ALX4

Summary

ALX4 (ALX homeobox 4, HGNC:450) is a protein-coding gene on chromosome 11p11.2, encoding Homeobox protein aristaless-like 4 (Q9H161). Transcription factor involved in skull and limb development. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a paired-like homeodomain transcription factor expressed in the mesenchyme of developing bones, limbs, hair, teeth, and mammary tissue. Mutations in this gene cause parietal foramina 2 (PFM2); an autosomal dominant disease characterized by deficient ossification of the parietal bones. Mutations in this gene also cause a form of frontonasal dysplasia with alopecia and hypogonadism; suggesting a role for this gene in craniofacial development, mesenchymal-epithelial communication, and hair follicle development. Deletion of a segment of chromosome 11 containing this gene, del(11)(p11p12), causes Potocki-Shaffer syndrome (PSS); a syndrome characterized by craniofacial anomalies, cognitive disability, multiple exostoses, and genital abnormalities in males. In mouse, this gene has been shown to use dual translation initiation sites located 16 codons apart.

Source: NCBI Gene 60529 — RefSeq curated summary.

At a glance

• Gene–disease (curated): frontonasal dysplasia with alopecia and genital anomaly (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 12
• Clinical variants (ClinVar): 337 total — 16 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 100
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_021926

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:450
Approved symbol	ALX4
Name	ALX homeobox 4
Location	11p11.2
Locus type	gene with protein product
Status	Approved
Aliases	FPP, PFM, KIAA1788
Ensembl gene	ENSG00000052850
Ensembl biotype	protein_coding
OMIM	605420
Entrez	60529

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000652299

RefSeq mRNA: 1 — MANE Select: NM_021926 NM_021926

CCDS: CCDS31468

Canonical transcript exons

ENST00000652299 — 4 exons

Exon	Start	End
ENSE00001136152	44267494	44267622
ENSE00001245801	44275348	44275658
ENSE00001317275	44260440	44265183
ENSE00003842515	44309597	44310139

Expression profiles

Bgee: expression breadth broad, 82 present calls, max score 76.93.

FANTOM5 (CAGE): breadth broad, TPM avg 1.3130 / max 186.8078, expressed in 292 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
119434	0.8120	236
119436	0.2380	83
119433	0.1042	70
119439	0.0593	15
119438	0.0318	12
119437	0.0245	9
119435	0.0218	6
119440	0.0215	6

Top tissues by expression

238 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	76.93	gold quality
buccal mucosa cell	CL:0002336	60.08	gold quality
cranial nerve II	UBERON:0000941	60.05	silver quality
tendon of biceps brachii	UBERON:0008188	59.11	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	58.77	gold quality
bone marrow cell	CL:0002092	57.57	gold quality
tendon	UBERON:0000043	57.57	gold quality
myocardium	UBERON:0002349	57.45	gold quality
hindlimb stylopod muscle	UBERON:0004252	56.96	gold quality
calcaneal tendon	UBERON:0003701	56.77	gold quality
ganglionic eminence	UBERON:0004023	54.54	silver quality
skin of abdomen	UBERON:0001416	51.59	gold quality
sural nerve	UBERON:0015488	51.41	gold quality
skin of leg	UBERON:0001511	50.88	gold quality
zone of skin	UBERON:0000014	49.91	gold quality
nasal cavity mucosa	UBERON:0001826	49.89	gold quality
muscle of leg	UBERON:0001383	49.64	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	gold quality
colonic epithelium	UBERON:0000397	48.81	gold quality
medial globus pallidus	UBERON:0002477	48.60	gold quality
stromal cell of endometrium	CL:0002255	47.84	gold quality
skeletal muscle tissue	UBERON:0001134	47.66	silver quality
prefrontal cortex	UBERON:0000451	47.64	gold quality
globus pallidus	UBERON:0001875	47.60	gold quality
gastrocnemius	UBERON:0001388	47.45	gold quality
minor salivary gland	UBERON:0001830	47.45	gold quality
saliva-secreting gland	UBERON:0001044	47.43	gold quality
renal glomerulus	UBERON:0000074	47.29	gold quality
muscle tissue	UBERON:0002385	47.26	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.10

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
NCAM1	Repression

Upstream regulators (CollecTRI, top): FOXC1

miRNA regulators (miRDB)

