HOXA2

Summary

HOXA2 (homeobox A2, HGNC:5103) is a protein-coding gene on chromosome 7p15.2, encoding Homeobox protein Hox-A2 (O43364). Sequence-specific transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis.

In vertebrates, the genes encoding the class of transcription factors called homeobox genes are found in clusters named A, B, C, and D on four separate chromosomes. Expression of these proteins is spatially and temporally regulated during embryonic development. This gene is part of the A cluster on chromosome 7 and encodes a DNA-binding transcription factor which may regulate gene expression, morphogenesis, and differentiation. The encoded protein may be involved in the placement of hindbrain segments in the proper location along the anterior-posterior axis during development.

Source: NCBI Gene 3199 — RefSeq curated summary.

At a glance

• Gene–disease (curated): bilateral microtia-deafness-cleft palate syndrome (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 107 total — 5 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 17
• MANE Select transcript: NM_006735

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5103
Approved symbol	HOXA2
Name	homeobox A2
Location	7p15.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000105996
Ensembl biotype	protein_coding
OMIM	604685
Entrez	3199

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 retained_intron

ENST00000222718, ENST00000612779

RefSeq mRNA: 1 — MANE Select: NM_006735 NM_006735

CCDS: CCDS5403

Canonical transcript exons

ENST00000222718 — 2 exons

Exon	Start	End
ENSE00000674254	27102110	27102683
ENSE00001147206	27100354	27101465

Expression profiles

Bgee: expression breadth ubiquitous, 133 present calls, max score 82.78.

FANTOM5 (CAGE): breadth broad, TPM avg 0.8720 / max 31.1128, expressed in 353 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
83259	0.8720	353

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	82.78	silver quality
mucosa of transverse colon	UBERON:0004991	77.52	gold quality
descending thoracic aorta	UBERON:0002345	76.91	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	76.23	gold quality
mucosa of stomach	UBERON:0001199	75.03	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	74.87	gold quality
left uterine tube	UBERON:0001303	74.42	gold quality
lower esophagus	UBERON:0013473	73.99	gold quality
lower esophagus muscularis layer	UBERON:0035833	73.99	gold quality
spinal cord	UBERON:0002240	73.88	gold quality
thoracic aorta	UBERON:0001515	73.28	gold quality
ascending aorta	UBERON:0001496	72.87	gold quality
transverse colon	UBERON:0001157	72.63	gold quality
muscle layer of sigmoid colon	UBERON:0035805	72.04	gold quality
adrenal tissue	UBERON:0018303	71.63	gold quality
metanephros cortex	UBERON:0010533	71.54	gold quality
aorta	UBERON:0000947	70.84	gold quality
esophagus	UBERON:0001043	70.37	gold quality
small intestine Peyer’s patch	UBERON:0003454	69.69	gold quality
body of uterus	UBERON:0009853	69.63	gold quality
popliteal artery	UBERON:0002250	69.29	gold quality
tibial artery	UBERON:0007610	69.29	gold quality
sigmoid colon	UBERON:0001159	68.88	gold quality
rectum	UBERON:0001052	68.18	gold quality
stromal cell of endometrium	CL:0002255	68.03	gold quality
colon	UBERON:0001155	67.85	gold quality
esophagus mucosa	UBERON:0002469	67.59	gold quality
omental fat pad	UBERON:0010414	67.58	gold quality
peritoneum	UBERON:0002358	67.50	gold quality
lower esophagus mucosa	UBERON:0035834	67.15	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.74

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

7 targets.

