FBXL3

Summary

FBXL3 (F-box and leucine rich repeat protein 3, HGNC:13599) is a protein-coding gene on chromosome 13q22.3, encoding F-box/LRR-repeat protein 3 (Q9UKT7). Substrate-recognition component of the SCF(FBXL3) E3 ubiquitin ligase complex involved in circadian rhythm function.

This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbls class and, in addition to an F-box, contains several tandem leucine-rich repeats and is localized in the nucleus.

Source: NCBI Gene 26224 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual disability, short stature, facial anomalies, and joint dislocations (Strong, GenCC)
• GWAS associations: 5
• Clinical variants (ClinVar): 46 total — 4 pathogenic
• Phenotypes (HPO): 23
• MANE Select transcript: NM_012158

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13599
Approved symbol	FBXL3
Name	F-box and leucine rich repeat protein 3
Location	13q22.3
Locus type	gene with protein product
Status	Approved
Aliases	FBL3, FBL3A
Ensembl gene	ENSG00000005812
Ensembl biotype	protein_coding
OMIM	605653
Entrez	26224

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 9 protein_coding, 4 protein_coding_CDS_not_defined

ENST00000355619, ENST00000417323, ENST00000470210, ENST00000472949, ENST00000477982, ENST00000485797, ENST00000885159, ENST00000885160, ENST00000885161, ENST00000885162, ENST00000885163, ENST00000885164, ENST00000914959

RefSeq mRNA: 1 — MANE Select: NM_012158 NM_012158

CCDS: CCDS9457

Canonical transcript exons

ENST00000355619 — 5 exons

Exon	Start	End
ENSE00000802462	77018600	77018722
ENSE00001422335	77005260	77007788
ENSE00001473895	77021513	77021861
ENSE00001655332	77026827	77027159
ENSE00003668654	77015409	77015580

Expression profiles

Bgee: expression breadth ubiquitous, 254 present calls, max score 97.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 30.4000 / max 267.7466, expressed in 1816 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
137680	27.6778	1814
137681	1.2707	798
137682	1.1376	741
137679	0.3139	132

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cardiac muscle of right atrium	UBERON:0003379	97.99	gold quality
calcaneal tendon	UBERON:0003701	97.85	gold quality
upper arm skin	UBERON:0004263	97.82	gold quality
kidney epithelium	UBERON:0004819	97.76	gold quality
superficial temporal artery	UBERON:0001614	97.75	gold quality
skin of hip	UBERON:0001554	97.42	gold quality
trabecular bone tissue	UBERON:0002483	97.38	gold quality
germinal epithelium of ovary	UBERON:0001304	97.37	gold quality
endothelial cell	CL:0000115	97.34	gold quality
upper leg skin	UBERON:0004262	97.34	gold quality
synovial joint	UBERON:0002217	97.29	gold quality
layer of synovial tissue	UBERON:0007616	97.27	gold quality
left ventricle myocardium	UBERON:0006566	97.19	gold quality
myocardium	UBERON:0002349	97.08	gold quality
deltoid	UBERON:0001476	97.04	gold quality
heart right ventricle	UBERON:0002080	96.97	gold quality
tibialis anterior	UBERON:0001385	96.89	gold quality
biceps brachii	UBERON:0001507	96.88	gold quality
ileal mucosa	UBERON:0000331	96.83	gold quality
mammary duct	UBERON:0001765	96.83	gold quality
epithelium of mammary gland	UBERON:0003244	96.81	gold quality
epithelial cell of pancreas	CL:0000083	96.80	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	96.77	gold quality
cauda epididymis	UBERON:0004360	96.66	gold quality
oral cavity	UBERON:0000167	96.48	gold quality
lower lobe of lung	UBERON:0008949	96.47	gold quality
vastus lateralis	UBERON:0001379	96.40	gold quality
urethra	UBERON:0000057	96.36	gold quality
Brodmann (1909) area 46	UBERON:0006483	96.33	gold quality
quadriceps femoris	UBERON:0001377	96.26	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.46

