SGSM3

Summary

SGSM3 (small G protein signaling modulator 3, HGNC:25228) is a protein-coding gene on chromosome 22q13.1, encoding Small G protein signaling modulator 3 (Q96HU1). GTPase-activating protein (GAP) specific for Rab5 small GTPase for which it accelerates the intrinsic GTP hydrolysis rate, thereby controlling trafficking through the early endocytic pathway.

Enables GTPase activator activity and small GTPase binding activity. Involved in several processes, including Rap protein signal transduction; positive regulation of GTPase activity; and regulation of Rab protein signal transduction. Located in cytosol.

Source: NCBI Gene 27352 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 8
• Clinical variants (ClinVar): 196 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 58
• MANE Select transcript: NM_015705

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25228
Approved symbol	SGSM3
Name	small G protein signaling modulator 3
Location	22q13.1
Locus type	gene with protein product
Status	Approved
Aliases	DJ1042K10.2, RUSC3, RabGAP-5, RABGAP5
Ensembl gene	ENSG00000100359
Ensembl biotype	protein_coding
OMIM	610440
Entrez	27352

Gene structure

Transcript identifiers

Ensembl transcripts: 45 — 36 protein_coding, 9 retained_intron

ENST00000248929, ENST00000417424, ENST00000427834, ENST00000457767, ENST00000462457, ENST00000467915, ENST00000469719, ENST00000470518, ENST00000478085, ENST00000480830, ENST00000481028, ENST00000481408, ENST00000485962, ENST00000851447, ENST00000851448, ENST00000851449, ENST00000851450, ENST00000851451, ENST00000851452, ENST00000851453, ENST00000851454, ENST00000851455, ENST00000851456, ENST00000851457, ENST00000851458, ENST00000851459, ENST00000851460, ENST00000851461, ENST00000851462, ENST00000925006, ENST00000925007, ENST00000925008, ENST00000925009, ENST00000956258, ENST00000956259, ENST00000956260, ENST00000956261, ENST00000956262, ENST00000956263, ENST00000956264, ENST00000956265, ENST00000956266, ENST00000956267, ENST00000956268, ENST00000956269

RefSeq mRNA: 12 — MANE Select: NM_015705 NM_001301849, NM_001350039, NM_001350040, NM_001350041, NM_001350042, NM_001350043, NM_001350044, NM_001350045, NM_001350046, NM_001350047, NM_001350048, NM_015705

CCDS: CCDS14002

Canonical transcript exons

ENST00000248929 — 22 exons

Exon	Start	End
ENSE00001698903	40407201	40407328
ENSE00001946816	40370594	40370688
ENSE00003487177	40400696	40400813
ENSE00003489270	40408794	40408842
ENSE00003526160	40407789	40407843
ENSE00003530925	40407413	40407568
ENSE00003537503	40407017	40407071
ENSE00003544079	40408071	40408120
ENSE00003552018	40408277	40408429
ENSE00003562502	40408933	40409018
ENSE00003575081	40404557	40404664
ENSE00003599148	40409682	40410289
ENSE00003600763	40408627	40408697
ENSE00003602498	40402139	40402205
ENSE00003614209	40406438	40406662
ENSE00003636975	40409465	40409525
ENSE00003638923	40404247	40404455
ENSE00003648881	40405141	40405284
ENSE00003667289	40405649	40405844
ENSE00003679049	40409250	40409372
ENSE00003684601	40401593	40401675
ENSE00003789758	40406078	40406223

Expression profiles

Bgee: expression breadth ubiquitous, 142 present calls, max score 98.18.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.5663 / max 134.6198, expressed in 1820 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
192422	26.5663	1820