Target	Regulation
BARX1	Repression
BMP4	Repression
HOXA2
MSX1	Repression
NKX3-2	Repression
PCP4
SIX2

JASPAR motifs

Motif	Name	Family
MA0900.1	HOXA2	HOX
MA0900.2	HOXA2	HOX
MA0900.3	HOXA2	HOX
MA1948.1	ETV5::HOXA2	Ets-related::HOX-related factors
MA1948.2	ETV5::HOXA2	Ets-related::HOX-related factors

JASPAR matrix evidence (PMIDs): PMID:18585359, PMID:24218641

Upstream regulators (CollecTRI, top): CHD8, EGR2, HOXA2, HOXB1, SATB2

miRNA regulators (miRDB)

35 targeting HOXA2, 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-4668-3P	100.00	68.74	2635
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-12130	99.75	65.47	452
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-497-3P	99.61	69.71	1990
HSA-MIR-3609	99.52	69.89	2587
HSA-MIR-548AH-5P	99.52	69.73	2626
HSA-MIR-519D-5P	99.41	69.30	2057
HSA-MIR-19A-5P	99.36	66.93	1675
HSA-MIR-19B-1-5P	99.36	67.07	1669
HSA-MIR-19B-2-5P	99.36	67.07	1669
HSA-MIR-296-3P	99.21	66.56	474
HSA-MIR-4426	99.17	66.74	1949
HSA-MIR-6797-3P	99.17	66.94	668
HSA-MIR-760	98.81	66.65	1392
HSA-MIR-6076	98.61	65.69	637
HSA-MIR-3145-5P	98.57	67.83	900
HSA-MIR-4662B	98.33	66.37	1163
HSA-MIR-4647	98.30	66.41	1139
HSA-MIR-3179	98.22	65.90	1445

Literature-anchored findings (GeneRIF, showing 13)

• A missense mutation in the HOXA2 in a consanguineous iranian family with bilateral microtia was reported. (PMID:18394579)
• Lack of mutations in the coding region of HOXA2 among the sporadic microtia patients. (PMID:20542577)
• we have identified a nonsense mutation (Q235*) in HOXA2 that segregates with bilateral nonsyndromic microtia and hearing loss through three generations of a family in an autosomal dominant pattern. (PMID:23775976)
• HOXA2 acts as a suppressor or TBP-antagonist to inhibit MMP-9 expression; while methylation-mediated inactivation of HOXA2 in NPC derepresses MMP-9 production and increases invasion of NPC cells. (PMID:24243817)
• The Hoxa2-mediated decay of RCHY1 involves both the 19S and 20S proteasome complexes (PMID:26496426)
• The role of HOXA2 gene in dominant isolated microtia and the dysmorphogenetic effect of this gene on ear development (PMID:27503514)
• Performed mutational analysis of TCOF1, GSC, and HOXA2 to determine the mutational features of the 3 genes in Chinese patients with Treacher Collins syndrome. (PMID:27526242)
• 5 genomic variants in GSC, HOXA2 and PRKRA were identified through mutational analysis in Chinese patients with microtia. (PMID:28109504)
• our experiments support that PPP1CB and KPC2 together inhibit the activity of HOXA2 by activating its nuclear export, but favored HOXA2 de-ubiquitination and stabilization thereby establishing a store of HOXA2 in the cytoplasm. (PMID:31323436)
• lncRNA HOTAIRM1 promotes osteogenesis of hDFSCs by epigenetically regulating HOXA2 via DNMT1 in vitro. (PMID:32324272)
• Abnormally high expression of HOXA2 as an independent factor for poor prognosis in glioma patients. (PMID:32436804)
• Identification of loss-of-function HOXA2 mutations in Chinese families with dominant bilateral microtia. (PMID:32649979)
• Comprehensive Landscape of HOXA2, HOXA9, and HOXA10 as Potential Biomarkers for Predicting Progression and Prognosis in Prostate Cancer. (PMID:35372588)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Hoxa2	ENSMUSG00000014704
rattus_norvegicus	Hoxa2	ENSRNOG00000005968