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

207 targeting FBXL3, 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-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-340-5P	100.00	72.50	4437
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-3658	99.96	73.87	4379

Literature-anchored findings (GeneRIF, showing 11)

• study demonstrates that the SCF(Fbxl3)ubiquitin ligase controls the oscillations of the circadian clock by mediating the degradation of Cry1 and Cry2 proteins (PMID:17463251)
• crystal structures of mammalian CRY2 in its apo, FAD-bound and FBXL3-SKP1-complexed forms (PMID:23503662)
• Mutation in the Fbxl3 protein reveals distinct roles for CRY1 and CRY2 in the circadian molecular clockwork. (PMID:23616524)
• Substrate binding promotes formation of the Skp1-Cul1-Fbxl3 (SCF(Fbxl3)) protein complex. (PMID:24085301)
• Data show that CRISPR/Cas9 genome editing generated F-box and leucine-rich repeat protein 3 (Fbxl3) knockout in circadian clock model U2OS cells. (PMID:26243628)
• These results demonstrate that CRY2 stability controlled by FBXL3 plays a key role in the regulation of human sleep wake behavior. (PMID:27529127)
• CRY2 and FBXL3 cooperatively degrade c-MYC preventing the development of cancer. (PMID:27840026)
• data indicate an oncogenic role of miR-181d in CRC by promoting glycolysis, and miR-181d/CRY2/FBXL3/c-myc feedback loop might be a therapeutic target for patients with CRC. (PMID:28749470)
• we conclude that homozygous FBXL3 LoF variants likely cause autosomal recessive ID, short stature, developmental delay and facial dysmorphism in humans, and that the Cys358Arg FBXL3 variant likely adds the circadian phenotype because of abnormal interaction with CRY1 and CRY2 (PMID:30481285)
• FBXL3 was regulated by miR-4735-3p and suppressed cell proliferation and invasion in non-small cell lung cancer. (PMID:30594330)
• [Tumor-associated fibroblasts promotes proliferation and migration of prostate cancer cells by suppressing FBXL3 via upregulating hsa-miR-18b-5p]. (PMID:39051074)

Cross-species orthologs

30 orthologs

Organism	Symbol	Gene ID
danio_rerio	fbxl3a	ENSDARG00000103505
mus_musculus	Fbxl3	ENSMUSG00000022124
rattus_norvegicus	Fbxl3	ENSRNOG00000059334
drosophila_melanogaster	CG15056	FBGN0030918
drosophila_melanogaster	CG8272	FBGN0033337
drosophila_melanogaster	CG9003	FBGN0033639
drosophila_melanogaster	Skp2	FBGN0037236
drosophila_melanogaster	CG14891	FBGN0038445
drosophila_melanogaster	CG5003	FBGN0039554
drosophila_melanogaster	FipoQ	FBGN0039667
caenorhabditis_elegans		WBGENE00007206
caenorhabditis_elegans		WBGENE00007208
caenorhabditis_elegans		WBGENE00007887
caenorhabditis_elegans		WBGENE00008177
caenorhabditis_elegans		WBGENE00009689
caenorhabditis_elegans	gadr-6	WBGENE00009823
caenorhabditis_elegans		WBGENE00010365
caenorhabditis_elegans	K05C4.9	WBGENE00010585
caenorhabditis_elegans		WBGENE00012655
caenorhabditis_elegans		WBGENE00015350
caenorhabditis_elegans		WBGENE00018561
caenorhabditis_elegans		WBGENE00018613
caenorhabditis_elegans		WBGENE00018766
caenorhabditis_elegans		WBGENE00019239
caenorhabditis_elegans		WBGENE00020884
caenorhabditis_elegans		WBGENE00021053
caenorhabditis_elegans		WBGENE00021180
caenorhabditis_elegans	zeel-1	WBGENE00021463
caenorhabditis_elegans		WBGENE00044459
caenorhabditis_elegans	gadr-5	WBGENE00045058

