RFX3

Summary

RFX3 (regulatory factor X3, HGNC:9984) is a protein-coding gene on chromosome 9p24.2, encoding Transcription factor RFX3 (P48380). Transcription factor required for ciliogenesis and islet cell differentiation during endocrine pancreas development. It is haploinsufficient (ClinGen: sufficient evidence).

This gene is a member of the regulatory factor X gene family, which encodes transcription factors that contain a highly-conserved winged helix DNA binding domain. The protein encoded by this gene is structurally related to regulatory factors X1, X2, X4, and X5. It is a transcriptional activator that can bind DNA as a monomer or as a heterodimer with other RFX family members. Multiple transcript variants encoding different isoforms have been described for this gene.

Source: NCBI Gene 5991 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 9
• Clinical variants (ClinVar): 161 total — 3 pathogenic, 9 likely-pathogenic
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001282116

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9984
Approved symbol	RFX3
Name	regulatory factor X3
Location	9p24.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000080298
Ensembl biotype	protein_coding
OMIM	601337
Entrez	5991

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 19 protein_coding

ENST00000302303, ENST00000358730, ENST00000381984, ENST00000382004, ENST00000420720, ENST00000442560, ENST00000449190, ENST00000449234, ENST00000451859, ENST00000457373, ENST00000458034, ENST00000617270, ENST00000876564, ENST00000876565, ENST00000876566, ENST00000876567, ENST00000968851, ENST00000968852, ENST00000968853

RefSeq mRNA: 5 — MANE Select: NM_001282116 NM_001282116, NM_001282117, NM_001377999, NM_002919, NM_134428

CCDS: CCDS6449, CCDS6450, CCDS75809

Canonical transcript exons

ENST00000617270 — 17 exons

Exon	Start	End
ENSE00001599359	3218297	3225280
ENSE00001607664	3270371	3270525
ENSE00001623759	3346667	3346764
ENSE00001654051	3288131	3288250
ENSE00001676553	3266208	3266305
ENSE00001690409	3256991	3257199
ENSE00001702776	3271003	3271118
ENSE00001708298	3228847	3228889
ENSE00001717756	3301546	3301620
ENSE00001723747	3262935	3263084
ENSE00001738686	3330259	3330517
ENSE00001754617	3248032	3248185
ENSE00001758560	3275500	3275612
ENSE00001768594	3277340	3277461
ENSE00002702386	3293077	3293258
ENSE00002707387	3395472	3395596
ENSE00003711631	3525747	3526001

Expression profiles

Bgee: expression breadth ubiquitous, 253 present calls, max score 97.51.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.7090 / max 315.7795, expressed in 1705 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
99762	6.8596	1488
99758	6.3765	778
99763	2.0218	853
99759	0.4152	187
205413	0.0161	4
99754	0.0104	3
99755	0.0094	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
bronchial epithelial cell	CL:0002328	97.51	gold quality
mucosa of paranasal sinus	UBERON:0005030	93.69	gold quality
Brodmann (1909) area 23	UBERON:0013554	93.20	gold quality
middle temporal gyrus	UBERON:0002771	92.49	gold quality
cerebellar vermis	UBERON:0004720	89.30	gold quality
right uterine tube	UBERON:0001302	89.23	gold quality
epithelium of bronchus	UBERON:0002031	88.20	gold quality
caput epididymis	UBERON:0004358	88.06	gold quality
bronchus	UBERON:0002185	87.90	gold quality
ventricular zone	UBERON:0003053	87.77	gold quality
corpus callosum	UBERON:0002336	87.66	gold quality
entorhinal cortex	UBERON:0002728	87.63	gold quality
medial globus pallidus	UBERON:0002477	87.57	gold quality
endothelial cell	CL:0000115	87.40	gold quality
epithelium of nasopharynx	UBERON:0001951	85.94	gold quality
ganglionic eminence	UBERON:0004023	85.34	gold quality
globus pallidus	UBERON:0001875	85.12	gold quality
cortical plate	UBERON:0005343	84.94	gold quality
left testis	UBERON:0004533	84.31	gold quality
superior frontal gyrus	UBERON:0002661	84.17	gold quality
buccal mucosa cell	CL:0002336	84.00	gold quality
germinal epithelium of ovary	UBERON:0001304	83.94	gold quality
postcentral gyrus	UBERON:0002581	83.89	gold quality
parietal lobe	UBERON:0001872	83.88	gold quality
right testis	UBERON:0004534	83.82	gold quality
pigmented layer of retina	UBERON:0001782	83.44	gold quality
testis	UBERON:0000473	83.43	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	83.33	gold quality
primary visual cortex	UBERON:0002436	82.86	gold quality
parietal pleura	UBERON:0002400	81.91	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.26
E-GEOD-99795	no	100.77

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

6 targets.