181 targeting ALX4, 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-5193	100.00	67.26	1744
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-4531	99.99	69.70	3181
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 22)

• One subject with parietal foramina whose deletion does not include ALX4 indicates that ALX4 in this subject may be rendered functionally haploinsufficient by a position effect. (PMID:15852040)
• The ALX4 mutation p.R218Q tends to result in persistent cranium bifidum and is associated with anatomical abnormalities of the posterior fossa. (PMID:16319823)
• ALX4 plays a critical role in craniofacial and epidermal development. (PMID:19692347)
• data show a distinct pattern of expression of ALX4 in the human breast relative to the murine mammary gland, and the loss of ALX4 in tumours and the surrounding untransformed stroma is a basic characteristic of ductal carcinoma. (PMID:19783719)
• Data show that methylated DNA from advanced precancerous colorectal lesions can be detected using a panel of two DNA methylation markers, ALX4 and SEPT9. (PMID:20140221)
• Downregulation of HoxB2, HoxB4 and Alx4 expression during the narrow window of early embryogenesis may cause omphalocele in the Cd chick model by interfering with molecular signaling required for proper VBW formation. (PMID:20625746)
• Exclusion of mutations in ALX4 gene in patients with the syndrome of frontonasal dysgenesis, callosal agenesis, basal encephalocele, and eye anomalies (PMID:22496059)
• ALX4 variants may have an impact on the genetic etiology of nonsyndromic craniosynostosis. (PMID:22829454)
• study describes 2 related individuals with a heterozygous mutation in ALX4 presenting a distinct phenotype of frontonasal dysplasia; suggest that the loss of the ALX4 OAR domain with the maintenance of the homeodomain impairs the function of the normal allele in a dominant-negative effect (PMID:23401352)
• Epigenetic silencing of Aristaless-like homeobox-4 is associated with lung cancer. (PMID:24037716)
• We suggest that all ALX4 heterozygote carriers be examined in detail for possible changes in nasal configuration, to establish a detailed genotype-phenotype correlation, leading the way to more comprehensive genetic counseling. (PMID:24764194)
• High-quality solution NMR structures of three homeodomains from human proteins ALX4, ZHX1 and CASP8AP2 were solved. (PMID:24941917)
• Our results show that HOXB13/SLUG and ALX4/SLUG axes are novel pathways that promote EMT and invasion of ovarian cancer cells. (PMID:25944620)
• mother of Case 2 also had a mutation in the ALX4 gene, but no enlarged parietal foramina (PMID:27349084)
• overexpression of ALX4 inhibited the proliferation, invasion, and epithelial-mesenchymal transition (EMT) in HCC cells. ALX4 had an inhibitory effect on the sonic hedgehog (Shh) signaling pathway. (PMID:28081728)
• We reveal for the first time that ALX4 acts as a novel functional tumor suppressor inactivated by DNA methylation and is an independent prognostic factor in breast cancer (PMID:29183346)
• miR-1470 regulates cell proliferation and apoptosis by targeting ALX4 in hepatocellular carcinoma. (PMID:31791584)
• Variants in ALX4 and their association with genitourinary defects. (PMID:32385972)
• Overexpression of circ_0001445 decelerates hepatocellular carcinoma progression by regulating miR-942-5p/ALX4 axis. (PMID:32856218)
• Vertical transmission of a large calvarial ossification defect due to heterozygous variants of ALX4 and TWIST1. (PMID:33369125)
• De novo ALX4 variant detected in child with non-syndromic craniosynostosis. (PMID:34586326)
• Dominant frontonasal dysplasia with ectodermal defects results from increased activity of ALX4. (PMID:37724761)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	alx4b	ENSDARG00000074442
danio_rerio	alx4a	ENSDARG00000088332
danio_rerio	alx3	ENSDARG00000111246
mus_musculus	Alx4	ENSMUSG00000040310
rattus_norvegicus	Alx4	ENSRNOG00000000008

Paralogs (50): ARX (ENSG00000004848), PAX6 (ENSG00000007372), PAX7 (ENSG00000009709), 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), ALX1 (ENSG00000180318), MIXL1 (ENSG00000185155), SHOX (ENSG00000185960)

Protein

Protein identifiers

Homeobox protein aristaless-like 4 — Q9H161 (reviewed: Q9H161)

All UniProt accessions (1): Q9H161

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor involved in skull and limb development. Plays an essential role in craniofacial development, skin and hair follicle development.

