ALX1

Summary

ALX1 (ALX homeobox 1, HGNC:1494) is a protein-coding gene on chromosome 12q21.31, encoding ALX homeobox protein 1 (Q15699). Sequence-specific DNA-binding transcription factor that binds palindromic sequences within promoters and may activate or repress the transcription of a subset of genes.

The specific function of this gene has yet to be determined in humans; however, in rodents, it is necessary for survival of the forebrain mesenchyme and may also be involved in development of the cervix. Mutations in the mouse gene lead to neural tube defects such as acrania and meroanencephaly.

Source: NCBI Gene 8092 — RefSeq curated summary.

At a glance

• Gene–disease (curated): frontonasal dysplasia - severe microphthalmia - severe facial clefting syndrome (Definitive, ClinGen)
• GWAS associations: 8
• Clinical variants (ClinVar): 77 total — 3 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 35
• MANE Select transcript: NM_006982

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1494
Approved symbol	ALX1
Name	ALX homeobox 1
Location	12q21.31
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000180318
Ensembl biotype	protein_coding
OMIM	601527
Entrez	8092

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000316824

RefSeq mRNA: 1 — MANE Select: NM_006982 NM_006982

CCDS: CCDS9028

Canonical transcript exons

ENST00000316824 — 4 exons

Exon	Start	End
ENSE00001236627	85286853	85286981
ENSE00001236635	85283572	85283876
ENSE00001236646	85301155	85301784
ENSE00001236658	85280220	85280487

Expression profiles

Bgee: expression breadth broad, 86 present calls, max score 87.31.

FANTOM5 (CAGE): breadth broad, TPM avg 2.0244 / max 129.7192, expressed in 449 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
127180	1.1705	393
127178	0.4330	103
127181	0.3757	157
127177	0.0243	8
127179	0.0210	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.31	gold quality
metanephros cortex	UBERON:0010533	76.99	gold quality
sperm	CL:0000019	69.92	gold quality
male germ cell	CL:0000015	68.38	gold quality
diaphragm	UBERON:0001103	67.91	gold quality
left uterine tube	UBERON:0001303	67.48	gold quality
tongue squamous epithelium	UBERON:0006919	63.87	gold quality
minor salivary gland	UBERON:0001830	63.69	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	63.67	gold quality
metanephros	UBERON:0000081	62.37	gold quality
upper leg skin	UBERON:0004262	61.42	silver quality
buccal mucosa cell	CL:0002336	61.31	gold quality
stromal cell of endometrium	CL:0002255	61.08	gold quality
mouth mucosa	UBERON:0003729	60.69	gold quality
periodontal ligament	UBERON:0008266	58.07	gold quality
saliva-secreting gland	UBERON:0001044	58.01	gold quality
popliteal artery	UBERON:0002250	57.72	gold quality
mucosa of urinary bladder	UBERON:0001259	57.71	gold quality
tibial artery	UBERON:0007610	57.58	gold quality
nasal cavity mucosa	UBERON:0001826	57.36	gold quality
endocervix	UBERON:0000458	57.14	gold quality
fallopian tube	UBERON:0003889	57.12	gold quality
adult mammalian kidney	UBERON:0000082	57.03	gold quality
corpus epididymis	UBERON:0004359	56.92	silver quality
kidney	UBERON:0002113	56.09	gold quality
cauda epididymis	UBERON:0004360	56.08	silver quality
caput epididymis	UBERON:0004358	55.64	gold quality
cortex of kidney	UBERON:0001225	54.74	gold quality
cerebellar vermis	UBERON:0004720	54.02	gold quality
pancreatic ductal cell	CL:0002079	53.98	silver quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-HCAD-10	yes	46.62
E-ANND-3	no	1.43

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

5 targets.

