DLX4

Summary

DLX4 (distal-less homeobox 4, HGNC:2917) is a protein-coding gene on chromosome 17q21.33, encoding Homeobox protein DLX-4 (Q92988). May play a role in determining the production of hemoglobin S.

Many vertebrate homeo box-containing genes have been identified on the basis of their sequence similarity with Drosophila developmental genes. Members of the Dlx gene family contain a homeobox that is related to that of Distal-less (Dll), a gene expressed in the head and limbs of the developing fruit fly. The Distal-less (Dlx) family of genes comprises at least 6 different members, DLX1-DLX6. The DLX proteins are postulated to play a role in forebrain and craniofacial development. Three transcript variants have been described for this gene, however, the full length nature of one variant has not been described. Studies of the two splice variants revealed that one encoded isoform functions as a repressor of the beta-globin gene while the other isoform lacks that function.

Source: NCBI Gene 1748 — RefSeq curated summary.

At a glance

• Gene–disease (curated): orofacial cleft 15 (Limited, GenCC)
• GWAS associations: 8
• Clinical variants (ClinVar): 64 total
• Phenotypes (HPO): 41
• Transcription factor: yes — 49 downstream targets (CollecTRI)
• MANE Select transcript: NM_138281

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2917
Approved symbol	DLX4
Name	distal-less homeobox 4
Location	17q21.33
Locus type	gene with protein product
Status	Approved
Aliases	DLX8, BP1
Ensembl gene	ENSG00000108813
Ensembl biotype	protein_coding
OMIM	601911
Entrez	1748

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 4 protein_coding_CDS_not_defined, 1 protein_coding, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000240306, ENST00000503276, ENST00000503410, ENST00000505318, ENST00000611342, ENST00000705772, ENST00000706528

RefSeq mRNA: 1 — MANE Select: NM_138281 NM_138281

CCDS: CCDS11555

Canonical transcript exons

ENST00000240306 — 3 exons

Exon	Start	End
ENSE00001192549	49973701	49974959
ENSE00001293328	49969190	49969751
ENSE00003690390	49973073	49973269

Expression profiles

Bgee: expression breadth ubiquitous, 161 present calls, max score 95.12.

FANTOM5 (CAGE): breadth broad, TPM avg 2.6866 / max 175.3502, expressed in 480 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
161561	0.6499	357
161562	0.6034	160
161563	0.5441	95
161565	0.3927	84
161564	0.2905	78
161566	0.1449	55
208246	0.0612	45

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	95.12	gold quality
tendon of biceps brachii	UBERON:0008188	85.64	silver quality
synovial joint	UBERON:0002217	82.36	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.98	gold quality
periodontal ligament	UBERON:0008266	79.33	gold quality
layer of synovial tissue	UBERON:0007616	79.31	gold quality
placenta	UBERON:0001987	77.79	gold quality
paraflocculus	UBERON:0005351	75.99	gold quality
frontal pole	UBERON:0002795	75.89	silver quality
middle frontal gyrus	UBERON:0002702	75.28	silver quality
pancreatic ductal cell	CL:0002079	74.98	silver quality
Brodmann (1909) area 10	UBERON:0013541	73.58	gold quality
diaphragm	UBERON:0001103	70.91	gold quality
olfactory bulb	UBERON:0002264	70.68	gold quality
type B pancreatic cell	CL:0000169	70.56	gold quality
tongue squamous epithelium	UBERON:0006919	70.23	gold quality
skin of leg	UBERON:0001511	69.91	gold quality
nasal cavity epithelium	UBERON:0005384	69.22	gold quality
skin of abdomen	UBERON:0001416	68.71	gold quality
endometrium epithelium	UBERON:0004811	67.75	gold quality
zone of skin	UBERON:0000014	67.45	gold quality
quadriceps femoris	UBERON:0001377	65.94	gold quality
cerebellar vermis	UBERON:0004720	65.89	gold quality
cervix squamous epithelium	UBERON:0006922	65.71	gold quality
mucosa of paranasal sinus	UBERON:0005030	65.61	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	65.41	gold quality
granulocyte	CL:0000094	65.32	gold quality
hair follicle	UBERON:0002073	65.21	gold quality
vastus lateralis	UBERON:0001379	65.10	gold quality
triceps brachii	UBERON:0001509	64.96	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.15

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

49 targets.