Paralogs (15): FBXL19 (ENSG00000099364), FBXL15 (ENSG00000107872), FBXL20 (ENSG00000108306), FBXL4 (ENSG00000112234), FBXL5 (ENSG00000118564), FBXL16 (ENSG00000127585), SKP2 (ENSG00000145604), FBXL17 (ENSG00000145743), FBXL2 (ENSG00000153558), FBXL18 (ENSG00000155034), FBXL13 (ENSG00000161040), FBXL14 (ENSG00000171823), FBXL6 (ENSG00000182325), FBXL7 (ENSG00000183580), FBXL22 (ENSG00000197361)

Protein

Protein identifiers

F-box/LRR-repeat protein 3 — Q9UKT7 (reviewed: Q9UKT7)

Alternative names: F-box and leucine-rich repeat protein 3A, F-box/LRR-repeat protein 3A

All UniProt accessions (2): Q9UKT7, C9J0Y7

UniProt curated annotations — full annotation on UniProt →

Function. Substrate-recognition component of the SCF(FBXL3) E3 ubiquitin ligase complex involved in circadian rhythm function. Plays a key role in the maintenance of both the speed and the robustness of the circadian clock oscillation. The SCF(FBXL3) complex mainly acts in the nucleus and mediates ubiquitination and subsequent degradation of CRY1 and CRY2. Activity of the SCF(FBXL3) complex is counteracted by the SCF(FBXL21) complex.

Subunit / interactions. Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXL3) composed of CUL1, SKP1, RBX1 and FBXL3. Interacts with CRY1 and CRY2 (phosphorylated). Interacts with HDAC3. Interacts with KDM8.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Widely expressed.

Post-translational modifications. Undergoes autophagy-mediated degradation in the liver in a time-dependent manner.

Disease relevance. Intellectual developmental disorder with short stature, facial anomalies, and speech defects (IDDSFAS) [MIM:606220] An autosomal recessive disorder characterized by global developmental delay, mildly to severely impaired intellectual development, delayed or slurred speech, and short stature. Dysmorphic features included a large bulbous nose and variable microretrognathia. Some patients show joint hyperlaxity and dislocations. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Protein modification; protein ubiquitination.

RefSeq proteins (1): NP_036290* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001810	F-box_dom	Domain
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR036047	F-box-like_dom_sf	Homologous_superfamily

Pfam: PF12937

UniProt features (58 total): helix 19, strand 15, repeat 7, sequence conflict 5, turn 4, sequence variant 2, mutagenesis site 2, chain 1, domain 1, compositionally biased region 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4I6J	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UKT7-F1	90.36	0.81

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Mutagenesis-validated functional residues (2):

Position	Phenotype
358	loss of binding with cry1.
358	decrease in binding efficiency with cry2 and of cry2 ubiquitination efficiency, loss of binding with cry1.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-390471	Association of TriC/CCT with target proteins during biosynthesis
R-HSA-8951664	Neddylation
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-9932298	Degradation of CRY and PER proteins

MSigDB gene sets: 279 (showing top): GOBP_CIRCADIAN_RHYTHM, WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, GOBP_PHOTOPERIODISM, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP, CTATGCA_MIR153, ATGTTAA_MIR302C, GOBP_REGULATION_OF_CIRCADIAN_RHYTHM, GOBP_PROTEIN_DESTABILIZATION, MODULE_256, GOBP_RESPONSE_TO_RADIATION, GOBP_ENTRAINMENT_OF_CIRCADIAN_CLOCK

GO Biological Process (7): protein ubiquitination (GO:0016567), SCF-dependent proteasomal ubiquitin-dependent protein catabolic process (GO:0031146), protein destabilization (GO:0031648), regulation of circadian rhythm (GO:0042752), entrainment of circadian clock by photoperiod (GO:0043153), rhythmic process (GO:0048511), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161)

GO Molecular Function (2): ubiquitin-protein transferase activity (GO:0004842), protein binding (GO:0005515)