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	98.18	gold quality
lower esophagus mucosa	UBERON:0035834	97.90	gold quality
pituitary gland	UBERON:0000007	97.85	gold quality
body of stomach	UBERON:0001161	97.85	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.80	gold quality
right uterine tube	UBERON:0001302	97.76	gold quality
mucosa of transverse colon	UBERON:0004991	97.75	gold quality
granulocyte	CL:0000094	97.51	gold quality
cerebellar hemisphere	UBERON:0002245	97.51	gold quality
adenohypophysis	UBERON:0002196	97.50	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	97.48	gold quality
cerebellar cortex	UBERON:0002129	97.46	gold quality
cerebellum	UBERON:0002037	97.45	gold quality
saliva-secreting gland	UBERON:0001044	97.42	gold quality
minor salivary gland	UBERON:0001830	97.39	gold quality
prostate gland	UBERON:0002367	97.34	gold quality
right lobe of thyroid gland	UBERON:0001119	97.24	gold quality
fundus of stomach	UBERON:0001160	97.23	gold quality
spleen	UBERON:0002106	97.23	gold quality
right frontal lobe	UBERON:0002810	97.16	gold quality
left lobe of thyroid gland	UBERON:0001120	97.09	gold quality
thyroid gland	UBERON:0002046	96.81	gold quality
stomach	UBERON:0000945	96.74	gold quality
small intestine Peyer’s patch	UBERON:0003454	96.64	gold quality
transverse colon	UBERON:0001157	96.56	gold quality
endocervix	UBERON:0000458	96.42	gold quality
small intestine	UBERON:0002108	96.25	gold quality
esophagus mucosa	UBERON:0002469	96.24	gold quality
left testis	UBERON:0004533	96.12	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.07	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.07

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

19 targeting SGSM3, 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-1184	99.99	68.19	1458
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-150-3P	99.43	70.51	920
HSA-MIR-4318	99.38	66.94	1505
HSA-MIR-4685-5P	99.25	65.99	1563
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-4436B-3P	98.25	65.26	1494
HSA-MIR-6735-5P	98.24	65.36	1488
HSA-MIR-7843-5P	98.12	65.26	1421
HSA-MIR-4457	98.09	67.12	1274
HSA-MIR-4632-5P	97.82	65.38	1470
HSA-MIR-6879-5P	97.77	65.52	1521
HSA-MIR-492	94.02	64.46	413

Literature-anchored findings (GeneRIF, showing 7)

• MAP decreased the AP-1-dependent promoter activity additively with merlin in NIH3T3 cells.Results suggest that MAP may play a cooperative role in the merlin-mediated growth suppression of cells. (PMID:15541357)
• Identification of novel protein SGSM3 which modulates small G protein (RAP and RAB)-mediated signaling pathway. (PMID:17509819)
• The CIP85 was observed to interact with clathrin, which suggested a role for CIP85 in the clathrin-mediated internalization of Cx43. (PMID:23586710)
• rs56228771 may contribute to hepatocarcinogenesis, possibly by affecting SGSM3 expression through a miRNA-mediated regulation. (PMID:23918301)
• SGSM3 gene polymorphism is associated with the risk of breast cancer in Chinese population. (PMID:27432265)
• findings support an association between 4-bp ins/del polymorphism in the 3’UTR of SGSM3 and the risk of bladder cancer in an Iranian population. (PMID:29693742)
• Intellectual disability syndrome associated with a homozygous founder variant in SGSM3 in Ashkenazi Jews. (PMID:37833060)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	sgsm3	ENSDARG00000019038
mus_musculus	Sgsm3	ENSMUSG00000042303
rattus_norvegicus	Sgsm3	ENSRNOG00000018745
drosophila_melanogaster	CG12241	FBGN0038304
caenorhabditis_elegans		WBGENE00018281