Target	Regulation
CREBBP
NOTCH1
OGA
PRL	Repression
TRAF4

Upstream regulators (CollecTRI, top): PBX1

miRNA regulators (miRDB)

34 targeting ALX1, 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-5692A	100.00	74.40	6850
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-493-5P	99.96	72.47	2382
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-205-3P	99.92	69.92	3165
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-4517	99.76	69.19	1867
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-646	99.68	67.84	1645
HSA-MIR-6848-3P	99.64	66.49	885
HSA-MIR-8061	99.63	69.44	1411
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-21-5P	99.46	70.54	1035
HSA-MIR-6843-3P	99.26	66.42	915
HSA-MIR-590-5P	99.25	70.76	930
HSA-MIR-664A-3P	99.22	71.08	2696
HSA-MIR-501-5P	98.77	68.88	1328
HSA-MIR-1304-3P	98.29	66.44	1207
HSA-MIR-4257	97.86	68.05	1190
HSA-MIR-1279	97.83	67.50	1898
HSA-MIR-376A-5P	97.70	65.61	863
HSA-MIR-495-5P	97.62	68.28	682
HSA-MIR-320E	97.49	65.96	865
HSA-MIR-6131	97.22	66.72	960

Literature-anchored findings (GeneRIF, showing 10)

• Disruption of CART1 (ALX1) causes extreme microphthalmia and severe facial clefting. (PMID:20451171)
• ALX1 upregulated expression of the key EMT regulator Snail (SNAI1) and that it mediated EMT activation and cell invasion by ALX1. (PMID:23288509)
• hypermethylation of HIST1H4F, PCDHGB6, NPBWR1, ALX1, and HOXA9 was significantly associated with shorter survival in stage 1 Non-small-cell lung cancer (PMID:24081945)
• we found that depletion of ALX1 caused a dramatic cell cycle arrest, followed by massive apoptotic cell death, and eventually resulted in a significant decrease in migration and invasion of the osteosarcoma cell line studied. (PMID:25736924)
• we identify critical roles of ALX1 in lung cancer development and progression (PMID:26722397)
• Knockdown of the CART1 gene significantly inhibited cell invasion and proliferation and induce cell cycle arrest in S phase. (PMID:27053613)
• Our study concludes that the splice site variant identified in the ALX1 gene causes mild form of Frontonasal dysplasia. (PMID:27324866)
• According to our analysis, three proteins, namely aristaless-like homeobox1 isoform X1 (ALX1), major histocompatibility complex polypeptide-related sequence A (MICA), and uncharacterized protein C14orf105 isoform X12 were found to be potential markers for Opisthorchis viverrini (OV)- infection, as they were predominantly found in all OV-infected groups (PMID:29936472)
• ALX1 is highly expressed in human melanoma tissues and cell lines. Knockdown of ALX1 suppressed the proliferation and invasion of melanoma cells. (PMID:30773258)
• Promoter Methylation-mediated Silencing of the MiR-192-5p Promotes Endometrial Cancer Progression by Targeting ALX1. (PMID:34104082)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	alx1	ENSDARG00000062824
mus_musculus	Alx1	ENSMUSG00000036602
rattus_norvegicus	Alx1	ENSRNOG00000004390

Paralogs (50): ARX (ENSG00000004848), PAX6 (ENSG00000007372), PAX7 (ENSG00000009709), ALX4 (ENSG00000052850), GSC2 (ENSG00000063515), PITX1 (ENSG00000069011), PAX2 (ENSG00000075891), RHOXF1 (ENSG00000101883), CRX (ENSG00000105392), EVX1 (ENSG00000106038), PAX4 (ENSG00000106331), NOBOX (ENSG00000106410), PITX3 (ENSG00000107859), PHOX2B (ENSG00000109132), OTX1 (ENSG00000115507), PRRX1 (ENSG00000116132), VSX2 (ENSG00000119614), ESX1 (ENSG00000123576), PAX8 (ENSG00000125618), PAX1 (ENSG00000125813), RHOXF2 (ENSG00000131721), GSC (ENSG00000133937), RAX (ENSG00000134438), PAX3 (ENSG00000135903), ALX3 (ENSG00000156150), HESX1 (ENSG00000163666), PITX2 (ENSG00000164093), UNCX (ENSG00000164853), PHOX2A (ENSG00000165462), OTX2 (ENSG00000165588), DRGX (ENSG00000165606), PRRX2 (ENSG00000167157), SHOX2 (ENSG00000168779), OTP (ENSG00000171540), RAX2 (ENSG00000173976), EVX2 (ENSG00000174279), PROP1 (ENSG00000175325), ISX (ENSG00000175329), MIXL1 (ENSG00000185155), SHOX (ENSG00000185960)