Target	Regulation
ABCB1
ACHE
ALB
AXIN2
BCL2
BMP4	Unknown
BRCA1	Repression
CDH1
CLDN7
CTBP1
EIF4E
FGF2	Activation
FN1
GATA1	Unknown
GNAS
HBB
ICAM1	Unknown
IFNA1
IFNB1
IFNG
IGFBP1
IGH
IKBKE
IL7
KRT5
MIA
MYC	Unknown
NLGN1
NOS1
NOTCH1

Upstream regulators (CollecTRI, top): DLX2, DLX3, RBPJ

miRNA regulators (miRDB)

56 targeting DLX4, 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-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-3910	99.95	71.13	2227
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-8076	99.78	68.52	1170
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-6751-5P	99.56	64.99	1145
HSA-MIR-4708-3P	99.51	67.99	870
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-183-3P	99.41	69.41	1598
HSA-MIR-520A-5P	99.35	66.72	1632
HSA-MIR-525-5P	99.35	66.85	1615
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-8085	99.28	67.56	2362
HSA-MIR-3191-5P	99.24	66.52	1722
HSA-MIR-4279	99.19	66.70	2437
HSA-MIR-6803-5P	99.19	63.90	1026
HSA-MIR-6510-5P	99.14	66.59	1081
HSA-MIR-3160-3P	99.07	64.78	955
HSA-MIR-939-3P	98.97	65.07	2347

Literature-anchored findings (GeneRIF, showing 35)