Subunit / interactions. Binds DNA.

Subcellular location. Nucleus.

Tissue specificity. Expression is likely to be restricted to bone. Found in parietal bone.

Disease relevance. Parietal foramina 2 (PFM2) [MIM:609597] Autosomal dominant disease characterized by oval defects of the parietal bones caused by deficient ossification around the parietal notch, which is normally obliterated during the fifth fetal month. PFM2 is also a clinical feature of Potocki-Shaffer syndrome. The disease is caused by variants affecting the gene represented in this entry. Frontonasal dysplasia 2 (FND2) [MIM:613451] 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. Potocki-Shaffer syndrome (POSHS) [MIM:601224] A syndrome characterized by foramina parietalia permagna, multiple exostoses, and craniofacial dysostosis, and intellectual disability in some cases. The disease is caused by variants affecting the gene represented in this entry. Craniosynostosis 5 (CRS5) [MIM:615529] A primary abnormality of skull growth involving premature fusion of one or more cranial sutures. The growth velocity of the skull often cannot match that of the developing brain resulting in an abnormal head shape and, in some cases, increased intracranial pressure, which must be treated promptly to avoid permanent neurodevelopmental disability. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Similarity. Belongs to the paired homeobox family.

RefSeq proteins (1): NP_068745* (*=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 (19 total): sequence variant 8, helix 3, region of interest 2, chain 1, DNA-binding region 1, sequence conflict 1, short sequence motif 1, compositionally biased region 1, modified residue 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
9D9R	X-RAY DIFFRACTION	2.39
9D9V	X-RAY DIFFRACTION	2.39
8OSB	X-RAY DIFFRACTION	2.9
2M0C	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H161-F1	59.00	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 (1): 200

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 342 (showing top): GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_EMBRYONIC_DIGIT_MORPHOGENESIS, GOBP_HINDLIMB_MORPHOGENESIS, GOBP_EMBRYONIC_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_EMBRYONIC_SKELETAL_SYSTEM_MORPHOGENESIS, GOBP_NEUROGENESIS, TGACCTY_ERR1_Q2, GOBP_FORELIMB_MORPHOGENESIS, GGGTGGRR_PAX4_03, GOBP_DIGESTIVE_SYSTEM_DEVELOPMENT, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_EMBRYONIC_FORELIMB_MORPHOGENESIS

GO Biological Process (20): skeletal system development (GO:0001501), hair follicle development (GO:0001942), regulation of transcription by RNA polymerase II (GO:0006357), muscle organ development (GO:0007517), post-embryonic development (GO:0009791), anterior/posterior pattern specification (GO:0009952), embryonic forelimb morphogenesis (GO:0035115), embryonic hindlimb morphogenesis (GO:0035116), embryonic digit morphogenesis (GO:0042733), regulation of apoptotic process (GO:0042981), digestive tract development (GO:0048565), neuron development (GO:0048666), embryonic skeletal system morphogenesis (GO:0048704), roof of mouth development (GO:0060021), regulation of DNA-templated transcription (GO:0006355), pattern specification process (GO:0007389), limb morphogenesis (GO:0035108), positive regulation of transcription by RNA polymerase II (GO:0045944), animal organ development (GO:0048513), skeletal system morphogenesis (GO:0048705)

GO Molecular Function (9): 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), DNA binding (GO:0003677), HMG box domain binding (GO:0071837), sequence-specific double-stranded DNA binding (GO:1990837), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anatomical structure development	3
embryonic limb morphogenesis	3
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
multicellular organism development	2
multicellular organismal process	2
regulation of 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
system development	1
hair cycle process	1
skin epidermis development	1
animal organ development	1
muscle structure development	1
regionalization	1
forelimb morphogenesis	1
hindlimb morphogenesis	1
embryonic morphogenesis	1
apoptotic process	1
regulation of programmed cell death	1
tube development	1
digestive system development	1
neuron differentiation	1
cell development	1
embryonic organ morphogenesis	1
skeletal system morphogenesis	1
embryonic skeletal system development	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
appendage morphogenesis	1
limb development	1
positive regulation of DNA-templated transcription	1
skeletal system development	1
animal organ morphogenesis	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