Paralogs (42): HOXA11 (ENSG00000005073), HOXC8 (ENSG00000037965), HOXA1 (ENSG00000105991), HOXA3 (ENSG00000105997), HOXA5 (ENSG00000106004), HOXA6 (ENSG00000106006), HOXA13 (ENSG00000106031), TLX1 (ENSG00000107807), HOXB6 (ENSG00000108511), TLX2 (ENSG00000115297), HOXB8 (ENSG00000120068), HOXB5 (ENSG00000120075), HOXB3 (ENSG00000120093), HOXB1 (ENSG00000120094), HOXA7 (ENSG00000122592), HOXC13 (ENSG00000123364), HOXC11 (ENSG00000123388), HOXC12 (ENSG00000123407), HOXD1 (ENSG00000128645), HOXD3 (ENSG00000128652), HOXD9 (ENSG00000128709), HOXD10 (ENSG00000128710), HOXD11 (ENSG00000128713), HOXD13 (ENSG00000128714), PDX1 (ENSG00000139515), HOXB13 (ENSG00000159184), TLX3 (ENSG00000164438), HOXD4 (ENSG00000170166), HOXD12 (ENSG00000170178), HOXB9 (ENSG00000170689), HOXC5 (ENSG00000172789), HOXB2 (ENSG00000173917), HOXD8 (ENSG00000175879), GSX2 (ENSG00000180613), HOXC9 (ENSG00000180806), HOXC10 (ENSG00000180818), HOXB4 (ENSG00000182742), HOXA4 (ENSG00000197576), HOXC6 (ENSG00000197757), HOXC4 (ENSG00000198353)

Protein

Protein identifiers

Homeobox protein Hox-A2 — O43364 (reviewed: O43364)

Alternative names: Homeobox protein Hox-1K

All UniProt accessions (1): O43364

UniProt curated annotations — full annotation on UniProt →

Function. Sequence-specific transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis.

Subcellular location. Nucleus.

Disease relevance. Microtia, hearing impairment, and cleft palate (MHICP) [MIM:612290] A disease characterized by microtia, mixed symmetric severe to profound hearing impairment, and partial cleft palate. Microtia is a congenital deformity of the outer ear that is small and abnormally shaped. In classic microtia, the pinna is essentially absent, except for a vertical sausage-shaped skin remnant. The superior aspect of this sausage-shaped skin remnant consists of underlying unorganized cartilage, and the inferior aspect of this remnant consists of a relatively well-formed lobule. Syndromic forms of microtia occur in conjunction with other abnormalities including cleft palate, a congenital fissure of the soft and/or hard palate due to faulty fusion. The disease is caused by variants affecting the gene represented in this entry. Microtia with or without hearing impairment (MCRT) [MIM:612290] Microtia is a congenital deformity of the outer ear that is small and abnormally shaped. In classic microtia, the pinna is essentially absent, except for a vertical sausage-shaped skin remnant. The superior aspect of this sausage-shaped skin remnant consists of underlying unorganized cartilage, and the inferior aspect of this remnant consists of a relatively well-formed lobule. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the Antp homeobox family. Proboscipedia subfamily.

RefSeq proteins (1): NP_006726* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR001827	Homeobox_Antennapedia_CS	Conserved_site
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR020479	HD_metazoa	Domain

Pfam: PF00046

UniProt features (7 total): region of interest 3, chain 1, DNA-binding region 1, short sequence motif 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43364-F1	58.47	0.17

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5617472	Activation of anterior HOX genes in hindbrain development during early embryogenesis
R-HSA-9010553	Regulation of expression of SLITs and ROBOs

MSigDB gene sets: 249 (showing top): GOBP_HINDBRAIN_DEVELOPMENT, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_NEGATIVE_REGULATION_OF_NEURON_DIFFERENTIATION, BENPORATH_ES_WITH_H3K27ME3, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_CELLULAR_RESPONSE_TO_LIPID, GCANCTGNY_MYOD_Q6, GOBP_EMBRYONIC_SKELETAL_SYSTEM_DEVELOPMENT, CMYB_01, GOBP_EMBRYONIC_SKELETAL_SYSTEM_MORPHOGENESIS, GOBP_OSTEOBLAST_DIFFERENTIATION, GOBP_NEUROGENESIS, TGACCTY_ERR1_Q2

