SIX4

Summary

SIX4 (SIX homeobox 4, HGNC:10890) is a protein-coding gene on chromosome 14q23.1, encoding Homeobox protein SIX4 (Q9UIU6). Transcriptional regulator which can act as both a transcriptional repressor and activator by binding a DNA sequence on these target genes and is involved in processes like cell differentiation, cell migration and cell survival.

This gene encodes a member of the homeobox family, subfamily SIX. The drosophila homolog is a nuclear homeoprotein required for eye development. Studies in mouse show that this gene product functions as a transcription factor, and may have a role in the differentiation or maturation of neuronal cells.

Source: NCBI Gene 51804 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 100 total
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• Transcription factor: yes — 10 downstream targets (CollecTRI)
• MANE Select transcript: NM_017420

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10890
Approved symbol	SIX4
Name	SIX homeobox 4
Location	14q23.1
Locus type	gene with protein product
Status	Approved
Aliases	AREC3
Ensembl gene	ENSG00000100625
Ensembl biotype	protein_coding
OMIM	606342
Entrez	51804

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000216513, ENST00000554079, ENST00000556952

RefSeq mRNA: 1 — MANE Select: NM_017420 NM_017420

CCDS: CCDS9749

Canonical transcript exons

ENST00000216513 — 3 exons

Exon	Start	End
ENSE00000658203	60709539	60714203
ENSE00001137601	60723212	60724351
ENSE00003678541	60719760	60720445

Expression profiles

Bgee: expression breadth ubiquitous, 205 present calls, max score 96.19.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 3.5132 / max 48.7986, expressed in 1236 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
143519	1.8900	936
143520	1.2513	729
143517	0.2461	108
143518	0.1258	56

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
bronchial epithelial cell	CL:0002328	96.19	gold quality
vastus lateralis	UBERON:0001379	95.82	gold quality
quadriceps femoris	UBERON:0001377	95.71	gold quality
bronchus	UBERON:0002185	95.23	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	94.56	gold quality
biceps brachii	UBERON:0001507	94.44	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	94.24	gold quality
deltoid	UBERON:0001476	93.54	gold quality
nasal cavity epithelium	UBERON:0005384	93.41	gold quality
skeletal muscle tissue	UBERON:0001134	92.59	gold quality
mucosa of paranasal sinus	UBERON:0005030	92.30	gold quality
cartilage tissue	UBERON:0002418	92.28	gold quality
parotid gland	UBERON:0001831	91.85	gold quality
epithelium of nasopharynx	UBERON:0001951	90.72	gold quality
tibialis anterior	UBERON:0001385	90.24	silver quality
palpebral conjunctiva	UBERON:0001812	89.35	gold quality
muscle tissue	UBERON:0002385	87.50	gold quality
tibia	UBERON:0000979	86.23	gold quality
skeletal muscle organ	UBERON:0014892	86.19	gold quality
Brodmann (1909) area 23	UBERON:0013554	84.59	gold quality
gastrocnemius	UBERON:0001388	84.37	gold quality
muscle of leg	UBERON:0001383	84.04	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.18	gold quality
hindlimb stylopod muscle	UBERON:0004252	81.96	gold quality
middle temporal gyrus	UBERON:0002771	81.14	gold quality
germinal epithelium of ovary	UBERON:0001304	80.88	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	79.96	gold quality
caput epididymis	UBERON:0004358	79.92	gold quality
nasal cavity mucosa	UBERON:0001826	79.46	gold quality
stromal cell of endometrium	CL:0002255	79.15	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.04

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

10 targets.