Protein

Protein identifiers

ALX homeobox protein 1 — Q15699 (reviewed: Q15699)

Alternative names: Cartilage homeoprotein 1

All UniProt accessions (2): Q15699, V9HWA7

UniProt curated annotations — full annotation on UniProt →

Function. Sequence-specific DNA-binding transcription factor that binds palindromic sequences within promoters and may activate or repress the transcription of a subset of genes. Most probably regulates the expression of genes involved in the development of mesenchyme-derived craniofacial structures. Early on in development, it plays a role in forebrain mesenchyme survival. May also induce epithelial to mesenchymal transition (EMT) through the expression of SNAI1.

Subunit / interactions. Binds DNA as a homodimer; required for transcriptional activation. Interacts (via homeobox domain) with EP300; acetylates ALX1 and stimulates its transcriptional activity.

Subcellular location. Nucleus.

Tissue specificity. Cartilage and cervix tissue.

Post-translational modifications. Acetylated at Lys-131 by EP300; increases interaction with EP300 and stimulates ALX1 transcriptional activity.

Disease relevance. Frontonasal dysplasia 3 (FND3) [MIM:613456] The term frontonasal dysplasia describes an array of abnormalities affecting the eyes, forehead and nose and linked to midfacial dysraphia. The clinical picture is highly variable. Major findings include true ocular hypertelorism; broadening of the nasal root; median facial cleft affecting the nose and/or upper lip and palate; unilateral or bilateral clefting of the alae nasi; lack of formation of the nasal tip; anterior cranium bifidum occultum; a V-shaped or widow’s peak frontal hairline. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The OAR motif may negatively regulate DNA-binding and therefore transcriptional activity. It is found in the C-terminal transactivation domain that stimulates transcription.

Similarity. Belongs to the paired homeobox family.

RefSeq proteins (1): NP_008913* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR003654	OAR_dom	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR050649	Paired_Homeobox_TFs	Family

Pfam: PF00046, PF03826

UniProt features (9 total): modified residue 4, chain 1, DNA-binding region 1, region of interest 1, short sequence motif 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15699-F1	61.32	0.20

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 (4): 12, 69, 131, 306

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 253 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, MULLIGHAN_NPM1_SIGNATURE_3_UP, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_EPITHELIAL_TO_MESENCHYMAL_TRANSITION, NKX25_02, GOBP_EMBRYONIC_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_EMBRYONIC_SKELETAL_SYSTEM_MORPHOGENESIS, GOBP_NEUROGENESIS, GOBP_NEURAL_TUBE_DEVELOPMENT, HNF1_Q6, GOBP_MORPHOGENESIS_OF_EMBRYONIC_EPITHELIUM, GOBP_ANIMAL_ORGAN_MORPHOGENESIS

GO Biological Process (14): negative regulation of transcription by RNA polymerase II (GO:0000122), neural tube closure (GO:0001843), anterior/posterior pattern specification (GO:0009952), positive regulation of epithelial to mesenchymal transition (GO:0010718), mesenchymal cell development (GO:0014031), embryonic limb morphogenesis (GO:0030326), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), neuron development (GO:0048666), embryonic skeletal system morphogenesis (GO:0048704), stem cell development (GO:0048864), roof of mouth development (GO:0060021), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (8): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), 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), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (6): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), Golgi apparatus (GO:0005794), nuclear body (GO:0016604)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	3
cell development	3
DNA-templated transcription	3
regulation of DNA-templated transcription	3
transcription by RNA polymerase II	2
transcription cis-regulatory region binding	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
cellular anatomical structure	2
intracellular membrane-bounded organelle	2
negative regulation of DNA-templated transcription	1
primary neural tube formation	1
tube closure	1
regionalization	1
epithelial to mesenchymal transition	1
regulation of epithelial to mesenchymal transition	1
positive regulation of cell differentiation	1
positive regulation of multicellular organismal process	1
mesenchymal cell differentiation	1
limb morphogenesis	1
embryonic appendage morphogenesis	1
negative regulation of RNA biosynthetic process	1
positive regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
neuron differentiation	1
embryonic organ morphogenesis	1
skeletal system morphogenesis	1
embryonic skeletal system development	1
stem cell differentiation	1
anatomical structure development	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
transcription regulator activity	1