• Genomic structure and functional control of the Dlx3-7 bigene cluster (PMID:11792834)
• BP1, a homeodomain-containing isoform of DLX4, represses the beta-globin gene. (PMID:11909945)
• involvement of BP1 in the mechanism of the negative regulation of beta-globin transcription. (PMID:15308321)
• BP1 can negatively modulate adult beta-globin gene expression and definitive erythroid cell differentiation, and suggest that BP1 could play a role in thalassemia. (PMID:17003054)
• Increased expression of homeobox gene DLX4 may be a contributing factor to the developmental abnormalities seen in the FGR-affected placentae. (PMID:17062780)
• we were able to show that enforced expression of the DLX4 homeobox gene markedly inhibited in vitro motility and invasion as well as in vivo metastasis via both hematogenous and lymphogenous routes. (PMID:17260014)
• results support the notion that BP1 might contribute to breast neoplastic transformation or tumor progression and suggest for the first time that BP1 mRNA level has potential as a prognostic predictor for breast cancer (PMID:17999690)
• BP1 may regulate bcl-2 and c-myc expression (PMID:18026954)
• BP1 may be part of a pathway contributing to non-small cell lung cancer (NSCLC) development and/or progression and mRNA level could be a novel prognostic marker for NSCLC. (PMID:18420035)
• BP1 is an important upstream factor in the carcinogenic pathway of prostate cancer and that the expression of BP1 may reflect or directly contribute to tumor progression and/or invasion. (PMID:18931648)
• Other mechanisms in addition to gene amplification play a role in BP1 protein expression om breast camcer/ (PMID:18992636)
• High BP1 expression is associated with inflammatory breast cancer and tumor aggressiveness (PMID:19242057)
• The ability of DLX4 to counteract key transcriptional control mechanisms of the TGF-beta cytostatic program could explain, in part, the resistance of tumors to the antiproliferative effect of TGF-beta. (PMID:21297662)
• findings suggest that decreased expression of homeobox protein DLX-4 leads to the pathogenesis of preeclampsia by inhibiting epithelial-mesenchymal transition in trophoblasts (PMID:21602546)
• DLX4 induces cancer cells to undergo epithelial to mesenchymal transition through TWIST, enhancing tumor migration, invasion and metastasis. (PMID:23091415)
• All trans retinoic acid can inhibit the proliferation and the expression of BP1 in breast cancer cells. (PMID:23158431)
• The results suggest that high expression of DLX4 predicts hepatocellular carcinoma prognosis. (PMID:24824934)
• DLX4 increased copy number was observed in 21.6% of the primary breast tumors and 24.3% of the sentinel lymph node metastasis (PMID:24947980)
• DLX4 can functionally replace c-MYC. (PMID:25471527)
• Aberrant DNA methylation of the DLX4 and SIM1 genes may be a novel progression marker for uterine cervical low-grade squamous intraepithelial lesions. (PMID:25614457)
• a DLX4 overexpression vector lacking the 3’UTR was shown to abolish miR-122-induced inhibition of proliferation in the HCC cell line Hep3B. (PMID:25823567)
• Methylated DLX4 is a potential biomarker that predicts poor prognosis after curative resection of pathologic stage I Non-Small Cell Lung Cancer. (PMID:25825198)
• DLX4 promotes ovarian tumor angiogenesis in part by stimulating iNOS expression. (PMID:25924901)
• This first finding of a DLX4 mutation in a family with Cleft lip and/or palate establishes DLX4 as a potential cause of human clefts (PMID:25954033)
• DLX4 induces CD44 by stimulating IL-1beta-mediated NF-kappaB activity, thereby promoting peritoneal metastasis of ovarian cancer (PMID:26067154)
• Collectively, our findings indicate that DLX4 exerts opposing effects on the megakaryocytic and erythroid lineages in part by inducing IL-1beta and NF-kappaB signaling. (PMID:26208636)
• Our study reveals that BP1 overexpression serves as an independent risk factor in de novo AML patients. (PMID:26325005)
• study indicated that DLX4 hypermethylation was a frequent event and acted as an independent prognostic biomarker in de novo myelodysplastic syndrome patients (PMID:26485746)
• indicate that gains of DLX4 and ERBB2 occur in South African breast cancer patients irrespectively of their race and factors known to influence prognosis (PMID:26524685)
• Beta protein 1 (BP1) binds to and regulates estrogen receptor. (PMID:27449292)
• the role of BP1 protein in tumorigenesis of breast cancer and four other malignancies (PMID:29575937)
• indicated the hypothesis that DLX4 variants contributing to nonsyndromic orofacial cleft risk should be interpreted with caution (PMID:29738288)
• Results demonstrate that high expression of BP1 is associated with poor prognosis in patients with endometrial cancer and promotes cell proliferation and migration. (PMID:31100338)
• Homeodomain protein DLX4 facilitates nasopharyngeal carcinoma progression via up-regulation of YB-1. (PMID:32281175)
• DNA methylation-mediated differential expression of DLX4 isoforms has opposing roles in leukemogenesis. (PMID:35883028)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	dlx4a	ENSDARG00000011956
danio_rerio	bsx	ENSDARG00000068976
danio_rerio	dlx4b	ENSDARG00000071560
danio_rerio	vox	ENSDARG00000099761
danio_rerio	vent	ENSDARG00000100483
mus_musculus	Dlx4	ENSMUSG00000020871
rattus_norvegicus	Dlx4	ENSRNOG00000004399
drosophila_melanogaster	Dll	FBGN0000157
caenorhabditis_elegans		WBGENE00000463

Paralogs (9): DLX6 (ENSG00000006377), DLX3 (ENSG00000064195), DLX5 (ENSG00000105880), NANOG (ENSG00000111704), DLX2 (ENSG00000115844), DLX1 (ENSG00000144355), VENTX (ENSG00000151650), BSX (ENSG00000188909), NANOGP8 (ENSG00000255192)

Protein

Protein identifiers

Homeobox protein DLX-4 — Q92988 (reviewed: Q92988)

Alternative names: Beta protein 1, Homeobox protein DLX-7, Homeobox protein DLX-8

All UniProt accessions (1): Q92988

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in determining the production of hemoglobin S. May act as a repressor. During embryonic development, plays a role in palatogenesis.

Subcellular location. Nucleus.

Tissue specificity. Expressed in leukemia cells and placenta. Also expressed in kidney and fetal liver.