Target	Regulation
ATP1A1
EIF3K
GDNF	Unknown
HMGCR
MYF6	Activation
MYOD1	Activation
OAP
PAX3	Unknown
SCX	Repression
UBA52	Activation

Upstream regulators (CollecTRI, top): MEF2C

miRNA regulators (miRDB)

331 targeting SIX4, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-186-5P	99.99	70.83	3707

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 11)

• SIX4 and SIX6 were linked to the lymph node metastasis in NSCLC. (PMID:27821176)
• MiRNA-621 inhibits the malignant progression of non-small cell lung cancer via targeting SIX4. (PMID:31210312)
• SIX4 acts as a master regulator of oncogenes that promotes tumorigenesis in non-small-cell lung cancer cells. (PMID:31266633)
• High SIX4 expression is associated with colorectal cancer angiogenesis. (PMID:31301290)
• Circular RNA-hsa-circ-0000670 promotes gastric cancer progression through the microRNA-384/SIX4 axis. (PMID:32535033)
• Reciprocal regulation of pancreatic ductal adenocarcinoma growth and molecular subtype by HNF4alpha and SIX1/4. (PMID:32826305)
• SIX4 promotes hepatocellular carcinoma metastasis through upregulating YAP1 and c-MET. (PMID:33046796)
• Upregulation of SIX4 indicates poor clinical outcome and promotes tumor growth and cell metastasis in esophageal squamous cell carcinoma. (PMID:33481352)
• IGF2BP3stabilized SIX4 promotes the proliferation, migration, invasion and tube formation of ovarian cancer cells. (PMID:35616130)
• SIX4 upregulates IDH1 and metabolic reprogramming to promote osteosarcoma progression. (PMID:36601689)
• Knockdown of SIX4 inhibits pancreatic cancer cells via apoptosis induction. (PMID:37656231)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	six4a	ENSDARG00000004695
danio_rerio	six4b	ENSDARG00000031983
mus_musculus	Six4	ENSMUSG00000034460
rattus_norvegicus	Six4	ENSRNOG00000007250
drosophila_melanogaster	Optix	FBGN0025360
drosophila_melanogaster	Six4	FBGN0027364
caenorhabditis_elegans		WBGENE00000453
caenorhabditis_elegans		WBGENE00000455
caenorhabditis_elegans		WBGENE00006775

Paralogs (6): SIX1 (ENSG00000126778), SIX3 (ENSG00000138083), SIX2 (ENSG00000170577), SIX5 (ENSG00000177045), SIX6 (ENSG00000184302), ANHX (ENSG00000227059)

Protein

Protein identifiers

Homeobox protein SIX4 — Q9UIU6 (reviewed: Q9UIU6)

Alternative names: Sine oculis homeobox homolog 4

All UniProt accessions (2): Q9UIU6, G3V2N2

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional regulator which can act as both a transcriptional repressor and activator by binding a DNA sequence on these target genes and is involved in processes like cell differentiation, cell migration and cell survival. Transactivates gene expression by binding a 5’-[CAT]A[CT][CT][CTG]GA[GAT]-3’ motif present in the Trex site and a 5’-TCA[AG][AG]TTNC-3’ motif present in the MEF3 site of the muscle-specific genes enhancer. Acts cooperatively with EYA proteins to transactivate their target genes through interaction and nuclear translocation of EYA protein. Acts synergistically with SIX1 to regulate target genes involved in formation of various organs, including muscle, kidney, gonad, ganglia, olfactory epithelium and cranial skeleton. Plays a role in several important steps of muscle development. Controls the genesis of hypaxial myogenic progenitors in the dermomyotome by transactivating PAX3 and the delamination and migration of the hypaxial precursors from the ventral lip to the limb buds through the transactivation of PAX3, MET and LBX1. Controls myoblast determination by transactivating MYF5, MYOD1 and MYF6. Controls somitic differentiation in myocyte through MYOG transactivation. Plays a role in synaptogenesis and sarcomere organization by participating in myofiber specialization during embryogenesis by activating fast muscle program in the primary myotome resulting in an up-regulation of fast muscle genes, including ATP2A1, MYL1 and TNNT3. Simultaneously, is also able to activate inhibitors of slow muscle genes, such as SOX6, HRASLS, and HDAC4, thereby restricting the activation of the slow muscle genes. During muscle regeneration, negatively regulates differentiation of muscle satellite cells through down-regulation of MYOG expression. During kidney development regulates the early stages of metanephros development and ureteric bud formation through regulation of GDNF, SALL1, PAX8 and PAX2 expression. Plays a role in gonad development by regulating both testis determination and size determination. In gonadal sex determination, transactivates ZFPM2 by binding a MEF3 consensus sequence, resulting in SRY up-regulation. In gonadal size determination, transactivates NR5A1 by binding a MEF3 consensus sequence resulting in gonadal precursor cell formation regulation. During olfactory development mediates the specification and patterning of olfactory placode through fibroblast growth factor and BMP4 signaling pathways and also regulates epithelial cell proliferation during placode formation. Promotes survival of sensory neurons during early trigeminal gangliogenesis. In the developing dorsal root ganglia, up-regulates SLC12A2 transcription. Regulates early thymus/parathyroid organogenesis through regulation of GCM2 and FOXN1 expression. Forms gustatory papillae during development of the tongue. Also plays a role during embryonic cranial skeleton morphogenesis.