Protein interactions and networks

STRING

1016 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ALX1	PCDHGB6	Q9Y5F9	621
ALX1	NPBWR1	P48145	580
ALX1	ETS1	P14921	549
ALX1	ALX4	Q9H161	485
ALX1	LRRIQ1	Q96JM4	450
ALX1	HSH2D	Q96JZ2	446
ALX1	IRX2	Q9BZI1	412
ALX1	TFAP2B	Q92481	405
ALX1	SIX1	Q15475	396
ALX1	TBX15	Q96SF7	377
ALX1	NOL11	Q9H8H0	365
ALX1	FOXD3	Q9UJU5	362
ALX1	SIX2	Q9NPC8	351
ALX1	TFAP2A	P05549	351
ALX1	LBX1	P52954	342

IntAct

47 interactions, top by confidence:

A	B	Type	Score
CLIC3	ALX1	psi-mi:“MI:0915”(physical association)	0.560
APCS	ALX1	psi-mi:“MI:0915”(physical association)	0.560
GRP	ALX1	psi-mi:“MI:0915”(physical association)	0.560
ALX1	KAT5	psi-mi:“MI:0915”(physical association)	0.560
ALX1	KRTAP4-4	psi-mi:“MI:0915”(physical association)	0.560
ALX1	RBM45	psi-mi:“MI:0915”(physical association)	0.560
ALX1	ZNF300	psi-mi:“MI:0915”(physical association)	0.560
EEF1D	ALX1	psi-mi:“MI:0915”(physical association)	0.560
ALX1	UROC1	psi-mi:“MI:0915”(physical association)	0.560
ALX1	PACRGL	psi-mi:“MI:0915”(physical association)	0.560
RARA	ALX1	psi-mi:“MI:0915”(physical association)	0.560
ALX1	OR52L1	psi-mi:“MI:0915”(physical association)	0.560
ALX1	IPO13	psi-mi:“MI:0915”(physical association)	0.510
CFTR	CNOT1	psi-mi:“MI:0914”(association)	0.480
	ALX1	psi-mi:“MI:0915”(physical association)	0.370
ALX1	ALX4	psi-mi:“MI:0915”(physical association)	0.370
M		psi-mi:“MI:0914”(association)	0.350
MPL	FAM171A2	psi-mi:“MI:0914”(association)	0.350
AFG2A	ESYT2	psi-mi:“MI:0914”(association)	0.350
POLD3	ESYT2	psi-mi:“MI:0914”(association)	0.350
AFG2B	MMP24OS	psi-mi:“MI:0914”(association)	0.350
CLIC3	ALX1	psi-mi:“MI:0915”(physical association)	0.000
UROC1	ALX1	psi-mi:“MI:0915”(physical association)	0.000
PACRGL	ALX1	psi-mi:“MI:0915”(physical association)	0.000
RARA	ALX1	psi-mi:“MI:0915”(physical association)	0.000
OR52L1	ALX1	psi-mi:“MI:0915”(physical association)	0.000
APCS	ALX1	psi-mi:“MI:0915”(physical association)	0.000
GRP	ALX1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (25): IPO13 (Two-hybrid), IPO13 (Affinity Capture-Western), ALX1 (Affinity Capture-MS), ALX1 (Two-hybrid), ALX1 (Two-hybrid), ALX1 (Two-hybrid), ALX1 (Two-hybrid), ALX1 (Two-hybrid), ALX1 (Two-hybrid), ALX1 (Two-hybrid), ALX1 (Two-hybrid), ALX1 (Two-hybrid), ALX1 (Two-hybrid), ALX1 (Two-hybrid), OR52L1 (Two-hybrid)