Protein interactions and networks

STRING

1110 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ALX4	EXT2	Q93063	912
ALX4	GLI3	P10071	725
ALX4	ZP2	Q05996	689
ALX4	PAX9	P55771	656
ALX4	SHH	Q15465	642
ALX4	SATB2	Q9UPW6	611
ALX4	NEUROG1	Q92886	609
ALX4	KIF11	P52732	607
ALX4	SEPTIN9	Q9UHD8	603
ALX4	SLC30A8	Q8IWU4	603
ALX4	PRDM6	Q9NQX0	593
ALX4	HHEX	Q03014	557
ALX4	LEF1	Q9UJU2	551
ALX4	RBFOX1	Q9NWB1	548
ALX4	DLX5	P56178	545

IntAct

27 interactions, top by confidence:

A	B	Type	Score
IQUB	ALX4	psi-mi:“MI:0915”(physical association)	0.560
ALX4	PARVG	psi-mi:“MI:0915”(physical association)	0.560
FHL2	CNOT1	psi-mi:“MI:0914”(association)	0.530
CCL1	ALX4	psi-mi:“MI:0915”(physical association)	0.370
	ALX4	psi-mi:“MI:0915”(physical association)	0.370
HOXB13	ALX4	psi-mi:“MI:0915”(physical association)	0.370
CEBPE	ALX4	psi-mi:“MI:0915”(physical association)	0.370
EMX1	ALX4	psi-mi:“MI:0915”(physical association)	0.370
GATA4	ALX4	psi-mi:“MI:0915”(physical association)	0.370
FOXA3	ALX4	psi-mi:“MI:0915”(physical association)	0.370
HOXA3	ALX4	psi-mi:“MI:0915”(physical association)	0.370
HOXB6	ALX4	psi-mi:“MI:0915”(physical association)	0.370
HOXD3	ALX4	psi-mi:“MI:0915”(physical association)	0.370
ALX4	ALX4	psi-mi:“MI:0915”(physical association)	0.370
SOX2	ALX4	psi-mi:“MI:0915”(physical association)	0.370
ALX1	ALX4	psi-mi:“MI:0915”(physical association)	0.370
FOXE1	DDX39A	psi-mi:“MI:0914”(association)	0.350
RBPJ	SAMD1	psi-mi:“MI:0914”(association)	0.350
FOXA1	PLOD2	psi-mi:“MI:0914”(association)	0.350
TLK2	PES1	psi-mi:“MI:2364”(proximity)	0.270
IQUB	ALX4	psi-mi:“MI:0915”(physical association)	0.000
PARVG	ALX4	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (25): ALX4 (Affinity Capture-MS), ALX4 (Affinity Capture-MS), ALX4 (Affinity Capture-MS), ALX4 (Affinity Capture-RNA), PARVG (Two-hybrid), IQUB (Two-hybrid), ALX4 (Affinity Capture-MS), ALX4 (Affinity Capture-MS), ALX4 (Proximity Label-MS), ALX4 (Proximity Label-MS), ALX4 (Proximity Label-MS), ALX4 (Proximity Label-MS), ALX4 (Proximity Label-MS), ALX4 (Proximity Label-MS), ALX4 (Proximity Label-MS)

ESM2 similar proteins: A1YER7, A1YF08, A1YFD8, A1YFY3, A1YG01, A1YG85, A2D4P8, A2D4R4, A2D5I1, A2D649, A2T6H5, A2T6X6, A2T6Z0, A2T748, A2T756, A2T7H5, A2T7J2, P06798, P09016, P09017, P09023, P09024, P10284, P10628, P13378, P14653, P17277, P17483, P17509, P18111, P18864, P23463, P23813, P31259, P31275, P31276, P31277, P31310, P47902, P50207

Diamond homologs: A0A1W2PPF3, A1YEY5, A1YFI3, A1YG57, A2T733, A2T7P4, A6NLW8, A6NNA5, F1NEA7, G5EBU4, G5EDS1, O18381, O35137, O35160, O42250, O43186, O43316, O43812, O54751, O70137, O73917, O75360, O75364, O95076, P09088, P0CJ85, P0CJ86, P0CJ87, P0CJ88, P0CJ89, P0CJ90, P21711, P22810, P26367, P26630, P29454, P32242, P32243, P34764, P34765