Disease relevance. Non-syndromic orofacial cleft 15 (OFC15) [MIM:616788] A birth defect consisting of cleft lips with or without cleft palate. Cleft lips are associated with cleft palate in two-third of cases. A cleft lip can occur on one or both sides and range in severity from a simple notch in the upper lip to a complete opening in the lip extending into the floor of the nostril and involving the upper gum. OFC15 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the distal-less homeobox family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q92988-1	1	yes
Q92988-2	2
Q92988-3	3

RefSeq proteins (1): NP_612138* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000047	HTH_motif	Conserved_site
IPR001356	HD	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR020479	HD_metazoa	Domain
IPR050460	Distal-less_Homeobox_TF	Family

Pfam: PF00046

UniProt features (13 total): sequence conflict 7, splice variant 2, chain 1, DNA-binding region 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92988-F1	66.80	0.27

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 214 (showing top): GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, BENPORATH_ES_WITH_H3K27ME3, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_EMBRYONIC_SKELETAL_SYSTEM_DEVELOPMENT, MODULE_45, TGACCTY_ERR1_Q2, SHEDDEN_LUNG_CANCER_GOOD_SURVIVAL_A5, IRF7_01, GGAANCGGAANY_UNKNOWN, BLALOCK_ALZHEIMERS_DISEASE_UP, TOMIDA_LUNG_CANCER_POOR_SURVIVAL, TCCAGAT_MIR5165P, GOBP_EMBRYO_DEVELOPMENT, SUZUKI_RESPONSE_TO_TSA_AND_DECITABINE_1B, EGR1_01

GO Biological Process (5): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), cell differentiation (GO:0030154), embryonic skeletal system development (GO:0048706)

GO Molecular Function (8): 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), DNA-binding transcription factor activity (GO:0003700), sequence-specific DNA binding (GO:0043565), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (3): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
regulation of DNA-templated transcription	2
cellular anatomical structure	2
negative regulation of DNA-templated transcription	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cellular developmental process	1
skeletal system development	1
chordate embryonic development	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
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription repressor activity	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
DNA binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1

Protein interactions and networks

STRING

732 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DLX4	XRCC5	P13010	459
DLX4	BARX1	Q9HBU1	451
DLX4	XRCC6	P12956	444
DLX4	PAX8	Q06710	427
DLX4	HOPX	Q9BPY8	425
DLX4	POU1F1	P28069	398
DLX4	PAX2	Q02962	398
DLX4	PAX4	O43316	387
DLX4	PAX5	Q02548	378
DLX4	NKX6-3	A6NJ46	370
DLX4	SST	P01166	368
DLX4	EPO	P01588	366
DLX4	BRCA1	P38398	361
DLX4	LHX6	Q9UPM6	359
DLX4	PAX9	P55771	330

IntAct

24 interactions, top by confidence:

A	B	Type	Score
DLX4	SMAD4	psi-mi:“MI:0915”(physical association)	0.600
SMAD4	DLX4	psi-mi:“MI:0915”(physical association)	0.600
DLX4	SMAD4	psi-mi:“MI:0407”(direct interaction)	0.600
SP1	DLX4	psi-mi:“MI:0915”(physical association)	0.600
DLX4	SP1	psi-mi:“MI:0407”(direct interaction)	0.600
DLX4	SMAD2	psi-mi:“MI:0407”(direct interaction)	0.440
DLX4	ABL1	psi-mi:“MI:0915”(physical association)	0.400
DLX4	CRK	psi-mi:“MI:0915”(physical association)	0.400
SRC	DLX4	psi-mi:“MI:0915”(physical association)	0.400
FYN	DLX4	psi-mi:“MI:0915”(physical association)	0.400
DLX4	GRB2	psi-mi:“MI:0915”(physical association)	0.400
DLX4	NCK1	psi-mi:“MI:0915”(physical association)	0.400
DLX4	PIK3R1	psi-mi:“MI:0915”(physical association)	0.400
PLCG1	DLX4	psi-mi:“MI:0915”(physical association)	0.400
LSM3	DLX4	psi-mi:“MI:0915”(physical association)	0.370
DLX4	DIS3	psi-mi:“MI:0914”(association)	0.350
AGO1	DDX39A	psi-mi:“MI:0914”(association)	0.350

BioGRID (6): DLX4 (Reconstituted Complex), GPC6 (Affinity Capture-MS), DIS3 (Affinity Capture-MS), DIS3 (Affinity Capture-MS), GPC6 (Affinity Capture-MS), LSM3 (Two-hybrid)