Target	Regulation
FGF1	Unknown
GCK	Unknown
GSK3B
IL5RA	Unknown
MAP1A	Repression
ODF2

JASPAR motifs

Motif	Name	Family
MA0798.1	RFX3	RFX-related factors
MA0798.2	RFX3	RFX-related factors
MA0798.3	RFX3	RFX-related factors

JASPAR matrix evidence (PMIDs): PMID:8754849, PMID:20378718

miRNA regulators (miRDB)

69 targeting RFX3, 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-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-498-3P	99.91	71.27	1114
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
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-373-3P	99.84	70.68	1668
HSA-MIR-520E-3P	99.84	70.55	1698
HSA-MIR-372-3P	99.83	70.58	1691
HSA-MIR-520A-3P	99.83	70.59	1687
HSA-MIR-520B-3P	99.83	70.56	1699
HSA-MIR-520C-3P	99.83	70.56	1699
HSA-MIR-520D-3P	99.83	70.78	1676
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-3156-3P	99.76	66.72	939
HSA-MIR-1976	99.74	65.48	1127
HSA-MIR-1825	99.72	68.11	1089
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-1283	99.69	72.42	3009

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 8)

• Data show that two regulatory factor for X box (RFX1 and 3) binding sites in exon1 of both the mouse and human microtubule-associated protein (MAP1A) gene are important for effective transcriptional repression in non-neuronal cells. (PMID:12411430)
• novel role for the RFX family of transcription factors as modulators of Ras signalling in epithelial cells. (PMID:15024578)
• RFX3 controls the expression of genes involved in primary ciliary dyskinesia. (PMID:19671664)
• Taken together, this study suggests ciliogenic RFX transcription factors regulate FGF-1B promoter activity and the maintenance of F1BGFP(+) NSPCs and GBM-SCs. (PMID:22415835)
• FOXJ1 is an important regulator of cilia gene expression during ciliated cell differentiation, with RFX3 as a transcriptional co-activator to FOXJ1. (PMID:23822649)
• RFX3 interacts with the D sequence of adeno-associated virus inverted terminal repeat and regulates AAV transduction. (PMID:29317724)
• findings reveal a regulation of RFX3 transcription factor and link fatty acid metabolism and protein lipidation to the regulation of ciliogenesis. (PMID:30127002)
• CircRFX3 Up-regulates Its Host Gene RFX3 to Facilitate Tumorigenesis and Progression of Glioma. (PMID:35416616)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	rfx3	ENSDARG00000014550
mus_musculus	Rfx3	ENSMUSG00000040929
rattus_norvegicus	Rfx3	ENSRNOG00000014486
drosophila_melanogaster	Rfx	FBGN0020379

Paralogs (7): RFX2 (ENSG00000087903), RFX4 (ENSG00000111783), RFX1 (ENSG00000132005), RFX5 (ENSG00000143390), RFX7 (ENSG00000181827), RFX6 (ENSG00000185002), RFX8 (ENSG00000196460)

Protein

Protein identifiers

Transcription factor RFX3 — P48380 (reviewed: P48380)

Alternative names: Regulatory factor X 3

All UniProt accessions (9): P48380, A9Z1Z2, F6UGA0, F6USP3, F6UV76, F6XM74, H0Y790, H0Y7W5, H0Y7Z4

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor required for ciliogenesis and islet cell differentiation during endocrine pancreas development. Essential for the differentiation of nodal monocilia and left-right asymmetry specification during embryogenesis. Required for the biogenesis of motile cilia by governing growth and beating efficiency of motile cells. Also required for ciliated ependymal cell differentiation. Regulates the expression of genes involved in ciliary assembly (DYNC2LI1, FOXJ1 and BBS4) and genes involved in ciliary motility (DNAH11, DNAH9 and DNAH5). Together with RFX6, participates in the differentiation of 4 of the 5 islet cell types during endocrine pancreas development, with the exception of pancreatic PP (polypeptide-producing) cells. Regulates transcription by forming a heterodimer with another RFX protein and binding to the X-box in the promoter of target genes. Represses transcription of MAP1A in non-neuronal cells but not in neuronal cells.

Subunit / interactions. Heterodimer; heterodimerizes with RFX1 and RFX2, and RFX6.

