction with pgr.
40	abolishes interaction with hsp90ab1; when associated with e-33. no effect on interaction with pgr.
70	abolishes interaction with hsp90ab1; when associated with d-77. no effect on interaction with pgr.
77	abolishes interaction with hsp90ab1; when associated with e-70. no effect on interaction with pgr.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 207 (showing top): AREB6_01, GOBP_PROTEIN_MATURATION, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, TGCTGAY_UNKNOWN, OCT1_03, TGTGTGA_MIR377, GOBP_PROTEIN_FOLDING, ATGCTGG_MIR338, BURTON_ADIPOGENESIS_1, GTGTGAG_MIR342, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_DN, ATGTTTC_MIR494, PARENT_MTOR_SIGNALING_UP, BARRIER_CANCER_RELAPSE_TUMOR_SAMPLE_DN, GOCC_NUCLEAR_SPECK

GO Biological Process (3): protein folding (GO:0006457), muscle organ development (GO:0007517), cell differentiation (GO:0030154)

GO Molecular Function (3): cadherin binding (GO:0045296), Hsp90 protein binding (GO:0051879), protein binding (GO:0005515)

GO Cellular Component (6): cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), cytosol (GO:0005829), nuclear speck (GO:0016607), perinuclear region of cytoplasm (GO:0048471), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cytoplasm	3
intracellular membrane-bounded organelle	2
cellular process	1
protein maturation	1
animal organ development	1
muscle structure development	1
cellular developmental process	1
cell adhesion molecule binding	1
heat shock protein binding	1
binding	1
intracellular anatomical structure	1
endomembrane system	1
nuclear ribonucleoprotein granule	1

Protein interactions and networks

STRING

1428 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UNC45A	AHSA1	O95433	827
UNC45A	HSP90AA1	P07900	803
UNC45A	PGR	P06401	562
UNC45A	HSP90AB1	P08238	512
UNC45A	SACK1H	Q6ZRV2	485
UNC45A	PTGES3	Q15185	466
UNC45A	C3orf18	Q9UK00	462
UNC45A	ABHD1	Q96SE0	456
UNC45A	FAM3A	P98173	447
UNC45A	ST13	P50502	443
UNC45A	NEK7	Q8TDX7	436
UNC45A	TCF12	Q99081	425
UNC45A	NR3C1	P04150	422
UNC45A	HEATR1	Q9H583	418
UNC45A	USP19	O94966	408

IntAct

204 interactions, top by confidence:

A	B	Type	Score
NPHP1	NPHP4	psi-mi:“MI:2364”(proximity)	0.930
CSNK1A1	FAM83G	psi-mi:“MI:0914”(association)	0.900
UNC45A	MARCHF10	psi-mi:“MI:0915”(physical association)	0.780
MARCHF10	UNC45A	psi-mi:“MI:0915”(physical association)	0.780
RPGR	NPHP4	psi-mi:“MI:2364”(proximity)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
MAX	UNC45A	psi-mi:“MI:0915”(physical association)	0.670
UNC45A	MAX	psi-mi:“MI:0915”(physical association)	0.670
HSP90AA1	CHUK	psi-mi:“MI:0914”(association)	0.670
CEP170	KIF2A	psi-mi:“MI:2364”(proximity)	0.650
IFT88	IFT56	psi-mi:“MI:0914”(association)	0.640
UNC45A	MAX	psi-mi:“MI:0915”(physical association)	0.560
MEOX2	UNC45A	psi-mi:“MI:0915”(physical association)	0.560
MID2	UNC45A	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (299): UNC45A (Affinity Capture-MS), UNC45A (Two-hybrid), UNC45A (Two-hybrid), UNC45A (Two-hybrid), MARCH10 (Two-hybrid), KRTAP10-3 (Two-hybrid), ATP6V1A (Co-fractionation), NAPA (Co-fractionation), PPME1 (Co-fractionation), RAP1GDS1 (Co-fractionation), RNF20 (Co-fractionation), UNC45A (Co-fractionation), UNC45A (Co-fractionation), UNC45A (Affinity Capture-MS), UNC45A (Proximity Label-MS)