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
LEF1	“up-regulates quantity by expression”	ALX4	binding
ALX4	“down-regulates quantity by repression”	NCAM1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	16
Likely pathogenic	6
Uncertain significance	171
Likely benign	48
Benign	78

Top pathogenic / likely-pathogenic (22)

Variant ID	HGVS	Classification
155902	NM_021926.4(ALX4):c.646C>G (p.Arg216Gly)	Pathogenic
155903	NM_021926.4(ALX4):c.673C>G (p.Gln225Glu)	Pathogenic
155904	NM_021926.4(ALX4):c.976_985delinsCTAAGATCTCAACAGAGATGGCAACT (p.Asp326fs)	Pathogenic
190380	NM_021926.4(ALX4):c.503del (p.Pro168fs)	Pathogenic
2032730	NM_021926.4(ALX4):c.331C>T (p.Gln111Ter)	Pathogenic
225543	NM_021926.4(ALX4):c.291del (p.Gln98fs)	Pathogenic
3244782	NC_000011.9:g.(?44129263)(44745049_?)del	Pathogenic
5013	NM_021926.4(ALX4):c.418C>T (p.Gln140Ter)	Pathogenic
5014	NM_021926.4(ALX4):c.736C>T (p.Gln246Ter)	Pathogenic
5015	NM_021926.4(ALX4):c.653G>A (p.Arg218Gln)	Pathogenic
5016	NM_021926.4(ALX4):c.504del (p.Asp169fs)	Pathogenic
5017	NM_021926.4(ALX4):c.815G>C (p.Arg272Pro)	Pathogenic
5018	NM_021926.4(ALX4):c.620C>A (p.Ser207Ter)	Pathogenic
5019	NM_021926.4(ALX4):c.385_394del (p.Cys129fs)	Pathogenic
5020	NM_021926.4(ALX4):c.793C>T (p.Arg265Ter)	Pathogenic
58891	GRCh38/hg38 11p11.2(chr11:44136593-46121139)x1	Pathogenic
1690439	NM_021926.4(ALX4):c.1017del (p.Gly340fs)	Likely pathogenic
1696378	NM_021926.4(ALX4):c.16dup (p.Cys6fs)	Likely pathogenic
3257723	NM_021926.4(ALX4):c.1016dup (p.Gly340fs)	Likely pathogenic
3776156	NM_021926.4(ALX4):c.676del (p.Leu226fs)	Likely pathogenic
426461	NM_021926.4(ALX4):c.398del (p.Pro133fs)	Likely pathogenic
4530610	NM_021926.4(ALX4):c.344dup (p.Pro116fs)	Likely pathogenic

SpliceAI

720 predictions. Top by Δscore:

Variant	Effect	Δscore
11:44267489:CTTA:C	donor_loss	1.0000
11:44267490:TTACC:T	donor_loss	1.0000
11:44267491:TA:T	donor_loss	1.0000
11:44267492:A:AC	donor_gain	1.0000
11:44267492:AC:A	donor_gain	1.0000
11:44267493:C:CC	donor_gain	1.0000
11:44267493:CC:C	donor_gain	1.0000
11:44267493:CCTG:C	donor_gain	1.0000
11:44267493:CCTGG:C	donor_gain	1.0000
11:44267618:CAGAC:C	acceptor_gain	1.0000
11:44267619:AGAC:A	acceptor_gain	1.0000
11:44267620:GAC:G	acceptor_gain	1.0000
11:44267621:AC:A	acceptor_gain	1.0000
11:44267622:CC:C	acceptor_gain	1.0000
11:44267623:C:CC	acceptor_gain	1.0000
11:44275659:C:CC	acceptor_gain	1.0000
11:44264878:A:AC	donor_gain	0.9900
11:44264879:C:CC	donor_gain	0.9900
11:44265184:C:G	acceptor_loss	0.9900
11:44265185:T:C	acceptor_loss	0.9900
11:44267493:CCT:C	donor_gain	0.9900
11:44267619:AGACC:A	acceptor_gain	0.9900
11:44267620:GACCT:G	acceptor_gain	0.9900
11:44267621:ACCT:A	acceptor_gain	0.9900
11:44267622:CCTAC:C	acceptor_gain	0.9900
11:44267623:CTAC:C	acceptor_gain	0.9900
11:44275345:GA:G	donor_loss	0.9900
11:44275346:A:AG	donor_loss	0.9900
11:44275402:CACGT:C	donor_gain	0.9900
11:44275654:TTTAG:T	acceptor_gain	0.9900