Subcellular location. Nucleus.

Similarity. Belongs to the RFX family.

Isoforms (3)

UniProt ID	Names	Canonical?
P48380-1	1	yes
P48380-2	2
P48380-3	3

RefSeq proteins (5): NP_001269045, NP_001269046, NP_001364928, NP_002910, NP_602304 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003150	DNA-bd_RFX	Domain
IPR007668	RFX1_trans_act	Domain
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR039779	RFX-like	Family
IPR057321	RFX1-4/6/8-like_BCD	Domain

Pfam: PF02257, PF04589, PF25340

UniProt features (10 total): splice variant 4, sequence conflict 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-P48380-F1	67.90	0.43

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 368 (showing top): GOBP_POSITIVE_REGULATION_OF_EPITHELIAL_CELL_DIFFERENTIATION, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_EPITHELIAL_CELL_DEVELOPMENT, TGCACTT_MIR519C_MIR519B_MIR519A, TTTGTAG_MIR520D, GOBP_INSULIN_SECRETION, GOBP_TYPE_B_PANCREATIC_CELL_DEVELOPMENT, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_HORMONE_TRANSPORT, GOBP_CELL_CELL_SIGNALING, GOBP_PANCREAS_DEVELOPMENT, GOBP_SPECIFICATION_OF_SYMMETRY, GOBP_REGULATION_OF_EPITHELIAL_CELL_DIFFERENTIATION

GO Biological Process (16): DNA-templated transcription (GO:0006351), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), endocrine pancreas development (GO:0031018), 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), cell maturation (GO:0048469), regulation of insulin secretion (GO:0050796), cilium assembly (GO:0060271), cilium-dependent cell motility (GO:0060285), epithelial cilium movement involved in determination of left/right asymmetry (GO:0060287), type B pancreatic cell maturation (GO:0072560), positive regulation of type B pancreatic cell development (GO:2000078), determination of left/right symmetry (GO:0007368), cell differentiation (GO:0030154)

GO Molecular Function (8): transcription cis-regulatory region binding (GO:0000976), 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 (GO:0003677), DNA-binding transcription factor activity (GO:0003700), sequence-specific double-stranded DNA binding (GO:1990837), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (4): chromatin (GO:0000785), extracellular region (GO:0005576), nucleus (GO:0005634), transcription regulator complex (GO:0005667)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	4
DNA-templated transcription	3
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
cellular developmental process	2
type B pancreatic cell development	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
cellular anatomical structure	2
gene expression	1
RNA biosynthetic process	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
pancreas development	1
endocrine system development	1
anatomical structure development	1
negative regulation of RNA biosynthetic process	1
positive regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
cell development	1
anatomical structure maturation	1
insulin secretion	1
regulation of protein secretion	1
regulation of peptide hormone secretion	1
axoneme assembly	1
intraciliary transport involved in cilium assembly	1
cilium organization	1
protein localization to cilium	1
organelle assembly	1
trans-Golgi to periciliary membrane compartment transport	1
plasma membrane bounded cell projection assembly	1
ciliary transition zone assembly	1
cilium or flagellum-dependent cell motility	1
cilium movement	1
epithelial cilium movement involved in extracellular fluid movement	1
determination of left/right symmetry	1
epithelial cell maturation	1
positive regulation of cell development	1
positive regulation of epithelial cell differentiation	1
positive regulation of multicellular organismal process	1
regulation of type B pancreatic cell development	1

Protein interactions and networks

STRING

1254 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RFX3	RPL30	P04645	846
RFX3	DTX2	Q86UW9	731
RFX3	CTCF	P49711	701
RFX3	SS18L1	O75177	690
RFX3	FOXJ1	Q92949	671
RFX3	CCNK	O75909	661
RFX3	NEUROG3	Q9Y4Z2	657
RFX3	FUT5	Q11128	645
RFX3	MCIDAS	D6RGH6	610
RFX3	LYL1	P12980	548
RFX3	IFT88	Q13099	539
RFX3	PPY	P01298	516
RFX3	DYNC2LI1	Q8TCX1	507
RFX3	MLLT1	Q03111	490
RFX3	PAX4	O43316	482

IntAct

64 interactions, top by confidence:

A	B	Type	Score
FHL2	RFX3	psi-mi:“MI:0915”(physical association)	0.900
RFX3	FHL2	psi-mi:“MI:0915”(physical association)	0.900
TRAF2	RFX3	psi-mi:“MI:0915”(physical association)	0.740
RFX3	TRAF2	psi-mi:“MI:0915”(physical association)	0.740
FOXJ1	RFX3	psi-mi:“MI:0914”(association)	0.730
RFX3	RFX1	psi-mi:“MI:0914”(association)	0.730
FHL3	RFX3	psi-mi:“MI:0915”(physical association)	0.670
RFX3	FHL3	psi-mi:“MI:0915”(physical association)	0.670
INPP5K	GART	psi-mi:“MI:0914”(association)	0.640
RFX3	TRIP6	psi-mi:“MI:0915”(physical association)	0.560
TRIP6	RFX3	psi-mi:“MI:0915”(physical association)	0.560
RFX3	MEOX2	psi-mi:“MI:0915”(physical association)	0.560
FHL2	CNOT1	psi-mi:“MI:0914”(association)	0.530
FOXJ1	PEX14	psi-mi:“MI:0914”(association)	0.530
FOXN3	RFX1	psi-mi:“MI:0914”(association)	0.530

BioGRID (82): RFX3 (Two-hybrid), RFX3 (Two-hybrid), TRIP6 (Two-hybrid), SEC63 (Affinity Capture-MS), PABPC5 (Affinity Capture-MS), TRAF2 (Two-hybrid), RFX6 (Two-hybrid), RFX3 (Two-hybrid), RFX3 (Affinity Capture-MS), RFX3 (Affinity Capture-MS), RFX3 (Affinity Capture-MS), RFX3 (Affinity Capture-MS), PABPC5 (Affinity Capture-MS), FAM188A (Affinity Capture-MS), IGSF8 (Affinity Capture-MS)

ESM2 similar proteins: A0JMF8, A2RSY1, A6QLW9, B1WAV2, B2GV50, O60271, O75069, O77627, P05412, P05627, P0C090, P17325, P22670, P48377, P48378, P48379, P48380, P48381, P56432, Q0V989, Q0V9K5, Q16656, Q32NR3, Q3KR73, Q499B3, Q49GP3, Q4R3I8, Q4R3Z4, Q4V872, Q4VGL6, Q58A65, Q5EAP5, Q5EY87, Q5RDR2, Q5RJA1, Q5TC82, Q62739, Q66IV1, Q6NRE7, Q6NUC6

Diamond homologs: A0A1L8GWK2, A0A1L8H0H2, A0JMF8, A2BGA0, A6QLW9, B1WAV2, B2GV50, D2HNW6, F8VPJ6, P22670, P48377, P48378, P48379, P48380, P48381, P48382, P48743, Q09555, Q0V9K5, Q2KHR2, Q32NR3, Q33E94, Q4R3I8, Q4R3Z4, Q59V88, Q5EAP5, Q5RDR2, Q5RJA1, Q7TNK1, Q8C7R7, Q8HWS3, Q9JL61, D3YU81, P48383, Q6ZV50, Q5AMQ6

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
RFX3	“up-regulates activity”	FOXJ1	binding
RFX3	up-regulates	Cilium_assembly

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 39 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.

GO biological processes:

GO term	Partners	Fold	FDR
chromatin remodeling	5	9.3×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	9
Uncertain significance	109
Likely benign	19
Benign	4

Top pathogenic / likely-pathogenic (12)

Variant ID	HGVS	Classification
1712325	NM_001282116.2(RFX3):c.115C>T (p.Gln39Ter)	Pathogenic
3377167	NM_001282116.2(RFX3):c.628C>T (p.Arg210Ter)	Pathogenic
3788555	NM_001282116.2(RFX3):c.1786C>T (p.Gln596Ter)	Pathogenic
1064862	NM_001282116.2(RFX3):c.1708dup (p.Ala570fs)	Likely pathogenic
1311522	NM_001282116.2(RFX3):c.937_938del (p.Val313fs)	Likely pathogenic
1710415	NM_001282116.2(RFX3):c.973+3A>G	Likely pathogenic
2429854	NM_001282116.2(RFX3):c.1473del (p.Phe492fs)	Likely pathogenic
2630540	NM_001282116.2(RFX3):c.855C>G (p.Tyr285Ter)	Likely pathogenic
3346579	NM_001282116.2(RFX3):c.106_109del (p.Val36fs)	Likely pathogenic
3380899	NM_001282116.2(RFX3):c.475-1G>C	Likely pathogenic
3432604	NM_001282116.2(RFX3):c.764G>A (p.Arg255His)	Likely pathogenic
4071461	NM_001282116.2(RFX3):c.973+1G>A	Likely pathogenic