ESM2 similar proteins: A0A1W2PPF3, A1A546, A1YGA4, A2T779, A2T7T2, A5YC49, A6NFQ7, A6NMT0, A6NNA5, F1Q4R9, O08686, O42173, O42358, P17278, P17482, P20615, P31272, P43688, P52950, P70368, P70436, P97436, P97458, Q01703, Q28ET4, Q2M1V0, Q3LU38, Q3LU39, Q3LU40, Q5NSW5, Q5TIS6, Q5TM83, Q61658, Q62798, Q80Z64, Q8BYH0, Q8JJ26, Q8MJI9, Q91926, Q92988

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

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 15 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
Downstream signal transduction	6	152.3×	4e-10
FCGR3A-mediated phagocytosis	6	74.9×	2e-08
VEGFA-VEGFR2 Pathway	5	46.4×	4e-06
PIP3 activates AKT signaling	5	22.3×	4e-05
Infectious disease	5	8.3×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
ephrin receptor signaling pathway	5	114.6×	2e-07
intracellular signal transduction	5	12.7×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	49
Likely benign	11
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

588 predictions. Top by Δscore:

Variant	Effect	Δscore
17:49969751:GGTA:G	donor_loss	1.0000
17:49969748:GCAG:G	donor_gain	0.9900
17:49969752:G:GG	donor_gain	0.9900
17:49969753:T:G	donor_loss	0.9900
17:49973209:G:GG	donor_gain	0.9900
17:49969747:GGCAG:G	donor_gain	0.9800
17:49969748:GCAGG:G	donor_gain	0.9800
17:49972366:G:GT	donor_gain	0.9800
17:49973071:A:AG	acceptor_gain	0.9800
17:49973072:G:GG	acceptor_gain	0.9800
17:49973208:A:AG	donor_gain	0.9800
17:49973265:CCCAG:C	donor_loss	0.9800
17:49973266:CCAG:C	donor_loss	0.9800
17:49973267:CAGG:C	donor_loss	0.9800
17:49973268:AGGT:A	donor_loss	0.9800
17:49973269:GGTGG:G	donor_loss	0.9800
17:49973271:T:A	donor_loss	0.9800
17:49969749:C:T	donor_gain	0.9700
17:49969749:CAG:C	donor_gain	0.9700
17:49969750:AG:A	donor_gain	0.9700
17:49969751:GG:G	donor_gain	0.9700
17:49973049:ACACC:A	acceptor_gain	0.9700
17:49973050:C:G	acceptor_gain	0.9700
17:49973051:ACCGT:A	acceptor_gain	0.9700
17:49973072:GACTC:G	acceptor_gain	0.9700
17:49973051:ACC:A	acceptor_gain	0.9600
17:49969340:GATCT:G	donor_gain	0.9500
17:49973049:A:AG	acceptor_gain	0.9500
17:49973051:A:AG	acceptor_gain	0.9500
17:49973053:C:A	acceptor_gain	0.9500

AlphaMissense

1525 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:49973713:T:C	F165L	1.000
17:49973715:T:A	F165L	1.000
17:49973715:T:G	F165L	1.000
17:49973195:T:C	F136L	0.999
17:49973197:C:A	F136L	0.999
17:49973197:C:G	F136L	0.999
17:49973211:A:G	Y141C	0.999
17:49973714:T:C	F165S	0.999
17:49973719:A:G	N167D	0.999
17:49973720:A:G	N167S	0.999
17:49973725:C:A	R169S	0.999
17:49973151:G:T	R121M	0.998
17:49973196:T:C	F136S	0.998
17:49973196:T:G	F136C	0.998
17:49973210:T:C	Y141H	0.998
17:49973256:T:C	L156P	0.998
17:49973706:G:C	K162N	0.998
17:49973706:G:T	K162N	0.998
17:49973710:T:A	W164R	0.998
17:49973710:T:C	W164R	0.998
17:49973712:G:C	W164C	0.998
17:49973712:G:T	W164C	0.998
17:49973713:T:A	F165I	0.998
17:49973713:T:G	F165V	0.998
17:49973714:T:G	F165C	0.998
17:49973718:G:C	Q166H	0.998
17:49973718:G:T	Q166H	0.998
17:49973720:A:C	N167T	0.998
17:49973720:A:T	N167I	0.998
17:49973721:C:A	N167K	0.998