GO Biological Process (26): cell fate determination (GO:0001709), osteoblast development (GO:0002076), regulation of transcription by RNA polymerase II (GO:0006357), segment specification (GO:0007379), motor neuron axon guidance (GO:0008045), anterior/posterior pattern specification (GO:0009952), dorsal/ventral pattern formation (GO:0009953), rhombomere 2 development (GO:0021568), rhombomere 3 morphogenesis (GO:0021658), brain segmentation (GO:0035284), middle ear morphogenesis (GO:0042474), negative regulation of neuron differentiation (GO:0045665), negative regulation of osteoblast differentiation (GO:0045668), positive regulation of transcription by RNA polymerase II (GO:0045944), embryonic viscerocranium morphogenesis (GO:0048703), pharyngeal system development (GO:0060037), muscle structure development (GO:0061061), cellular response to retinoic acid (GO:0071300), negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of DNA-templated transcription (GO:0006355), pattern specification process (GO:0007389), rhombomere 3 development (GO:0021569), neuron differentiation (GO:0030182), cell fate commitment (GO:0045165), embryonic skeletal system morphogenesis (GO:0048704), embryonic skeletal system development (GO:0048706)

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 repressor activity, RNA polymerase II-specific (GO:0001227), 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 (3): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Activation of HOX genes during differentiation	1
Signaling by ROBO receptors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transcription by RNA polymerase II	3
regulation of transcription by RNA polymerase II	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
osteoblast differentiation	2
regulation of DNA-templated transcription	2
segmentation	2
regionalization	2
embryonic morphogenesis	2
negative regulation of cell differentiation	2
cellular anatomical structure	2
cell fate commitment	1
cellular developmental process	1
cell development	1
pattern specification process	1
axon guidance	1
rhombomere development	1
rhombomere 3 development	1
rhombomere morphogenesis	1
brain development	1
central nervous system segmentation	1
ear morphogenesis	1
neuron differentiation	1
regulation of neuron differentiation	1
regulation of osteoblast differentiation	1
positive regulation of DNA-templated transcription	1
embryonic cranial skeleton morphogenesis	1
chordate embryonic development	1
system development	1
anatomical structure development	1
response to retinoic acid	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
negative regulation of DNA-templated transcription	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
negative regulation of transcription by RNA polymerase II	1

Protein interactions and networks

STRING

1232 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HOXA2	IBSP	P21815	689
HOXA2	SATB2	Q9UPW6	683
HOXA2	LHX8	Q68G74	647
HOXA2	NEUROG2	Q9H2A3	632
HOXA2	ASCL1	P50553	611
HOXA2	FGF8	P55075	606
HOXA2	EGR2	P11161	605
HOXA2	NEUROD4	Q9HD90	600
HOXA2	PAX9	P55771	586
HOXA2	PBX1	P40424	582
HOXA2	MDK	P21741	541
HOXA2	DLX2	Q07687	525
HOXA2	RUNX1	Q01196	505
HOXA2	ATF4	P18848	498
HOXA2	ROBO1	Q9Y6N7	485

IntAct

6 interactions, top by confidence:

A	B	Type	Score
DMPK	HOXA2	psi-mi:“MI:0915”(physical association)	0.370
NDE1	HOXA2	psi-mi:“MI:0915”(physical association)	0.370
	HOXA2	psi-mi:“MI:0915”(physical association)	0.370
HOXA2	SYNJ1	psi-mi:“MI:0914”(association)	0.350
HOXA2	GPX1	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (18): RCHY1 (PCA), HOXA2 (Affinity Capture-Western), HOXA2 (PCA), UBAC1 (PCA), PARP1 (Affinity Capture-MS), HIST1H2BB (Affinity Capture-MS), RECQL (Affinity Capture-MS), LARP1 (Affinity Capture-MS), SYNJ1 (Affinity Capture-MS), ZNF518A (Proximity Label-MS), PRSS2 (Proximity Label-MS), ZNF518B (Proximity Label-MS), ATF7IP (Proximity Label-MS), H2AFV (Proximity Label-MS), GPX1 (Proximity Label-MS)