Subunit / interactions. Interacts with EYA3; acts cooperatively with EYA3 to transactivate target genes through interaction and nuclear translocation of EYA3 protein.

Subcellular location. Nucleus. Cytoplasm.

Similarity. Belongs to the SIX/Sine oculis homeobox family.

RefSeq proteins (1): NP_059116* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR031701	SIX1_SD	Domain

Pfam: PF00046, PF16878

UniProt features (14 total): sequence variant 4, compositionally biased region 3, region of interest 2, modified residue 2, initiator methionine 1, chain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UIU6-F1	50.19	0.15

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 (2): 2, 640

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 396 (showing top): GOBP_NEUROMUSCULAR_JUNCTION_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, RNGTGGGC_UNKNOWN, CREL_01, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_REGULATION_OF_MORPHOGENESIS_OF_A_BRANCHING_STRUCTURE, GOBP_METANEPHROS_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_SYNAPSE_ASSEMBLY, GOBP_REGULATION_OF_SKELETAL_MUSCLE_CELL_DIFFERENTIATION

GO Biological Process (36): regulation of transcription by RNA polymerase II (GO:0006357), skeletal muscle tissue development (GO:0007519), regulation of synaptic assembly at neuromuscular junction (GO:0008582), male gonad development (GO:0008584), anatomical structure morphogenesis (GO:0009653), male sex determination (GO:0030238), olfactory placode formation (GO:0030910), regulation of protein localization (GO:0032880), protein localization to nucleus (GO:0034504), inner ear morphogenesis (GO:0042472), negative regulation of apoptotic process (GO:0043066), negative regulation of neuron apoptotic process (GO:0043524), tongue development (GO:0043586), sarcomere organization (GO:0045214), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893), male sex differentiation (GO:0046661), thymus development (GO:0048538), generation of neurons (GO:0048699), embryonic cranial skeleton morphogenesis (GO:0048701), regulation of epithelial cell proliferation (GO:0050678), myoblast migration (GO:0051451), pharyngeal system development (GO:0060037), myotome development (GO:0061055), fungiform papilla morphogenesis (GO:0061197), trigeminal ganglion development (GO:0061551), metanephric mesenchyme development (GO:0072075), regulation of branch elongation involved in ureteric bud branching (GO:0072095), positive regulation of ureteric bud formation (GO:0072107), positive regulation of branching involved in ureteric bud morphogenesis (GO:0090190), skeletal muscle fiber differentiation (GO:0098528), negative regulation of satellite cell differentiation (GO:1902725), regulation of DNA-templated transcription (GO:0006355), regulation of gene expression (GO:0010468), positive regulation of transcription by RNA polymerase II (GO:0045944), embryonic skeletal system morphogenesis (GO:0048704)