GO Cellular Component (6): ubiquitin ligase complex (GO:0000151), nucleus (GO:0005634), cytosol (GO:0005829), nuclear body (GO:0016604), SCF ubiquitin ligase complex (GO:0019005), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Chaperonin-mediated protein folding	1
Post-translational protein modification	1
Class I MHC mediated antigen processing & presentation	1
Circadian clock	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
protein modification by small protein conjugation	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
regulation of protein stability	1
circadian rhythm	1
regulation of biological process	1
photoperiodism	1
entrainment of circadian clock	1
biological_process	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
ubiquitin-like protein transferase activity	1
binding	1
intracellular protein-containing complex	1
transferase complex	1
intracellular membrane-bounded organelle	1
cytoplasm	1
nucleoplasm	1
intracellular membraneless organelle	1
cullin-RING ubiquitin ligase complex	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1323 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FBXL3	CRY1	Q16526	995
FBXL3	CRY2	Q49AN0	981
FBXL3	SKP1	P34991	952
FBXL3	CLOCK	O15516	864
FBXL3	BMAL1	O00327	836
FBXL3	PER2	O15055	818
FBXL3	CSNK1E	P49674	760
FBXL3	BTRC	Q9Y297	750
FBXL3	CUL1	Q13616	739
FBXL3	CCNF	P41002	676
FBXL3	FBXL13	Q8NEE6	662
FBXL3	NR1D1	P20393	661
FBXL3	CSNK1D	P48730	635
FBXL3	PER3	P56645	630
FBXL3	SKP2	Q13309	622

IntAct

46 interactions, top by confidence:

A	B	Type	Score
FBXL3	Cry2	psi-mi:“MI:0915”(physical association)	0.780
Cry2	FBXL3	psi-mi:“MI:0407”(direct interaction)	0.780
Cry2	FBXL3	psi-mi:“MI:0915”(physical association)	0.780
FBXL3	Cry2	psi-mi:“MI:0914”(association)	0.780
Cry2	SKP1	psi-mi:“MI:0914”(association)	0.650
Cry2	SKP1	psi-mi:“MI:0915”(physical association)	0.650
FBXL3	CRY1	psi-mi:“MI:0914”(association)	0.640
CRY1	SKP1	psi-mi:“MI:0914”(association)	0.640
CRY2	SKP1	psi-mi:“MI:0914”(association)	0.640
SKP1	MYCBP2	psi-mi:“MI:0914”(association)	0.640
FBXL3	Skp1	psi-mi:“MI:0915”(physical association)	0.620
FBXL3	Cry1	psi-mi:“MI:0914”(association)	0.560
PICK1	FBXL3	psi-mi:“MI:0915”(physical association)	0.560
CEP57	FBXL3	psi-mi:“MI:0915”(physical association)	0.560
MSRA	FBXL3	psi-mi:“MI:0915”(physical association)	0.560
Cry1	PER1	psi-mi:“MI:0915”(physical association)	0.560
FBXL3	RFX1	psi-mi:“MI:0914”(association)	0.530
SKP1	FBXL3	psi-mi:“MI:0915”(physical association)	0.510
HSP90AB1	FBXL3	psi-mi:“MI:0915”(physical association)	0.400
Cry2	BMAL1	psi-mi:“MI:0914”(association)	0.350
FBXL3	SKP1	psi-mi:“MI:0914”(association)	0.350
SKP1	BHLHE40	psi-mi:“MI:0914”(association)	0.350

BioGRID (69): RFX2 (Affinity Capture-MS), RFX1 (Affinity Capture-MS), CRY1 (Affinity Capture-MS), FBXL3 (Affinity Capture-Western), FBXL3 (Affinity Capture-Western), FBXL3 (Affinity Capture-MS), FBXL3 (Affinity Capture-MS), CRY2 (Reconstituted Complex), CRY2 (Affinity Capture-Western), CRY1 (Affinity Capture-MS), RFX2 (Affinity Capture-MS), RFX1 (Affinity Capture-MS), PPP2R5D (Affinity Capture-MS), SKP1 (Affinity Capture-Western), FBXL3 (Affinity Capture-MS)