ESM2 similar proteins: A1Z6S7, A3LUY1, D7REX8, G5ED41, O14265, O44326, O60077, P21541, P29742, P34574, P38260, P40469, P41807, P46970, P51534, P53067, Q07395, Q22494, Q32PZ3, Q5RAP0, Q5ZI87, Q619W9, Q61A92, Q68F64, Q6BKV2, Q6CNM7, Q6CTY9, Q6DGE9, Q6FM01, Q75B89, Q75EM1, Q7K486, Q80XE1, Q80ZG0, Q8CGY6, Q8INF7, Q8IWX7, Q8MML6, Q95U54, Q99KD5

Diamond homologs: A4IFF3, A4IHU6, O35450, O35465, P26882, P53691, Q08752, Q14318, Q3B7U9, Q3V038, Q5RAP0, Q6DGG0, Q6MG81, Q6P5P3, Q7DMA9, Q810A3, Q8N5M4, Q8N6N2, Q92623, Q9BGT1, Q9CR16, Q9D6E4, Q9H3U1, A4K2V0, A6HD62, A6ZRW3, D7REX8, F1RBN2, F4IRM4, F4JTI1, F4K487, F4KCL7, O13754, O14217, O16259, O35814, O48802, O54981, O94826, O95801

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 188 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
Anchoring of the basal body to the plasma membrane	17	15.3×	5e-13
Loss of Nlp from mitotic centrosomes	8	10.1×	2e-04
Loss of proteins required for interphase microtubule organization from the centrosome	8	10.1×	2e-04
AURKA Activation by TPX2	8	9.7×	3e-04
Degradation of DVL	5	9.4×	9e-03
Cilium Assembly	10	8.6×	9e-05
Recruitment of mitotic centrosome proteins and complexes	8	8.6×	4e-04
Regulation of PLK1 Activity at G2/M Transition	8	8.1×	7e-04

GO biological processes:

GO term	Partners	Fold	FDR
centriole replication	5	21.6×	1e-03
motile cilium assembly	5	17.1×	2e-03
non-motile cilium assembly	9	15.4×	4e-06
mitotic spindle organization	6	9.6×	6e-03
cilium assembly	20	8.7×	2e-10

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	3
Uncertain significance	309
Likely benign	268
Benign	24

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
1164083	NM_018671.5(UNC45A):c.829C>T (p.Arg277Ter)	Pathogenic
1164087	NM_018671.5(UNC45A):c.1028G>T (p.Gly343Val)	Pathogenic
3061784	NM_018671.5(UNC45A):c.689C>G (p.Thr230Arg)	Pathogenic
3061786	NM_018671.5(UNC45A):c.2182G>A (p.Glu728Lys)	Pathogenic
3061787	NM_018671.5(UNC45A):c.1451_1452insG (p.Asp484fs)	Pathogenic
3062256	NM_018671.5(UNC45A):c.213+1G>C	Likely pathogenic
3381131	NM_018671.5(UNC45A):c.214-2A>G	Likely pathogenic
4764392	NM_018671.5(UNC45A):c.2073+1G>A	Likely pathogenic

SpliceAI

3294 predictions. Top by Δscore:

Variant	Effect	Δscore
15:90931702:AC:A	donor_gain	1.0000
15:90931703:CC:C	donor_gain	1.0000
15:90931703:CCCT:C	donor_gain	1.0000
15:90931941:CCGC:C	acceptor_gain	1.0000
15:90931942:CGCC:C	acceptor_gain	1.0000
15:90932050:GTTAC:G	donor_loss	1.0000
15:90932051:TTACC:T	donor_loss	1.0000
15:90932052:TAC:T	donor_loss	1.0000
15:90932053:ACCTG:A	donor_loss	1.0000
15:90932054:C:CA	donor_loss	1.0000
15:90932468:T:TA	donor_gain	1.0000
15:90935331:G:GG	donor_gain	1.0000
15:90935542:A:AG	acceptor_gain	1.0000
15:90935542:A:C	acceptor_loss	1.0000
15:90935543:G:GA	acceptor_gain	1.0000
15:90935543:GGCC:G	acceptor_gain	1.0000
15:90935543:GGCCA:G	acceptor_gain	1.0000
15:90935702:GCTG:G	donor_gain	1.0000
15:90935704:TGG:T	donor_loss	1.0000
15:90935706:G:GC	donor_loss	1.0000
15:90935706:G:GG	donor_gain	1.0000
15:90935707:T:G	donor_loss	1.0000
15:90935711:G:GT	donor_gain	1.0000
15:90936283:A:AG	acceptor_gain	1.0000
15:90936284:G:GG	acceptor_gain	1.0000
15:90936284:GCC:G	acceptor_gain	1.0000
15:90936457:GAAG:G	donor_gain	1.0000
15:90936458:AAGG:A	donor_loss	1.0000
15:90936461:G:GG	donor_gain	1.0000
15:90936462:T:A	donor_loss	1.0000

AlphaMissense

6116 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:90936327:G:C	R98P	0.999
15:90935685:G:C	A65P	0.998
15:90946910:T:C	L499P	0.998
15:90948207:T:C	L554P	0.998
15:90948229:G:C	K561N	0.998
15:90948229:G:T	K561N	0.998
15:90950218:C:A	A713D	0.998
15:90950582:T:C	L757P	0.998
15:90953008:G:C	A795P	0.998
15:90953009:C:A	A795D	0.998
15:90935698:T:C	L69P	0.997
15:90936313:A:C	K93N	0.997
15:90936313:A:T	K93N	0.997
15:90936335:G:C	A101P	0.997
15:90940319:T:C	L178P	0.997
15:90946700:G:A	G429D	0.997
15:90946859:T:C	L482P	0.997
15:90947800:T:C	L502P	0.997
15:90947804:T:G	C503W	0.997
15:90947872:T:C	L526P	0.997
15:90948194:G:C	G550R	0.997
15:90948751:T:C	L612P	0.997
15:90948754:C:A	A613D	0.997
15:90948763:C:A	A616D	0.997
15:90950217:G:C	A713P	0.997
15:90950569:G:C	A753P	0.997
15:90950573:T:C	L754P	0.997
15:90950585:C:T	T758I	0.997
15:90950591:T:C	L760P	0.997
15:90953246:C:A	A838D	0.997

dbSNP variants (sampled 300 via entrez): RS1000056507 (15:90937078 G>A), RS1000110959 (15:90953864 G>A), RS1000297807 (15:90937384 A>T), RS1000379590 (15:90951083 C>A,T), RS1000537951 (15:90942126 A>G), RS1000900879 (15:90947351 G>T), RS1000934902 (15:90947149 T>C), RS1000999872 (15:90941318 T>C), RS1001058612 (15:90935895 G>A,T), RS1001091484 (15:90952008 G>A), RS1001142882 (15:90941064 C>A,T), RS1001228773 (15:90952268 T>C), RS1001240292 (15:90940786 G>A), RS1001298777 (15:90936165 A>T), RS1001590636 (15:90930458 G>A)

Disease associations

OMIM: gene MIM:611219 | disease phenotypes: MIM:619377, MIM:214900, MIM:210900

GenCC curated gene-disease

Disease	Classification	Inheritance
osteootohepatoenteric syndrome	Strong	Autosomal recessive

Mondo (4): osteootohepatoenteric syndrome (MONDO:0859164), Aagenaes syndrome (MONDO:0008966), Bloom syndrome (MONDO:0008876), hearing loss disorder (MONDO:0005365)

Orphanet (2): Cholestasis-lymphedema syndrome (Orphanet:1414), Bloom syndrome (Orphanet:125)