GO Molecular Function (7): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), transcription regulator complex (GO:0005667), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	4
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
multicellular organism development	2
DNA-templated transcription	2
cellular anatomical structure	2
transcription by RNA polymerase II	1
striated muscle tissue development	1
skeletal muscle organ development	1
regulation of developmental growth	1
synaptic assembly at neuromuscular junction	1
regulation of synapse assembly	1
regulation of neuromuscular junction development	1
gonad development	1
development of primary male sexual characteristics	1
developmental process	1
anatomical structure development	1
sex determination	1
nose development	1
ectodermal placode formation	1
olfactory placode morphogenesis	1
intracellular protein localization	1
regulation of localization	1
protein localization to organelle	1
ear morphogenesis	1
embryonic morphogenesis	1
inner ear development	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
negative regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
sensory organ development	1
myofibril assembly	1
actomyosin structure organization	1
negative regulation of RNA biosynthetic process	1
positive regulation of RNA biosynthetic process	1
sex differentiation	1
hematopoietic or lymphoid organ development	1
gland development	1

Protein interactions and networks

STRING

962 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SIX4	EYA2	O00167	892
SIX4	EYA1	Q99502	772
SIX4	LBX1	P52954	746
SIX4	DACH1	Q9UI36	716
SIX4	KDM6A	O15550	704
SIX4	RHOJ	Q9H4E5	690
SIX4	OTX2	P32243	659
SIX4	EYA4	O95677	609
SIX4	EYA3	Q99504	602
SIX4	PAX3	P23760	545
SIX4	MYOG	P15173	541
SIX4	MYOD1	P15172	518
SIX4	PAX2	Q02962	505
SIX4	MYF6	P23409	496
SIX4	TLE3	Q04726	494

IntAct

40 interactions, top by confidence:

A	B	Type	Score
NFIC	NFIB	psi-mi:“MI:2364”(proximity)	0.690
LRRC46	TFPT	psi-mi:“MI:0914”(association)	0.640
JUN	NFATC1	psi-mi:“MI:0914”(association)	0.610
SIX4	KDM6A	psi-mi:“MI:0915”(physical association)	0.400
CCL1	SIX4	psi-mi:“MI:0915”(physical association)	0.370
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
NTAQ1	SBNO1	psi-mi:“MI:0914”(association)	0.350
EYA1	SPAG9	psi-mi:“MI:0914”(association)	0.350
EYA4	SUPT5H	psi-mi:“MI:0914”(association)	0.350
S100A2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
PRKY	METTL15	psi-mi:“MI:0914”(association)	0.350
GOLGA6L2	GOLGA6L6	psi-mi:“MI:0914”(association)	0.350
HNRNPCL2	SMCHD1	psi-mi:“MI:0914”(association)	0.350
CCT8L2	DVL2	psi-mi:“MI:0914”(association)	0.350
CABP2	PPM1A	psi-mi:“MI:0914”(association)	0.350
EEF1AKMT3	SMCHD1	psi-mi:“MI:0914”(association)	0.350
AFG2B	MMP24OS	psi-mi:“MI:0914”(association)	0.350
EYA2	CNOT1	psi-mi:“MI:2364”(proximity)	0.270
SRF	ZNF292	psi-mi:“MI:2364”(proximity)	0.270
TBXT	BCL9	psi-mi:“MI:2364”(proximity)	0.270
FEV	TAF4	psi-mi:“MI:2364”(proximity)	0.270
FOXL1	PGRMC1	psi-mi:“MI:2364”(proximity)	0.270
GATA2	BCL9	psi-mi:“MI:2364”(proximity)	0.270
GATA3	BCL9	psi-mi:“MI:2364”(proximity)	0.270
HNF1B	BCL9	psi-mi:“MI:2364”(proximity)	0.270
LHX3	BCL9	psi-mi:“MI:2364”(proximity)	0.270
NFIA	BCL9	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (54): SIX4 (Affinity Capture-MS), SIX4 (Affinity Capture-MS), SIX4 (Affinity Capture-MS), SIX4 (Affinity Capture-MS), SIX4 (Proximity Label-MS), SIX4 (Affinity Capture-MS), SIX4 (Affinity Capture-MS), SIX4 (Affinity Capture-MS), SIX4 (Proximity Label-MS), SIX4 (Positive Genetic), SIX4 (Affinity Capture-MS), SIX4 (Affinity Capture-MS), SIX4 (Affinity Capture-MS), SIX4 (Proximity Label-MS), SIX4 (Two-hybrid)