ESM2 similar proteins: A0A1W2PPK0, A0A1W2PPM1, A1YFT7, A2D5V0, A2T7D1, A7Y7W3, A9L937, B0VXK3, F1Q4R9, G3X9P6, G3X9U1, O43364, P09025, P09092, P09632, P17278, P17481, P24342, P28358, P28359, P31245, P31246, P31263, P31273, Q0VCS4, Q1ECY2, Q1KKS8, Q1KKT2, Q1KKV1, Q1KKV4, Q1KKZ4, Q1KKZ6, Q3LTE0, Q3UT54, Q4JM65, Q4KL20, Q5TM83, Q5TM84, Q68EH7, Q6JIY4

Diamond homologs: A0JPN1, A1YG85, A5PKG8, A6NJ46, A6NMT0, A7MB54, A9L937, B0VXK3, D2KQB0, E7FDX5, M0R6D8, O08686, O13023, O35762, O42365, O43364, O43711, O55144, O88181, O93366, O93367, O93590, P0C1T1, P10035, P14652, P14837, P20009, P28468, P31245, P31246, P31261, P31314, P42583, P42584, P43120, P43345, P43688, P50219, P52945, P52950

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
HNRNPU	“up-regulates quantity by stabilization”	HOXA2	“post transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	2
Uncertain significance	82
Likely benign	10
Benign	4

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
1319942	NM_006735.4(HOXA2):c.235_242del (p.Gly79fs)	Pathogenic
2632947	NM_006735.4(HOXA2):c.687_691del (p.Glu229fs)	Pathogenic
522589	NM_006735.4(HOXA2):c.670G>T (p.Glu224Ter)	Pathogenic
5407	NM_006735.4(HOXA2):c.556C>A (p.Gln186Lys)	Pathogenic
88845	NM_006735.4(HOXA2):c.703C>T (p.Gln235Ter)	Pathogenic
3357785	NM_006735.4(HOXA2):c.271C>T (p.Gln91Ter)	Likely pathogenic
3769652	NM_006735.4(HOXA2):c.251del (p.Pro84fs)	Likely pathogenic

SpliceAI

111 predictions. Top by Δscore:

Variant	Effect	Δscore
7:27102105:CTGA:C	donor_loss	1.0000
7:27102106:TGAC:T	donor_loss	1.0000
7:27102107:GACC:G	donor_loss	1.0000
7:27101464:TT:T	acceptor_gain	0.9900
7:27101464:TTC:T	acceptor_loss	0.9900
7:27101465:TC:T	acceptor_loss	0.9900
7:27101466:C:CC	acceptor_gain	0.9900
7:27101467:T:G	acceptor_loss	0.9900
7:27101483:A:T	acceptor_gain	0.9900
7:27101462:GATT:G	acceptor_gain	0.9800
7:27102108:A:AC	donor_gain	0.9800
7:27102109:C:CC	donor_gain	0.9800
7:27101461:GGATT:G	acceptor_gain	0.9700
7:27101463:ATT:A	acceptor_gain	0.9700
7:27101470:G:T	acceptor_gain	0.9600
7:27101482:C:CT	acceptor_gain	0.9600
7:27102107:GACCT:G	donor_gain	0.9600
7:27101469:C:CT	acceptor_gain	0.9500
7:27102105:CT:C	donor_gain	0.9500
7:27102106:TGA:T	donor_gain	0.9500
7:27102108:A:AT	donor_gain	0.9500
7:27102109:C:CG	donor_gain	0.9500
7:27102104:AC:A	donor_gain	0.9300
7:27102110:C:G	donor_gain	0.9300
7:27102102:GGACT:G	donor_gain	0.9200
7:27102103:GACTG:G	donor_gain	0.9200
7:27102108:AC:A	donor_gain	0.9200
7:27102109:CC:C	donor_gain	0.9200
7:27101482:C:T	acceptor_gain	0.9000
7:27102109:CCT:C	donor_gain	0.9000