dbSNP variants (sampled 300 via entrez): RS1000134392 (17:49971836 C>A,G,T), RS1000188660 (17:49972016 G>A,C), RS1000361406 (17:49969736 C>T), RS1001080719 (17:49970006 C>A), RS1001212873 (17:49974840 C>G), RS1002023586 (17:49971515 A>G), RS1002442414 (17:49969095 G>A), RS1002479206 (17:49971799 G>A), RS1002807593 (17:49967710 T>C), RS1003084870 (17:49970154 C>T), RS1003187409 (17:49967343 C>G,T), RS1003440255 (17:49969998 G>A,C), RS1003706706 (17:49972371 G>A), RS1003913362 (17:49970306 G>C), RS1004766385 (17:49966973 C>T)

Disease associations

OMIM: gene MIM:601911 | disease phenotypes: MIM:616788

GenCC curated gene-disease

Disease	Classification	Inheritance
orofacial cleft 15	Limited	Autosomal dominant

Mondo (1): orofacial cleft 15 (MONDO:0014772)

Orphanet (0):

HPO phenotypes

41 total (30 of 41 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000175	Cleft palate
HP:0000202	Orofacial cleft
HP:0000220	Velopharyngeal insufficiency
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000327	Hypoplasia of the maxilla
HP:0000369	Low-set ears
HP:0000403	Recurrent otitis media
HP:0000405	Conductive hearing impairment
HP:0000411	Protruding ear
HP:0000414	Bulbous nose
HP:0000582	Upslanted palpebral fissure
HP:0000653	Sparse eyelashes
HP:0000689	Dental malocclusion
HP:0000750	Delayed speech and language development
HP:0000954	Single transverse palmar crease
HP:0001611	Hypernasal speech
HP:0002033	Poor suck
HP:0004395	Malnutrition
HP:0006292	Abnormality of dental eruption
HP:0006342	Peg-shaped maxillary lateral incisors
HP:0007651	Ectropion of lower eyelids
HP:0008872	Feeding difficulties in infancy
HP:0009088	Speech articulation difficulties
HP:0009743	Distichiasis
HP:0009890	High anterior hairline
HP:0010294	Palate fistula

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST003075_60	Cognitive decline rate in late mild cognitive impairment	5.000000e-07
GCST005986_27	Blood urea nitrogen levels	2.000000e-08
GCST006016_28	Serum alkaline phosphatase levels	8.000000e-09
GCST006988_55	Blond vs. brown/black hair color	6.000000e-26
GCST006988_72	Blond vs. brown/black hair color	3.000000e-11
GCST008462_10	Plasma factor V levels in venous thrombosis (conditioned on rs6027)	4.000000e-07
GCST011353_27	Serum alkaline phosphatase levels	2.000000e-09
GCST90011900_150	Serum alkaline phosphatase levels	7.000000e-25

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007710	cognitive decline measurement
EFO:0004533	alkaline phosphatase measurement
EFO:0003924	hair color

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, affects cotreatment	7
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	2
Estradiol	decreases expression, increases expression	2
Nickel	decreases expression	2
Silicon Dioxide	decreases expression	2
afuresertib	increases expression	1
apocarotenal	increases expression	1
trichostatin A	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
arsenite	increases methylation	1
sulforaphane	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	increases abundance, increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Poly(amidoamine)	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
Irinotecan	increases expression	1
Resveratrol	decreases expression, affects cotreatment	1
Arsenic Trioxide	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	increases abundance, increases expression	1
Cadmium	decreases expression, increases abundance	1
Carbamazepine	affects expression	1
Cisplatin	affects cotreatment, decreases expression	1
Diethylstilbestrol	decreases expression	1
Hydrogen Peroxide	affects expression	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A0Y6	SEES3-1V human DLX4, clone1	Embryonic stem cell	Male
CVCL_A0Y7	SEES3-1V human DLX4, clone2	Embryonic stem cell	Male
CVCL_A0Y8	SEES3-1V human DLX4, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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