ESM2 similar proteins: A0A1L8GSA2, A0A1L8H0H2, A0JN51, A0JP82, A2AWL7, A2BGM5, A2RRX6, F8VPJ6, K9JHZ4, O13186, O46567, O54826, O89091, P04150, P08235, P15822, P22199, P32519, P36197, P37275, P48552, P55197, P59759, P79269, P79686, Q29131, Q2KHR2, Q3YC04, Q4JM28, Q5R9P5, Q60775, Q61321, Q62947, Q64318, Q68DE3, Q6XLJ0, Q8AYC1, Q8AYC2, Q8BMA5, Q8IZQ8

Diamond homologs: A1YER0, A2D5H2, A6NDR6, A8K0S8, A8WL06, B3DM47, B4F6V6, O00470, O04134, O04135, O14770, O17894, O22299, O35317, O35984, O42406, O46339, O65034, O73916, O80416, O93307, O95343, O95475, P10842, P24345, P40424, P40425, P40426, P40427, P41778, P41779, P41817, P46608, P46609, P46639, P46640, P48731, P53147, P56661, P56662

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
SIX4	“up-regulates quantity by expression”	UBA52	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 57 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
positive regulation of DNA repair	5	34.5×	3e-05
positive regulation of miRNA transcription	5	27.9×	7e-05
anatomical structure morphogenesis	6	16.1×	1e-04
transcription by RNA polymerase II	9	12.2×	6e-06
chromatin remodeling	6	8.4×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	85
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

634 predictions. Top by Δscore:

Variant	Effect	Δscore
14:60723207:CTCA:C	donor_loss	1.0000
14:60723208:TCAC:T	donor_loss	1.0000
14:60723209:CACC:C	donor_loss	1.0000
14:60723210:A:AC	donor_gain	1.0000
14:60723211:C:CC	donor_gain	1.0000
14:60718628:A:C	donor_gain	0.9900
14:60720442:CTCA:C	acceptor_gain	0.9900
14:60723211:CCT:C	donor_gain	0.9900
14:60720444:CA:C	acceptor_gain	0.9800
14:60720446:C:CC	acceptor_gain	0.9800
14:60723206:GCTCA:G	donor_loss	0.9800
14:60723210:AC:A	donor_gain	0.9800
14:60723211:CC:C	donor_gain	0.9800
14:60723211:CCTT:C	donor_gain	0.9700
14:60719756:TTA:T	donor_loss	0.9600
14:60719757:TA:T	donor_loss	0.9600
14:60719758:A:AT	donor_loss	0.9600
14:60719759:CCTTG:C	donor_loss	0.9600
14:60720293:G:C	donor_gain	0.9600
14:60720443:TCA:T	acceptor_gain	0.9600
14:60720444:CAC:C	acceptor_gain	0.9600
14:60713251:A:C	donor_gain	0.9400
14:60719760:C:A	donor_loss	0.9400
14:60720450:A:AC	acceptor_gain	0.9300
14:60719947:TTTC:T	donor_gain	0.9100
14:60720448:G:C	acceptor_gain	0.9100
14:60714130:T:A	donor_gain	0.8900
14:60720450:A:C	acceptor_gain	0.8900
14:60723274:G:T	donor_gain	0.8900
14:60720239:G:A	donor_gain	0.8800