AlphaMissense

2464 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:27101257:C:A	R200S	1.000
7:27101257:C:G	R200S	1.000
7:27101258:C:A	R200M	1.000
7:27101258:C:G	R200T	1.000
7:27101260:C:A	K199N	1.000
7:27101260:C:G	K199N	1.000
7:27101262:T:C	K199E	1.000
7:27101266:C:A	K197N	1.000
7:27101266:C:G	K197N	1.000
7:27101268:T:C	K197E	1.000
7:27101269:C:A	M196I	1.000
7:27101269:C:G	M196I	1.000
7:27101269:C:T	M196I	1.000
7:27101270:A:C	M196R	1.000
7:27101270:A:G	M196T	1.000
7:27101270:A:T	M196K	1.000
7:27101272:C:A	R195S	1.000
7:27101272:C:G	R195S	1.000
7:27101273:C:A	R195M	1.000
7:27101273:C:G	R195T	1.000
7:27101274:T:A	R195W	1.000
7:27101274:T:C	R195G	1.000
7:27101276:C:A	R194L	1.000
7:27101276:C:G	R194P	1.000
7:27101277:G:A	R194W	1.000
7:27101277:G:C	R194G	1.000
7:27101278:G:C	N193K	1.000
7:27101278:G:T	N193K	1.000
7:27101279:T:A	N193I	1.000
7:27101279:T:C	N193S	1.000

dbSNP variants (sampled 300 via entrez): RS1000629186 (7:27103532 GC>G,GCC), RS1001636046 (7:27104435 A>G), RS1001971574 (7:27102672 T>C), RS1002066396 (7:27103063 C>G,T), RS1005022815 (7:27102788 TTTGA>T), RS1006293321 (7:27104166 A>G), RS1006343835 (7:27103872 GT>G), RS1007473608 (7:27101061 T>C,G), RS1007523896 (7:27101608 T>A,G), RS1007639724 (7:27101949 A>G), RS1008527928 (7:27103294 A>C), RS1009544450 (7:27102457 T>C), RS1009941212 (7:27104382 C>T), RS1010670407 (7:27100130 G>T), RS1010889088 (7:27104165 A>G)

Disease associations

OMIM: gene MIM:604685 | disease phenotypes: MIM:612290, MIM:615849

GenCC curated gene-disease

Disease	Classification	Inheritance
bilateral microtia-deafness-cleft palate syndrome	Strong	Autosomal dominant
microtia	Supportive	Autosomal dominant

Mondo (4): bilateral microtia-deafness-cleft palate syndrome (MONDO:0012854), hearing loss disorder (MONDO:0005365), postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome (MONDO:0014369), microtia (MONDO:0010920)

Orphanet (2): Bilateral microtia-deafness-cleft palate syndrome (Orphanet:140963), Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome (Orphanet:420584)

HPO phenotypes

17 total (17 of 17 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000175	Cleft palate
HP:0000377	Abnormal pinna morphology
HP:0000396	Overfolded helix
HP:0000402	Stenosis of the external auditory canal
HP:0000410	Mixed hearing impairment
HP:0000413	Atresia of the external auditory canal
HP:0000750	Delayed speech and language development
HP:0001360	Holoprosencephaly
HP:0003577	Congenital onset
HP:0007018	Attention deficit hyperactivity disorder
HP:0008551	Microtia
HP:0008589	Hypoplastic helices
HP:0009892	Anotia
HP:0031229	Increased incisura length
HP:0040119	Unilateral conductive hearing impairment