ESM2 similar proteins: A1YFT7, A2D5V0, A2D635, A2T6F8, A2T7D1, G3X9P6, O42502, O57374, P09092, P21711, P24342, P28358, P28359, P31257, P31263, P42583, P79724, Q08820, Q15699, Q1ECY2, Q1KKS8, Q1KKT0, Q1KKV1, Q1KKV4, Q1KKZ4, Q1KKZ6, Q6JIY4, Q6JIY5, Q6NSW7, Q8AWY2, Q8JJ26, Q90469, Q90470, Q91685, Q91926, Q9DDU1, Q9DDU2, Q9H9S0, Q9IA13, Q9IA14

Diamond homologs: A0A1W2PPK0, A0A1W2PPM1, A1A546, A1YEY5, A1YFI3, A1YG57, A1YGA2, A2T733, A2T777, A2T7P4, A6NFQ7, G5EC89, L8E946, O14813, O15499, O35690, O42250, O42356, O42357, O42477, O70137, O73917, O75360, O95076, O97670, P0DMV5, P26367, P26630, P29454, P41935, P47237, P47238, P53544, P53545, P53546, P54366, P55813, P55864, P56915, P56916

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	46
Likely benign	15
Benign	9

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
3069063	NC_000012.11:g.(?85673997)(85695563_?)del	Pathogenic
8111	NM_006982.3(ALX1):c.531+1G>A	Pathogenic
827658	NM_006982.3(ALX1):c.661-1G>C	Pathogenic
2572390	NM_006982.3(ALX1):c.151C>T (p.Gln51Ter)	Likely pathogenic

SpliceAI

828 predictions. Top by Δscore:

Variant	Effect	Δscore
12:85280485:GCG:G	donor_gain	1.0000
12:85281431:T:G	donor_gain	1.0000
12:85283563:T:TA	acceptor_gain	1.0000
12:85283564:G:A	acceptor_gain	1.0000
12:85283570:A:AG	acceptor_gain	1.0000
12:85283571:G:GG	acceptor_gain	1.0000
12:85280488:G:GC	donor_loss	0.9900
12:85280488:G:GG	donor_gain	0.9900
12:85280489:TGA:T	donor_loss	0.9900
12:85280490:GAGTC:G	donor_loss	0.9900
12:85285025:G:GT	donor_gain	0.9900
12:85280491:AGT:A	donor_loss	0.9800
12:85283570:AGT:A	acceptor_gain	0.9800
12:85283571:GT:G	acceptor_gain	0.9800
12:85283571:GTG:G	acceptor_gain	0.9800
12:85283571:GTGA:G	acceptor_gain	0.9800
12:85283571:GTGAA:G	acceptor_gain	0.9800
12:85280483:CAGCG:C	donor_gain	0.9700
12:85283568:A:AG	acceptor_gain	0.9700
12:85283568:ACAGT:A	acceptor_gain	0.9700
12:85283569:CA:C	acceptor_loss	0.9700
12:85283570:A:AC	acceptor_loss	0.9700
12:85286979:CAG:C	donor_loss	0.9700
12:85286980:AG:A	donor_loss	0.9700
12:85286981:GG:G	donor_loss	0.9700
12:85286982:G:GA	donor_loss	0.9700
12:85301149:TTCCA:T	acceptor_loss	0.9700
12:85301150:TCCA:T	acceptor_loss	0.9700
12:85301151:CCAG:C	acceptor_loss	0.9700
12:85301152:CA:C	acceptor_loss	0.9700

AlphaMissense

2174 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:85283746:G:C	R134T	1.000
12:85283746:G:T	R134M	1.000
12:85283747:G:C	R134S	1.000
12:85283747:G:T	R134S	1.000
12:85283751:C:G	R136G	1.000
12:85283752:G:A	R136Q	1.000
12:85283752:G:C	R136P	1.000
12:85283752:G:T	R136L	1.000
12:85283755:C:A	T137N	1.000
12:85283755:C:T	T137I	1.000
12:85283760:T:A	F139I	1.000
12:85283760:T:C	F139L	1.000
12:85283760:T:G	F139V	1.000
12:85283761:T:C	F139S	1.000
12:85283761:T:G	F139C	1.000
12:85283762:C:A	F139L	1.000
12:85283762:C:G	F139L	1.000
12:85283764:C:T	T140I	1.000
12:85283773:A:G	Q143R	1.000
12:85283774:G:C	Q143H	1.000
12:85283774:G:T	Q143H	1.000
12:85283776:T:A	L144Q	1.000
12:85283776:T:C	L144P	1.000
12:85283785:T:A	L147Q	1.000
12:85283785:T:C	L147P	1.000
12:85283785:T:G	L147R	1.000
12:85283787:G:A	E148K	1.000
12:85283788:A:T	E148V	1.000
12:85283789:G:C	E148D	1.000
12:85283789:G:T	E148D	1.000