ESM2 similar proteins: A1A5X2, A2RT62, A6H639, A8Y3R9, B3FL73, D3Z902, D3ZXS4, G5EDB9, O49286, P34284, P87053, Q09299, Q0P4D1, Q0VD31, Q17R01, Q19857, Q32PG9, Q4R642, Q570C0, Q5BJ29, Q5JU00, Q5MJ12, Q65XV2, Q8BFZ4, Q8BH70, Q8BID8, Q8BVU0, Q8C4V4, Q8CDU4, Q8CFJ9, Q8J2J3, Q8LB33, Q8N1E6, Q8N461, Q8W104, Q96S15, Q9EPX5, Q9LPL4, Q9LW29, Q9NXK8

Diamond homologs: A8QGZ7, B3FL73, Q3ZBA7, Q5NBU5, Q66H10, Q8BFZ4, Q8C4V4, Q9UKT6, Q9UKT7, Q32PG9, Q7Z6M2, Q8VE08, Q9EPX5, Q9NXK8, Q8N4B4, Q9FLX3

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
FBXL3	“down-regulates quantity by destabilization”	CRY2	binding
FBXL3	“up-regulates activity”	“Cullin 1-RBX1-Skp1”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 26 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
The CRY:PER:kinase complex represses transactivation by the BMAL:CLOCK (ARNTL:CLOCK) complex	5	209.9×	1e-09
Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes	6	167.9×	1e-10
Degradation of CRY and PER proteins	5	64.6×	4e-07

GO biological processes:

GO term	Partners	Fold	FDR
entrainment of circadian clock by photoperiod	5	174.4×	4e-09
circadian regulation of gene expression	7	78.0×	4e-10
circadian rhythm	6	69.8×	9e-09
regulation of circadian rhythm	5	61.7×	5e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	0
Uncertain significance	29
Likely benign	5
Benign	4

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
1177304	NM_012158.4(FBXL3):c.751C>T (p.Arg251Ter)	Pathogenic
625419	NM_012158.4(FBXL3):c.445C>T (p.Arg149Ter)	Pathogenic
625420	NM_012158.4(FBXL3):c.884del (p.Leu295fs)	Pathogenic
625421	NM_012158.4(FBXL3):c.1072T>C (p.Cys358Arg)	Pathogenic

SpliceAI

1476 predictions. Top by Δscore:

Variant	Effect	Δscore
13:76995058:ATTAG:A	acceptor_gain	1.0000
13:76995059:TTA:T	acceptor_loss	1.0000
13:76995060:TAGGC:T	acceptor_loss	1.0000
13:76995061:A:AG	acceptor_gain	1.0000
13:76995061:AG:A	acceptor_gain	1.0000
13:76995062:G:A	acceptor_loss	1.0000
13:76995062:G:GG	acceptor_gain	1.0000
13:76995062:GG:G	acceptor_gain	1.0000
13:76995062:GGC:G	acceptor_gain	1.0000
13:76995225:CTTG:C	donor_gain	1.0000
13:76995226:TTGG:T	donor_loss	1.0000
13:76995227:TGGT:T	donor_loss	1.0000
13:76995228:GGTA:G	donor_loss	1.0000
13:76995229:G:GC	donor_loss	1.0000
13:76995229:G:GG	donor_gain	1.0000
13:76995230:T:A	donor_loss	1.0000
13:76995234:G:GT	donor_gain	1.0000
13:77007790:T:C	acceptor_gain	1.0000
13:77015404:CATA:C	donor_loss	1.0000
13:77015405:ATAC:A	donor_loss	1.0000
13:77015406:TAC:T	donor_loss	1.0000
13:77015407:A:AG	donor_loss	1.0000
13:77015408:C:CT	donor_loss	1.0000
13:77015408:CCTG:C	donor_gain	1.0000
13:77015576:TGAGA:T	acceptor_gain	1.0000
13:77015577:GAGA:G	acceptor_gain	1.0000
13:77015578:AGA:A	acceptor_gain	1.0000
13:77015579:GA:G	acceptor_gain	1.0000
13:77015579:GACTG:G	acceptor_loss	1.0000
13:77015581:C:CC	acceptor_gain	1.0000