AlphaMissense

2677 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:44264891:G:T	A400D	1.000
11:44264892:C:G	A400P	1.000
11:44264900:C:G	R397P	1.000
11:44264901:G:T	R397S	1.000
11:44264903:A:G	L396P	1.000
11:44264903:A:T	L396H	1.000
11:44264912:A:C	I393S	1.000
11:44264912:A:T	I393N	1.000
11:44264914:G:C	S392R	1.000
11:44264914:G:T	S392R	1.000
11:44264916:T:G	S392R	1.000
11:44267585:C:G	R272P	1.000
11:44267587:C:A	K271N	1.000
11:44267587:C:G	K271N	1.000
11:44267588:T:A	K271M	1.000
11:44267589:T:C	K271E	1.000
11:44267590:C:A	R270S	1.000
11:44267590:C:G	R270S	1.000
11:44267591:C:A	R270M	1.000
11:44267591:C:G	R270T	1.000
11:44267592:T:A	R270W	1.000
11:44267592:T:C	R270G	1.000
11:44267593:C:A	W269C	1.000
11:44267593:C:G	W269C	1.000
11:44267594:C:G	W269S	1.000
11:44267595:A:G	W269R	1.000
11:44267595:A:T	W269R	1.000
11:44267596:C:A	K268N	1.000
11:44267596:C:G	K268N	1.000
11:44267597:T:A	K268M	1.000

dbSNP variants (sampled 300 via entrez): RS1000117776 (11:44264776 G>A,C,T), RS1000132165 (11:44268582 G>A), RS1000241371 (11:44300141 C>T), RS1000254441 (11:44268366 G>A,C,T), RS1000308592 (11:44273716 C>T), RS1000343980 (11:44294599 T>G), RS1000451284 (11:44278132 A>G,T), RS1000480232 (11:44305082 A>C), RS1000501069 (11:44283722 C>A), RS1000541586 (11:44309710 G>A,T), RS1000592025 (11:44299799 G>A), RS1000647022 (11:44304812 C>G), RS1000852476 (11:44288874 A>G), RS1000889235 (11:44295249 G>C), RS1000939497 (11:44284805 C>T)

Disease associations

OMIM: gene MIM:605420 | disease phenotypes: MIM:609597, MIM:613451, MIM:615529

GenCC curated gene-disease

Disease	Classification	Inheritance
parietal foramina 2	Definitive	Autosomal dominant
frontonasal dysplasia with alopecia and genital anomaly	Definitive	Autosomal recessive
craniosynostosis 5, susceptibility to	Strong	Autosomal dominant
parietal foramina	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
frontonasal dysplasia with alopecia and genital anomaly	Definitive	AR

Mondo (7): optic nerve glioma (MONDO:0003235), parietal foramina 2 (MONDO:0012309), frontonasal dysplasia with alopecia and genital anomaly (MONDO:0013268), craniosynostosis 5, susceptibility to (MONDO:0014232), skeletal dysplasia (MONDO:0018230), SIN3A-related intellectual disability syndrome due to a point mutation (MONDO:0044700), parietal foramina (MONDO:0018953)

Orphanet (6): Frontonasal dysplasia-alopecia-genital anomalies syndrome (Orphanet:228390), Enlarged parietal foramina (Orphanet:60015), Non-syndromic sagittal craniosynostosis (Orphanet:35093), Primary bone dysplasia (Orphanet:364526), SIN3-related intellectual disability syndrome due to a point mutation (Orphanet:500166), 15q24 microdeletion syndrome (Orphanet:94065)

HPO phenotypes

100 total (30 of 100 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000046	Small scrotum
HP:0000054	Micropenis
HP:0000135	Hypogonadism
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000268	Dolichocephaly
HP:0000269	Prominent occiput
HP:0000286	Epicanthus
HP:0000289	Broad philtrum
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000426	Prominent nasal bridge
HP:0000430	Underdeveloped nasal alae
HP:0000431	Wide nasal bridge
HP:0000437	Depressed nasal tip
HP:0000455	Broad nasal tip
HP:0000456	Bifid nasal tip
HP:0000457	Depressed nasal ridge
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000506	Telecanthus
HP:0000568	Microphthalmia
HP:0000581	Blepharophimosis