dbSNP variants (sampled 300 via entrez): RS1000060900 (12:85278580 A>C), RS1000312242 (12:85278401 G>A,C,T), RS1000341600 (12:85284629 T>A), RS1000462091 (12:85291013 G>A), RS1000531801 (12:85295580 A>T), RS1000542557 (12:85301866 G>C,T), RS1000659807 (12:85289758 A>G), RS1000664655 (12:85295604 T>A,C), RS1000796713 (12:85289504 C>A,G), RS1000964669 (12:85295908 T>C), RS1000969177 (12:85301667 G>A), RS1001167335 (12:85290882 G>A,C), RS1001190110 (12:85283907 G>C), RS1001316068 (12:85278986 A>C), RS1001367966 (12:85278772 A>C,G)

Disease associations

OMIM: gene MIM:601527 | disease phenotypes: MIM:613456

GenCC curated gene-disease

Disease	Classification	Inheritance
frontonasal dysplasia - severe microphthalmia - severe facial clefting syndrome	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
frontonasal dysplasia - severe microphthalmia - severe facial clefting syndrome	Definitive	AR

Mondo (2): lung adenocarcinoma (MONDO:0005061), frontonasal dysplasia - severe microphthalmia - severe facial clefting syndrome (MONDO:0013271)

Orphanet (2): Frontonasal dysplasia-severe microphthalmia-severe facial clefting syndrome (Orphanet:306542), NON RARE IN EUROPE: Adenocarcinoma of the lung (Orphanet:415268)

HPO phenotypes

35 total (30 of 35 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000175	Cleft palate
HP:0000248	Brachycephaly
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000327	Hypoplasia of the maxilla
HP:0000349	Widow’s peak
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000384	Preauricular skin tag
HP:0000405	Conductive hearing impairment
HP:0000430	Underdeveloped nasal alae
HP:0000431	Wide nasal bridge
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000568	Microphthalmia
HP:0000625	Eyelid coloboma
HP:0000636	Upper eyelid coloboma
HP:0000653	Sparse eyelashes
HP:0001156	Brachydactyly
HP:0001249	Intellectual disability
HP:0001274	Agenesis of corpus callosum
HP:0001636	Tetralogy of Fallot
HP:0002006	Tessier cleft
HP:0002057	Prominent glabella
HP:0002223	Absent eyebrow
HP:0004423	Cranium bifidum occultum
HP:0005258	Pectoral muscle hypoplasia/aplasia
HP:0005466	Hypoplasia of the frontal bone
HP:0006931	Pericallosal lipoma

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST003654_17	Bone mineral density (Ward’s triangle area)	6.000000e-07
GCST003999_14	Nose size	4.000000e-08
GCST006481_24	Lung function (FEV1)	4.000000e-08
GCST006483_56	Lung function (FVC)	1.000000e-08
GCST006483_57	Lung function (FVC)	8.000000e-08
GCST006483_7	Lung function (FVC)	2.000000e-08
GCST009357_5	Nonsyndromic cleft lip	4.000000e-08
GCST010703_58	Brain morphology (MOSTest)	2.000000e-08

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0007785	femoral neck bone mineral density
EFO:0004314	forced expiratory volume
EFO:0004312	vital capacity
EFO:0003959	cleft lip
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	6
trichostatin A	increases expression, affects cotreatment	3
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
TAK-243	increases sumoylation	1
titanium dioxide	increases methylation	1
sodium arsenite	increases expression	1
butylbenzyl phthalate	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	increases expression, affects response to substance	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Catechin	affects cotreatment, decreases expression	1
Lipopolysaccharides	affects response to substance, increases expression	1
Tretinoin	increases expression	1
Aflatoxin B1	decreases methylation	1
Okadaic Acid	decreases expression	1
Particulate Matter	increases expression	1
Magnetite Nanoparticles	increases methylation	1