AlphaMissense

2817 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:77007174:A:G	W420R	1.000
13:77007174:A:T	W420R	1.000
13:77007422:A:G	L337P	1.000
13:77007603:A:G	W277R	1.000
13:77007603:A:T	W277R	1.000
13:77007746:A:G	L229P	1.000
13:77015444:A:G	L203S	1.000
13:77018640:A:G	L144P	1.000
13:77021523:A:T	V113D	1.000
13:77021532:A:G	L110P	1.000
13:77021619:A:G	F81S	1.000
13:77021633:C:A	W76C	1.000
13:77021633:C:G	W76C	1.000
13:77021634:C:G	W76S	1.000
13:77021635:A:G	W76R	1.000
13:77021635:A:T	W76R	1.000
13:77021665:A:G	W66R	1.000
13:77021665:A:T	W66R	1.000
13:77021694:C:G	R56P	1.000
13:77007150:A:G	W428R	0.999
13:77007150:A:T	W428R	0.999
13:77007155:G:T	P426H	0.999
13:77007156:G:A	P426S	0.999
13:77007167:G:T	P422H	0.999
13:77007172:C:A	W420C	0.999
13:77007172:C:G	W420C	0.999
13:77007242:A:G	L397P	0.999
13:77007263:A:G	L390S	0.999
13:77007325:A:C	C369W	0.999
13:77007326:C:T	C369Y	0.999

dbSNP variants (sampled 300 via entrez): RS1000071706 (13:77016319 A>G), RS1000128363 (13:77014729 A>G), RS1000258878 (13:77020872 T>C,G), RS1000273495 (13:77027884 T>C), RS1000672931 (13:77010416 C>G), RS1000891509 (13:77016687 C>A,T), RS1000952462 (13:77010201 A>G), RS1000965625 (13:77022581 C>G), RS1000968825 (13:77015137 C>G), RS1000998610 (13:77022933 A>C), RS1001301987 (13:77013787 T>C), RS1001312199 (13:77009677 T>C), RS1001410396 (13:77009294 A>G), RS1001424181 (13:77015944 C>A,T), RS1001536387 (13:77025746 G>A,T)

Disease associations

OMIM: gene MIM:605653 | disease phenotypes: MIM:606220

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, short stature, facial anomalies, and joint dislocations	Strong	Autosomal recessive

Mondo (1): intellectual disability, short stature, facial anomalies, and joint dislocations (MONDO:0011651)

Orphanet (0):

HPO phenotypes

23 total (23 of 23 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000308	Microretrognathia
HP:0000414	Bulbous nose
HP:0000431	Wide nasal bridge
HP:0000448	Prominent nose
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000718	Aggressive behavior
HP:0000750	Delayed speech and language development
HP:0000894	Short clavicles
HP:0001249	Intellectual disability
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001373	Joint dislocation
HP:0001382	Joint hypermobility
HP:0002465	Poor speech
HP:0003593	Infantile onset
HP:0004322	Short stature
HP:0006979	Sleep-wake cycle disturbance
HP:0010044	Short 4th metacarpal
HP:0031936	Delayed ability to walk

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST002682_13	Tourette’s syndrome or obsessive-compulsive disorder	1.000000e-06
GCST003429_16	Morning vs. evening chronotype	4.000000e-08
GCST007565_102	Morning person	5.000000e-36
GCST007576_299	Chronotype	5.000000e-36
GCST009391_1055	Metabolite levels	5.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0008328	chronotype measurement
EFO:0010363	lysophosphatidylcholine 20:4 measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C565248	Mental Retardation, Short Stature, Facial Anomalies, and Joint Dislocations (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
Valproic Acid	decreases expression	3
aristolochic acid I	decreases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
dicrotophos	decreases expression	1
bisphenol A	affects cotreatment, increases expression	1
trichostatin A	increases expression	1
sodium arsenite	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
entinostat	decreases expression	1
monomethylarsonous acid	increases expression	1
jinfukang	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Aspirin	increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Estradiol	decreases expression	1
Indomethacin	increases expression, affects cotreatment	1
Plant Extracts	affects cotreatment, increases expression	1
Urethane	increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Cadmium Chloride	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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