SpliceAI

5798 predictions. Top by Δscore:

Variant	Effect	Δscore
9:3225063:T:TA	donor_gain	1.0000
9:3225099:TGTG:T	donor_gain	1.0000
9:3225278:CAT:C	acceptor_gain	1.0000
9:3225280:TC:T	acceptor_loss	1.0000
9:3225281:C:CA	acceptor_loss	1.0000
9:3225281:C:CC	acceptor_gain	1.0000
9:3228842:CTTAC:C	donor_loss	1.0000
9:3228844:TA:T	donor_loss	1.0000
9:3228885:CCAAA:C	acceptor_gain	1.0000
9:3228886:CAAAC:C	acceptor_gain	1.0000
9:3228890:C:CC	acceptor_gain	1.0000
9:3248181:TTGAG:T	acceptor_gain	1.0000
9:3257019:G:GA	donor_gain	1.0000
9:3257047:T:TA	donor_gain	1.0000
9:3257206:CAG:C	acceptor_gain	1.0000
9:3257207:A:T	acceptor_gain	1.0000
9:3257208:G:C	acceptor_gain	1.0000
9:3257208:G:GC	acceptor_gain	1.0000
9:3257212:C:CT	acceptor_gain	1.0000
9:3257214:C:CT	acceptor_gain	1.0000
9:3257215:A:T	acceptor_gain	1.0000
9:3262929:GAATA:G	donor_loss	1.0000
9:3262930:AATAC:A	donor_loss	1.0000
9:3262931:ATAC:A	donor_loss	1.0000
9:3262932:TACC:T	donor_loss	1.0000
9:3262933:A:AT	donor_loss	1.0000
9:3263085:C:CC	acceptor_gain	1.0000
9:3263085:CTGT:C	acceptor_loss	1.0000
9:3263086:T:A	acceptor_loss	1.0000
9:3266202:GTATA:G	donor_loss	1.0000

AlphaMissense

4934 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:3248072:G:T	A643D	1.000
9:3248073:C:G	A643P	1.000
9:3248075:A:T	V642D	1.000
9:3248078:C:G	R641P	1.000
9:3248094:A:C	Y636D	1.000
9:3248105:T:A	E632V	1.000
9:3248105:T:G	E632A	1.000
9:3248106:C:T	E632K	1.000
9:3248108:T:A	D631V	1.000
9:3248108:T:C	D631G	1.000
9:3248108:T:G	D631A	1.000
9:3248109:C:A	D631Y	1.000
9:3248109:C:G	D631H	1.000
9:3248114:A:G	L629P	1.000
9:3248114:A:T	L629H	1.000
9:3248117:A:C	L628R	1.000
9:3248117:A:G	L628P	1.000
9:3248117:A:T	L628Q	1.000
9:3248120:C:G	R627P	1.000
9:3248126:A:C	L625R	1.000
9:3248126:A:G	L625P	1.000
9:3248126:A:T	L625Q	1.000
9:3248128:G:C	H624Q	1.000
9:3248128:G:T	H624Q	1.000
9:3248129:T:C	H624R	1.000
9:3248129:T:G	H624P	1.000
9:3248130:G:C	H624D	1.000
9:3248130:G:T	H624N	1.000
9:3248131:G:C	F623L	1.000
9:3248131:G:T	F623L	1.000

dbSNP variants (sampled 300 via entrez): RS1000006808 (9:3428113 C>G), RS1000010243 (9:3221010 T>C), RS1000035033 (9:3254534 C>A,G), RS1000035398 (9:3526635 T>A,C,G), RS1000053327 (9:3396539 C>G), RS1000065310 (9:3329586 C>A,G,T), RS1000065608 (9:3301362 A>T), RS1000068516 (9:3295865 A>G,T), RS1000075559 (9:3392257 G>C), RS1000087119 (9:3525359 A>C), RS1000089260 (9:3494380 T>C), RS1000104964 (9:3424008 G>A,C,T), RS1000115591 (9:3459949 C>T), RS1000122326 (9:3480099 C>T), RS1000150636 (9:3409941 T>A)

Disease associations

OMIM: gene MIM:601337 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Strong	Autosomal dominant
autism spectrum disorder	Limited	Autosomal dominant
complex neurodevelopmental disorder	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AD