AlphaMissense

5076 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:60723239:C:A	R279M	1.000
14:60723245:C:G	R277P	1.000
14:60723246:G:A	R277C	1.000
14:60723246:G:T	R277S	1.000
14:60723247:C:A	Q276H	1.000
14:60723247:C:G	Q276H	1.000
14:60723248:T:G	Q276P	1.000
14:60723251:C:G	R275P	1.000
14:60723252:G:C	R275G	1.000
14:60723254:C:G	R274P	1.000
14:60723255:G:C	R274G	1.000
14:60723255:G:T	R274S	1.000
14:60723256:G:C	N273K	1.000
14:60723256:G:T	N273K	1.000
14:60723257:T:A	N273I	1.000
14:60723257:T:C	N273S	1.000
14:60723257:T:G	N273T	1.000
14:60723258:T:C	N273D	1.000
14:60723258:T:G	N273H	1.000
14:60723259:C:A	K272N	1.000
14:60723259:C:G	K272N	1.000
14:60723260:T:A	K272M	1.000
14:60723260:T:G	K272T	1.000
14:60723261:T:C	K272E	1.000
14:60723261:T:G	K272Q	1.000
14:60723262:G:C	F271L	1.000
14:60723262:G:T	F271L	1.000
14:60723263:A:C	F271C	1.000
14:60723263:A:G	F271S	1.000
14:60723264:A:C	F271V	1.000

dbSNP variants (sampled 300 via entrez): RS1000037734 (14:60721668 A>C,G), RS1000102938 (14:60719669 A>C,G), RS1000205824 (14:60718469 T>C), RS1000232272 (14:60712744 A>C,G), RS1000408693 (14:60721933 A>T), RS1000465975 (14:60716267 T>G), RS1000491025 (14:60719904 C>A,T), RS1000569864 (14:60714702 T>C), RS1000576243 (14:60715014 C>A,T), RS1001347843 (14:60714997 G>C), RS1001378882 (14:60714776 C>T), RS1001496797 (14:60722440 A>C,T), RS1001592420 (14:60722231 A>G), RS1001763319 (14:60721689 G>A), RS1001789779 (14:60709907 A>G)

Disease associations

OMIM: gene MIM:606342 | disease phenotypes: MIM:605192, MIM:608389

GenCC curated gene-disease

Mondo (2): autosomal dominant nonsyndromic hearing loss 23 (MONDO:0011519), branchiootic syndrome 3 (MONDO:0012025)

Orphanet (1): Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635)

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST005919_2	Exhaled carbon monoxide levels in smokers with chronic obstructive pulmonary disease	6.000000e-08
GCST008839_160	Height	2.000000e-10
GCST010002_153	Refractive error	2.000000e-40

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006520	carbon monoxide exhalation measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C564248	Branchiootic Syndrome 3 (supp.)
C565357	Deafness, Autosomal Dominant 23 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, affects cotreatment, increases abundance, increases expression	3
Valproic Acid	affects expression, decreases expression	3
potassium chromate(VI)	affects cotreatment, increases expression	2
FR900359	increases phosphorylation	1
TAK-243	increases sumoylation	1
urushiol	decreases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	affects expression	1
arsenite	affects binding, decreases reaction	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
coumarin	affects phosphorylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
epigallocatechin gallate	affects cotreatment, increases expression	1
chromium hexavalent ion	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Leflunomide	increases expression	1
Arsenic	increases expression, affects cotreatment, increases abundance	1
Caffeine	increases phosphorylation	1
Carbamazepine	affects expression	1
Cisplatin	affects cotreatment, decreases expression	1
Diuron	decreases expression	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	increases O-linked glycosylation, decreases activity	1
Lipopolysaccharides	affects cotreatment, increases expression, affects response to substance	1
Manganese	increases abundance, increases expression, affects cotreatment	1
Plant Extracts	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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