Cellosaurus cell lines

4 cell lines: 4 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A0A6	SEES3-1V human ALX1, clone1	Embryonic stem cell	Male
CVCL_A0A7	SEES3-1V human ALX1, clone2	Embryonic stem cell	Male
CVCL_A0A8	SEES3-1V human ALX1, clone3	Embryonic stem cell	Male
CVCL_A7II	WAe001-A-60	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02399566	PHASE4	UNKNOWN	Clinical Trial of Erlotinib and Pemetrexed for Maintenance Treatment in Lung Adenocarcinoma
NCT02804646	PHASE4	UNKNOWN	Endostar Durative Transfusion Combined With Chemotherapy in the Treatment of Advanced Lung Adenocarcinoma
NCT00002852	PHASE3	COMPLETED	Surgery With or Without Chemotherapy in Treating Patients With Stage I Non-small Cell Lung Cancer
NCT00005838	PHASE3	COMPLETED	Combination Chemotherapy Plus Radiation Therapy With or Without AE-941 in Treating Patients With Stage III Non-small Cell Lung Cancer That Cannot Be Removed By Surgery
NCT00020709	PHASE3	COMPLETED	Combination Chemotherapy and Radiation Therapy With or Without Gefitinib in Treating Patients With Stage III Non-Small Cell Lung Cancer That Cannot Be Removed By Surgery
NCT00049543	PHASE3	COMPLETED	Gefitinib in Treating Patients With Stage IB, II, or IIIA Non-small Cell Lung Cancer That Was Completely Removed by Surgery
NCT00946712	PHASE3	TERMINATED	S0819: Carboplatin and Paclitaxel With or Without Bevacizumab and/or Cetuximab in Treating Patients With Stage IV or Recurrent Non-Small Cell Lung Cancer
NCT01798485	PHASE3	TERMINATED	A Phase 3 Study of Ganetespib in Combination With Docetaxel Versus Docetaxel Alone in Patients With Advanced NSCLC
NCT02011997	PHASE3	UNKNOWN	Comparison of cVATS Segmentectomy Versus Lobectomy for Lung Adenocarcinoma in Situ and With Microinvasion
NCT03391869	PHASE3	ACTIVE_NOT_RECRUITING	Nivolumab and Ipilimumab With or Without Local Consolidation Therapy in Treating Patients With Stage IV Non-Small Cell Lung Cancer
NCT03676192	PHASE3	COMPLETED	To Compare Efficacy and Safety of CT-P16 and European Union-Approved Avastin as First-Line Treatment for Metastatic or Recurrent Non-Squamous Non-Small Cell Lung Cancer
NCT04339218	PHASE3	RECRUITING	Cryoablation in Combination (or Not) With Pembrolizumab and Pemetrexed-carboplatin in 1st-line Treatment for Patients With Metastatic Lung Adenocarcinoma
NCT05204758	PHASE3	COMPLETED	Prophylactic TCM for Mitigation of EGFR-TKI Related Dermatological Adverse Effect
NCT05717803	PHASE3	RECRUITING	Segmentectomy for Ground Glass-dominant Invasive Lung Cancer (ECTOP-1012)
NCT05943795	PHASE3	ACTIVE_NOT_RECRUITING	A Clinical Study of SI-B001 Combined With Docetaxel in the Treatment of Non-small Cell Lung Adenocarcinoma and Lung Squamous Cell Carcinoma
NCT06031181	PHASE3	RECRUITING	Sublobar Resection for Adenocarcinoma in Situ/Minimally Invasive Adenocarcinoma Diagnosed by Intraoperative Frozen Section (ECTOP-1019)
NCT06031246	PHASE3	RECRUITING	Selective Lymph Node Dissection for cT1N0M0 Invasive NSCLC With CTR>0.5 Located in the Apical Segment (ECTOP-1018)
NCT06634966	PHASE3	RECRUITING	Segmentectomy for Solid-dominant Lung Cancer
NCT07169903	PHASE3	NOT_YET_RECRUITING	Segmentectomy vs Lobectomy for 2 - 3cm IASLC Grade 1-2 Lung Adenocarcinoma: A Multi-center RCT