Paralogs (45): RABGAP1 (ENSG00000011454), TBC1D22A (ENSG00000054611), TBC1D22B (ENSG00000065491), TBC1D1 (ENSG00000065882), EVI5 (ENSG00000067208), TBC1D25 (ENSG00000068354), TBC1D2 (ENSG00000095383), TBC1D10A (ENSG00000099992), TBC1D17 (ENSG00000104946), TBC1D13 (ENSG00000107021), TBC1D12 (ENSG00000108239), TBC1D9 (ENSG00000109436), TBC1D30 (ENSG00000111490), TBC1D15 (ENSG00000121749), TBC1D5 (ENSG00000131374), TBC1D14 (ENSG00000132405), TBC1D8B (ENSG00000133138), TBC1D4 (ENSG00000136111), GRTP1 (ENSG00000139835), SGSM2 (ENSG00000141258), EVI5L (ENSG00000142459), TBCK (ENSG00000145348), USP6NL (ENSG00000148429), RABGAP1L (ENSG00000152061), SGSM1 (ENSG00000167037), TBC1D21 (ENSG00000167139), TBC1D2B (ENSG00000167202), TBC1D16 (ENSG00000167291), TBC1D10B (ENSG00000169221), TBC1D10C (ENSG00000175463), TBC1D28 (ENSG00000189375), TBC1D9B (ENSG00000197226), TBC1D8 (ENSG00000204634), TBC1D26 (ENSG00000214946), TBC1D3G (ENSG00000260287), TBC1D3K (ENSG00000273513), TBC1D3H (ENSG00000274226), TBC1D3D (ENSG00000274419), TBC1D3L (ENSG00000274512), TBC1D3 (ENSG00000274611)

Protein

Protein identifiers

Small G protein signaling modulator 3 — Q96HU1 (reviewed: Q96HU1)

Alternative names: Merlin-associated protein, RUN and TBC1 domain-containing protein 3, Rab-GTPase-activating protein-like protein, RabGAP-5

All UniProt accessions (5): Q96HU1, B0QY80, B0QY81, B9A6J5, H0Y7V2

UniProt curated annotations — full annotation on UniProt →

Function. GTPase-activating protein (GAP) specific for Rab5 small GTPase for which it accelerates the intrinsic GTP hydrolysis rate, thereby controlling trafficking through the early endocytic pathway. May play a cooperative role in NF2-mediated growth suppression of cells.

Subunit / interactions. Interacts with GJA1; interaction with GJA1 induces its degradation. Interacts via its RUN domain with the C-terminal region of NF2. Interacts with GTP-bound RAB5A, RAB5B and RAB5C; functions as a GAP. Doesn’t interact with other GTP-bound Rabs. Interacts with RAB3A, RAB4A, RAB5A, RAB8A, RAB11A, RAP1A, RAP1B, RAP2A, RAP2B and PDCD6IP. No interaction with RAB27A. No interaction with GJB1 or GJD2.

Subcellular location. Cytoplasm.

Tissue specificity. Widely expressed.

Similarity. Belongs to the small G protein signaling modulator family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96HU1-1	1	yes
Q96HU1-2	2

RefSeq proteins (12): NP_001288778, NP_001336968, NP_001336969, NP_001336970, NP_001336971, NP_001336972, NP_001336973, NP_001336974, NP_001336975, NP_001336976, NP_001336977, NP_056520* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000195	Rab-GAP-TBC_dom	Domain
IPR001452	SH3_domain	Domain
IPR004012	Run_dom	Domain
IPR035833	SGSM3_SH3	Domain
IPR035969	Rab-GAP_TBC_sf	Homologous_superfamily
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR037213	Run_dom_sf	Homologous_superfamily
IPR050302	Rab_GAP_TBC_domain	Family

Pfam: PF00018, PF00566, PF02759

UniProt features (10 total): domain 3, sequence variant 2, chain 1, coiled-coil region 1, modified residue 1, splice variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96HU1-F1	82.99	0.51

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): 406

Mutagenesis-validated functional residues (1):

Position	Phenotype
165	decreased gap activity towards rab5b.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 159 (showing top): GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_GTPASE_ACTIVITY, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_VESICLE_MEDIATED_TRANSPORT, GOMF_GTPASE_BINDING, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, BROWNE_HCMV_INFECTION_48HR_DN, GOBP_POSITIVE_REGULATION_OF_CATALYTIC_ACTIVITY, GOBP_REGULATION_OF_HYDROLASE_ACTIVITY, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, GOBP_POSITIVE_REGULATION_OF_MOLECULAR_FUNCTION, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CATABOLIC_PROCESS