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST001356_18	Gout	1.000000e-07
GCST002249_2	Blood pressure measurement (high sodium intervention)	2.000000e-06
GCST002249_5	Blood pressure measurement (high sodium intervention)	3.000000e-07
GCST002936_20	Cadmium levels	2.000000e-07
GCST003983_28	Male-pattern baldness	6.000000e-10
GCST003996_50	Monobrow	8.000000e-13
GCST005116_41	Male-pattern baldness	2.000000e-19
GCST005411_11	Thrombin-activatable fibrinolysis inhibitor activation peptide	3.000000e-07
GCST006095_6	Excessive hairiness	6.000000e-06
GCST006817_2	Response to antidepressants in depression	1.000000e-07
GCST010703_251	Brain morphology (MOSTest)	3.000000e-14
GCST012316_11	ghrelin levels	9.000000e-07

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0005401	response to high sodium diet
EFO:0006336	diastolic blood pressure
EFO:0006340	mean arterial pressure
EFO:0007906	synophrys measurement
EFO:0004346	neuroimaging measurement
EFO:0600001	ghrelin measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D020339	Optic Nerve Glioma	C04.557.465.625.600.380.795; C04.557.470.670.380.795; C04.557.580.625.600.380.795; C04.588.614.300.600.600; C04.588.614.596.240.240.500; C10.292.225.800.500; C10.292.700.500.500; C10.551.360.500.500; C10.551.775.250.500.500; C11.640.544.500
C566826	Parietal Foramina (supp.)
C566510	Parietal Foramina 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases methylation	1
terbufos	increases methylation	1
arsenite	increases methylation	1
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	decreases methylation	1
ferrous chloride	decreases expression	1
aflatoxin B2	increases methylation	1
abrine	decreases expression	1
Decitabine	decreases methylation, increases expression	1
Arsenic Trioxide	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cadmium	decreases expression	1
Diazinon	increases methylation	1
Diethylhexyl Phthalate	increases abundance, increases methylation	1
Fonofos	increases methylation	1
Formaldehyde	increases expression	1
Methapyrilene	decreases methylation	1
Parathion	increases methylation	1
Tetrachlorodibenzodioxin	decreases expression	1
Triclosan	increases expression	1
Aflatoxin B1	decreases methylation	1
Particulate Matter	increases abundance, increases 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_A0B2	SEES3-1V human ALX4, clone1	Embryonic stem cell	Male
CVCL_A0B3	SEES3-1V human ALX4, clone2	Embryonic stem cell	Male
CVCL_A0B4	SEES3-1V human ALX4, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01260103	PHASE3	WITHDRAWN	Phase 3 Study of ANP Therapy vs. TMZ for Optic Pathway Glioma
NCT02839720	PHASE2	COMPLETED	Selumetinib in Treating Patients With Neurofibromatosis Type 1 and Cutaneous Neurofibroma
NCT01837862	PHASE1/PHASE2	COMPLETED	A Phase I Study of Mebendazole for the Treatment of Pediatric Gliomas
NCT03326388	PHASE1/PHASE2	COMPLETED	Intermittent Dosing Of Selumetinib In Childhood NF1 Associated Tumours
NCT02976441	EARLY_PHASE1	WITHDRAWN	Autologous Stem Cell Collection and Reinfusion in Newly Diagnosed High Grade Gliomas
NCT04648462	Not specified	RECRUITING	Proton Therapy Research Infrastructure- ProTRAIT- Neuro-oncology
NCT00001754	Not specified	COMPLETED	Study of Skeletal Disorders and Short Stature
NCT02762318	Not specified	TERMINATED	Identification and Characterization of Bone-related Genetic Variants in Families
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT05247645	Not specified	RECRUITING	Data Collection of Patients With Rare Bone Diseases
NCT05876416	Not specified	RECRUITING	Decoding the Genetic Landscape of Skeletal Diseases
NCT05991609	Not specified	ACTIVE_NOT_RECRUITING	Extreme Morphology and Metabolic Health
NCT06002373	Not specified	UNKNOWN	Assessment of Artificial Intelligence for Treatment Decision Recommendation of Adult Skeletal Class III Patients