NCT07481786	PHASE3	RECRUITING	Bevacizumab Plus FSRT Versus Hippocampus-Avoidant WBRT in Lung Adenocarcinoma With Extensive Brain Metastases
NCT00040794	PHASE2	COMPLETED	Combination Chemotherapy, Radiation Therapy, and Gefitinib in Treating Patients With Stage III Non-Small Cell Lung Cancer
NCT00087412	PHASE2	COMPLETED	S0341: Erlotinib in Treating Patients With Advanced Primary Non-Small Cell Lung Cancer
NCT00118144	PHASE2	COMPLETED	Bortezomib in Treating Patients With Stage IIIB or Stage IV Lung Cancer
NCT00118183	PHASE2	COMPLETED	Docetaxel With Either Cetuximab or Bortezomib as First-Line Therapy in Treating Patients With Stage III or Stage IV Non-Small Cell Lung Cancer
NCT00126581	PHASE2	COMPLETED	Erlotinib Hydrochloride With or Without Carboplatin and Paclitaxel in Treating Patients With Stage III-IV Non-small Cell Lung Cancer
NCT00334815	PHASE2	ACTIVE_NOT_RECRUITING	Combination Chemotherapy, Radiation Therapy, and Bevacizumab in Treating Patients With Newly Diagnosed Stage III Non-small Cell Lung Cancer That Cannot Be Removed by Surgery
NCT00368992	PHASE2	COMPLETED	S0536: Cetuximab, Paclitaxel, Carboplatin, and Bevacizumab in Treating Patients With Advanced Non-Small Cell Lung Cancer
NCT00511485	PHASE2	COMPLETED	Study of Vintafolide (MK-8109, EC145) in Participants With Progressive Adenocarcinoma of the Lung (MK-8109-008, EC-FV-03)
NCT00950365	PHASE2	COMPLETED	Pemetrexed Disodium With or Without Erlotinib Hydrochloride in Treating Patients With Stage IIIB-IV or Recurrent Non-Small Cell Lung Cancer
NCT00955305	PHASE2	TERMINATED	Paclitaxel, Carboplatin, and Bevacizumab With or Without Cixutumumab in Treating Patients With Stage IV or Recurrent Non-small Cell Lung Cancer
NCT01218516	PHASE2	COMPLETED	A Safety and Efficacy Study of Farletuzumab in Participants With Adenocarcinoma of the Lung
NCT01294306	PHASE2	COMPLETED	MK2206 and Erlotinib Hydrochloride in Treating Patients With Advanced Non-Small Cell Lung Cancer Who Have Progressed After Previous Response to Erlotinib Hydrochloride Therapy
NCT01557959	PHASE2	COMPLETED	Docetaxel, Cisplatin, Pegfilgrastim, and Erlotinib Hydrochloride in Treating Patients With Stage IIIB or Stage IV Non-Small Cell Lung Cancer
NCT01561456	PHASE2	COMPLETED	Study of AXL1717 Compared to Docetaxel to Treat Squamous Cell Carcinoma or Adenocarcinoma of the Lung
NCT01578551	PHASE2	TERMINATED	Study of Metformin Plus Paclitaxel/Carboplatin/Bevacizumab in Patients With Adenocarcinoma.
NCT01578668	PHASE2	COMPLETED	Erlotinib Plus Pemetrexed to Treat Lung Adenocarcinoma With Brain Metastases
NCT01819428	PHASE2	TERMINATED	NOV120101 (Poziotinib) for 1st Line Monotherapy in Patients With Lung Adenocarcinoma
NCT01935336	PHASE2	COMPLETED	Study of Ponatinib in Patients With Lung Cancer Preselected Using Different Candidate Predictive Biomarkers
NCT02134912	PHASE2	TERMINATED	S1300: Pemetrexed Disodium With or Without Crizotinib in Treating Patients With Stage IV Non-Small Cell Lung Cancer That Has Progressed After Crizotinib
NCT02186847	PHASE2	COMPLETED	Chemotherapy and Radiation Therapy With or Without Metformin Hydrochloride in Treating Patients With Stage III Non-small Cell Lung Cancer