GO Biological Process (8): endosomal transport (GO:0016197), regulation of endocytosis (GO:0030100), regulation of Rab protein signal transduction (GO:0032483), Rap protein signal transduction (GO:0032486), positive regulation of GTPase activity (GO:0043547), positive regulation of protein catabolic process (GO:0045732), plasma membrane to endosome transport (GO:0048227), regulation of cell cycle (GO:0051726)

GO Molecular Function (3): GTPase activator activity (GO:0005096), small GTPase binding (GO:0031267), protein binding (GO:0005515)

GO Cellular Component (3): cytosol (GO:0005829), gap junction (GO:0005921), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
vesicle-mediated transport	2
GTPase activity	2
cellular anatomical structure	2
intracellular transport	1
endocytosis	1
regulation of cellular component organization	1
regulation of vesicle-mediated transport	1
Rab protein signal transduction	1
regulation of small GTPase mediated signal transduction	1
small GTPase-mediated signal transduction	1
regulation of GTPase activity	1
positive regulation of hydrolase activity	1
positive regulation of catabolic process	1
protein catabolic process	1
regulation of protein catabolic process	1
positive regulation of protein metabolic process	1
cell cycle	1
regulation of cellular process	1
enzyme activator activity	1
GTPase regulator activity	1
GTPase binding	1
binding	1
cytoplasm	1
cell-cell junction	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

876 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SGSM3	RAB5A	P20339	912
SGSM3	SGSM1	Q2NKQ1	911
SGSM3	SGSM2	O43147	907
SGSM3	RAB4A	P20338	807
SGSM3	RAP1B	P09526	762
SGSM3	RAB11A	P24410	742
SGSM3	RAB3A	P20336	729
SGSM3	RAB8A	P24407	715
SGSM3	RAP2A	P10114	713
SGSM3	RAP1A	P10113	649
SGSM3	RAP2B	P17964	649
SGSM3	GJA1	P17302	636
SGSM3	RABGEF1	Q9UJ41	575
SGSM3	TBC1D13	Q9NVG8	541
SGSM3	NTRK1	P04629	534

IntAct

21 interactions, top by confidence:

A	B	Type	Score
SGSM3	LEMD2	psi-mi:“MI:0915”(physical association)	0.590
SGSM3	FAD1	psi-mi:“MI:0915”(physical association)	0.560
FAD1	SGSM3	psi-mi:“MI:0915”(physical association)	0.560
FMO3	SGSM3	psi-mi:“MI:0915”(physical association)	0.560
CD226	MEN1	psi-mi:“MI:0914”(association)	0.530
HLA-B	LTN1	psi-mi:“MI:0914”(association)	0.530
SGSM3	CHRM3	psi-mi:“MI:0915”(physical association)	0.370
RPL35	SGSM3	psi-mi:“MI:0915”(physical association)	0.370
HLA-B		psi-mi:“MI:0914”(association)	0.350
	DENND11	psi-mi:“MI:0914”(association)	0.350
TACSTD2	RIMOC1	psi-mi:“MI:0914”(association)	0.350
NPTN	RTL8C	psi-mi:“MI:0914”(association)	0.350
HLA-B	RAB29	psi-mi:“MI:0914”(association)	0.350
SPINT2	SPAG9	psi-mi:“MI:0914”(association)	0.350
UPK2	IFT56	psi-mi:“MI:0914”(association)	0.350
FMO3	SGSM3	psi-mi:“MI:0915”(physical association)	0.000
DSCAM	SGSM3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (33): SGSM3 (Affinity Capture-RNA), SGSM3 (Affinity Capture-MS), SGSM3 (Affinity Capture-MS), SGSM3 (Affinity Capture-MS), SGSM3 (Affinity Capture-MS), SGSM3 (Affinity Capture-MS), LEMD2 (Affinity Capture-MS), SGSM3 (Affinity Capture-RNA), SGSM3 (Two-hybrid), SGSM3 (Two-hybrid), NF2 (Reconstituted Complex), NF2 (Affinity Capture-Western), NF2 (Co-localization), SGSM3 (Two-hybrid), SGSM3 (Affinity Capture-MS)