Mondo (6): neurodevelopmental disorder (MONDO:0700092), attention deficit-hyperactivity disorder (MONDO:0007743), autism spectrum disorder (MONDO:0005258), intellectual disability (MONDO:0001071), RFX3-related neurodevelopmental disorder with autism and other behavioural abnormalities (MONDO:0700361), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (2): NON RARE IN EUROPE: Autism (Orphanet:106), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST002187_8	Systolic blood pressure in sickle cell anemia	8.000000e-06
GCST002909_1	Gout	1.000000e-10
GCST003477_2	Monobrow thickness	2.000000e-06
GCST005566_24	Insomnia	1.000000e-07
GCST006041_17	Major depressive disorder	4.000000e-08
GCST007327_171	Smoking status (ever vs never smokers)	3.000000e-10
GCST008097_30	Bisphosphonate-associated atypical femoral fracture	2.000000e-06
GCST008152_50	Weight	1.000000e-06
GCST008158_68	Body mass index	1.000000e-07

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0004318	smoking behavior
EFO:0009958	response to bisphosphonate
EFO:0009960	atypical femoral fracture
EFO:0004338	body weight
EFO:0004340	body mass index

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, decreases methylation	8
trichostatin A	affects cotreatment, decreases expression	3
entinostat	decreases expression, affects cotreatment	2
Tobacco Smoke Pollution	decreases expression	2
Cyclosporine	increases expression	2
methylmercuric chloride	decreases expression	1
bisphenol A	decreases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	decreases expression	1
16 alpha-ethyl-21-hydroxy-19-nor-4-pregnene-3,20-dione	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
(+)-JQ1 compound	increases expression	1
Sunitinib	increases expression	1
Panobinostat	affects cotreatment, decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	decreases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	decreases methylation	1
Caffeine	decreases phosphorylation	1
Diazinon	increases methylation	1
Dimethyl Sulfoxide	affects expression	1
Diuron	decreases expression	1
Estradiol	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00152750	PHASE4	UNKNOWN	Study of Clonidine on Sleep Architecture in Children With Tourette’s Syndrome (TS) and Comorbid ADHD
NCT00181571	PHASE4	COMPLETED	A Double-Blind Comparison of Concerta and Placebo in Adults With Attention Deficit Hyperactivity Disorder
NCT00181675	PHASE4	COMPLETED	A Double-Blind Comparison of Galantamine HBr and Placebo in Adults With Attention Deficit Hyperactivity Disorder
NCT00181714	PHASE4	COMPLETED	Prevention of Cigarette Smoking in Attention Deficit Hyperactivity Disorder (ADHD) Youth With Concerta
NCT00181948	PHASE4	COMPLETED	Strattera Treatment in Children With ADHD Who Have Poor Response to Stimulant Therapy
NCT00181987	PHASE4	COMPLETED	Concerta in the Treatment of ADHD in Youth and Adults With Bipolar Disorder
NCT00190736	PHASE4	COMPLETED	Efficacy and Safety of Once-Daily Atomoxetine Hydrochloride in Adults With ADHD Over an Extended Period of Time (6 Months)
NCT00190775	PHASE4	COMPLETED	A Randomized, Double-Blind Comparison of Placebo and Atomoxetine Hydrochloride Given Once a Day in Adults With Attention-Deficit/Hyperactivity Disorder (ADHD)
NCT00190879	PHASE4	COMPLETED	Placebo-Controlled Study of Atomoxetine Hydrochloride in the Treatment of Adults With ADHD and Comorbid Social Anxiety Disorder
NCT00190957	PHASE4	COMPLETED	Atomoxetine Treatment of Adults With ADHD and Comorbid Alcohol Abuse
NCT00191035	PHASE4	COMPLETED	Maintenance of Benefit With Atomoxetine Hydrochloride in Adolescents With ADHD
NCT00191048	PHASE4	COMPLETED	Treatment With Atomoxetine Hydrochloride in Children and Adolescents With ADHD
NCT00191633	PHASE4	COMPLETED	Study of Atomoxetine in Children With ADHD to Assess Symptomatic and Functional Outcomes
NCT00191906	PHASE4	COMPLETED	Comparison of Atomoxetine and Placebo in Children With Attention-Deficit/Hyperactivity Disorder (ADHD) and/or Reading Disorder (RD)
NCT00216918	PHASE4	COMPLETED	Neuropsychological Functioning in Children With Attention-Deficit/Hyperactivity Disorder.
NCT00221962	PHASE4	COMPLETED	Study of Aripiprazole (Abilify) in Children With ADHD (Attention Deficit Hyperactivity Disorder)
NCT00223561	PHASE4	COMPLETED	Methylphenidate and Driving Ability in Adult Patients With Attention-Deficit Hyperactivity Disorder