HPO phenotypes

32 total (30 of 32 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000093	Proteinuria
HP:0000238	Hydrocephalus
HP:0000365	Hearing impairment
HP:0000592	Blue sclerae
HP:0000989	Pruritus
HP:0001263	Global developmental delay
HP:0001385	Hip dysplasia
HP:0001395	Hepatic fibrosis
HP:0001396	Cholestasis
HP:0001414	Microvesicular hepatic steatosis
HP:0001508	Failure to thrive
HP:0001824	Weight loss
HP:0001903	Anemia
HP:0001944	Dehydration
HP:0002003	Large forehead
HP:0002027	Abdominal pain
HP:0002099	Asthma
HP:0002572	Episodic vomiting
HP:0002757	Recurrent fractures
HP:0002900	Hypokalemia
HP:0004349	Reduced bone mineral density
HP:0005208	Secretory diarrhea
HP:0005743	Avascular necrosis of the capital femoral epiphysis
HP:0006579	Prolonged neonatal jaundice
HP:0006580	Portal fibrosis
HP:0011473	Villous atrophy
HP:0012202	Increased serum bile acid concentration
HP:0012537	Food intolerance
HP:0033309	Ileoileal intussusception

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D001816	Bloom Syndrome	C16.131.077.137; C16.320.798.313; C18.452.284.100; C20.673.795.313
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
C535330	Aagenaes syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	2
Acetaminophen	increases expression, affects response to substance	2
Valproic Acid	affects cotreatment, increases expression, decreases expression, increases methylation	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
propionaldehyde	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression, increases expression	1
beta-lapachone	increases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	increases expression	1
tetrabromobisphenol A	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
deguelin	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
ICG 001	decreases expression	1
bisphenol S	increases expression	1
LDN 193189	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Vehicle Emissions	increases methylation	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Caffeine	increases phosphorylation	1
Dactinomycin	affects cotreatment, increases secretion	1
Diazinon	increases methylation	1
Furaldehyde	affects cotreatment, affects localization, decreases expression, increases expression	1
Gasoline	increases abundance, increases expression, affects cotreatment	1
Hydralazine	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Polycyclic Aromatic Hydrocarbons	affects cotreatment, increases abundance, increases expression	1

Cellosaurus cell lines

2 cell lines: 1 induced pluripotent stem cell, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C1Q7	IMAGINi020-A	Induced pluripotent stem cell	Female
CVCL_D0R6	Caco-2 UNC45A KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	PHASE1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	PHASE1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	PHASE1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	PHASE1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	PHASE1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	PHASE1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	PHASE1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT00021437	Not specified	COMPLETED	Biological Significance of the Bloom’s Syndrome Protein
NCT04251325	Not specified	UNKNOWN	Socio-demographic Characteristics of Basic Life Support Course Participants
NCT04353089	Not specified	UNKNOWN	Geographical Association Between Basic Life Support Courses, Bystander Cardiopulmonary Resuscitation and Survival
NCT00486577	PHASE2/PHASE3	COMPLETED	Chronic Electrical Stimulation of the Auditory Cortex for Intractable Tinnitus
NCT00789061	PHASE2/PHASE3	UNKNOWN	Applying Proton Pump Inhibitor to Prevent and Treat Acute Fluctuating Hearing Loss in Patients With SLC26A4 Mutation
NCT01423409	PHASE2/PHASE3	COMPLETED	Multicenter Trial Assessing an Innovative VAS of Pain Among Deaf People
NCT05786378	PHASE2/PHASE3	UNKNOWN	Assessment of The Efficacy of Intratympanic Platelet Rich Plasma for Treatment of Sensorineural Hearing Loss.
NCT01108601	PHASE1/PHASE2	UNKNOWN	Transtympanic Ringer’s Lactate for the Prevention of Cisplatin Ototoxicity
NCT01621256	PHASE1/PHASE2	COMPLETED	Efficacy, Safety, and Tolerability of Ancrod in Patients With Sudden Hearing Loss
NCT06370351	PHASE1/PHASE2	RECRUITING	A Phase I/II Clinical Trial with SENS-501 in Children Suffering from Severe to Profound Hearing Loss Due to Otoferlin (OTOF) Mutations