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST003995_8	Tonsillectomy	2.000000e-13
GCST004343_3	Chronic venous disease	3.000000e-07
GCST005014_187	Tonsillectomy	2.000000e-13

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007924	tonsillectomy risk measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D065817	Congenital Microtia	C09.218.235; C16.131.287
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
C567359	Microtia, Hearing Impairment, And Cleft Palate (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tretinoin	affects reaction, increases reaction, affects cotreatment, decreases reaction, increases expression	3
bisphenol A	affects cotreatment, decreases reaction, increases expression, decreases methylation, increases reaction	2
Nickel	decreases expression	2
LY2955303	affects cotreatment, decreases reaction, increases expression	1
terbufos	increases methylation	1
beta-lapachone	decreases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
sodium arsenite	decreases expression	1
nickel sulfate	increases expression	1
4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid	increases expression, affects cotreatment	1
perfluorooctane sulfonic acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
LE 135	affects cotreatment, increases expression, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
Chir 99021	affects cotreatment, increases expression, affects binding	1
4-(2-(5,6-dihydro-5,5-dimethyl-8-(2-phenylethynyl)naphthalen-2-yl)ethen-1-yl)benzoic acid	affects cotreatment, decreases reaction, increases expression	1
4-(5,6-dihydro-5,5-dimethyl-8-(quinolin-3-yl)naphthalen-2-carboxamido)benzoic acid	affects cotreatment, decreases reaction, increases expression	1
bisphenol S	increases methylation	1
jinfukang	affects cotreatment, decreases expression	1
XAV939	affects binding, affects cotreatment, increases expression	1
LDN 193189	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta(c)quinoline	affects reaction, increases expression	1
3-(4-pyridyl)-1H-indole	affects cotreatment, increases expression	1
Arsenic Trioxide	decreases expression	1
Fulvestrant	affects cotreatment, increases expression, increases reaction	1
Troglitazone	decreases expression	1
Air Pollutants	decreases expression	1
Ascorbic Acid	affects binding, affects cotreatment, increases expression	1
Benzo(a)pyrene	affects methylation	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A2W7	SEES3-1V human HOXA2, clone1	Embryonic stem cell	Male
CVCL_A2W8	SEES3-1V human HOXA2, clone2	Embryonic stem cell	Male
CVCL_A2W9	SEES3-1V human HOXA2, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02518035	PHASE4	UNKNOWN	Silicone Gel to Improve Scar in Microtia Patients
NCT04192708	PHASE4	UNKNOWN	Study of Analgesic Efficacy of Nerve Blocks on Otoplastic Surgery
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
NCT05288790	PHASE2	RECRUITING	Microbiome Metabolites and Alcohol in HIV to Reduce CVD RCT
NCT06087874	PHASE2	RECRUITING	Preventive Effect of Perinatal Oral Probiotic Supplementation (POPS) on Neonatal Jaundice
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
NCT06225336	PHASE1	TERMINATED	Subcutaneous Implant Combination Product (AUR-201) in Patients With Unilateral Microtia (Australia)
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
NCT04399239	PHASE1/PHASE2	TERMINATED	AuriNovo for Auricular Reconstruction
NCT06072040	PHASE1/PHASE2	TERMINATED	Subcutaneous Implant Combination Product (AUR-201) in Patients With Unilateral Microtia
NCT06078566	PHASE1/PHASE2	TERMINATED	Long-Term Follow-Up Study of Unilateral Microtia Patients Implanted With AUR-201
NCT00958802	EARLY_PHASE1	COMPLETED	Tissue Engineering Microtia Auricular Reconstruction: in Vitro and in Vivo Studies
NCT04230746	EARLY_PHASE1	WITHDRAWN	Effect of Antibiotics on Urinary Microbiome