ESM2 similar proteins: A1A5K6, A6H8I2, F1M386, F1PBJ0, F1QRX7, F1QWA8, F6UMY3, O02697, O14830, O97790, P26675, P48736, Q08CX5, Q21029, Q29RJ2, Q2KI13, Q3UUG6, Q3UYK3, Q3V3E1, Q5E9C4, Q5R8B7, Q5SVR0, Q5ZJX5, Q66K14, Q6DDI6, Q6DDZ9, Q6DEY8, Q6P6R7, Q6ZT07, Q7T2D0, Q8BGG7, Q8CHG7, Q8R5A6, Q8TC07, Q8TEU7, Q8TF42, Q8VCZ6, Q8WZA2, Q91WS7, Q95LL3

Diamond homologs: A2AWA9, A3KGB4, A6H6A9, A6H8I2, A6QP29, B0R0W9, B1AVH7, B5DFA1, C8VDQ4, D2H0G5, F4HVW5, O60447, O95759, P53258, P58802, P87234, Q0IIM8, Q12317, Q28CB1, Q2KI13, Q3KR37, Q3KR56, Q3U0J8, Q3UYK3, Q4KMP7, Q4QQU7, Q5R372, Q5RAN1, Q5RCW6, Q5SVR0, Q5TC63, Q66K14, Q6C8M8, Q6GL87, Q6GLZ0, Q6P6R7, Q6PBU5, Q6ZT07, Q7T2D0, Q80TI0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	139
Likely benign	18
Benign	6

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
4528329	NM_015705.6(SGSM3):c.1576C>T (p.Arg526Ter)	Pathogenic
2500991	NM_015705.6(SGSM3):c.981dup (p.Glu328fs)	Likely pathogenic

SpliceAI

4228 predictions. Top by Δscore:

Variant	Effect	Δscore
22:40400694:A:AG	acceptor_gain	1.0000
22:40400695:G:GG	acceptor_gain	1.0000
22:40400695:GGGCA:G	acceptor_gain	1.0000
22:40400810:TCAG:T	donor_loss	1.0000
22:40400812:AGG:A	donor_loss	1.0000
22:40400814:GTAGA:G	donor_loss	1.0000
22:40400815:T:A	donor_loss	1.0000
22:40404230:T:A	acceptor_gain	1.0000
22:40404231:G:A	acceptor_gain	1.0000
22:40404241:T:A	acceptor_gain	1.0000
22:40404244:CA:C	acceptor_loss	1.0000
22:40404245:A:AG	acceptor_gain	1.0000
22:40404245:AGAAG:A	acceptor_gain	1.0000
22:40404246:G:GG	acceptor_gain	1.0000
22:40404246:GAAGG:G	acceptor_gain	1.0000
22:40404455:GGTAA:G	donor_loss	1.0000
22:40404456:G:C	donor_loss	1.0000
22:40404456:G:GG	donor_gain	1.0000
22:40404553:TCAG:T	acceptor_loss	1.0000
22:40404554:CAGC:C	acceptor_loss	1.0000
22:40404555:A:AC	acceptor_loss	1.0000
22:40404555:A:AG	acceptor_gain	1.0000
22:40404555:AGCT:A	acceptor_gain	1.0000
22:40404556:G:A	acceptor_loss	1.0000
22:40404556:G:GC	acceptor_gain	1.0000
22:40404556:GC:G	acceptor_gain	1.0000
22:40404556:GCT:G	acceptor_gain	1.0000
22:40404556:GCTG:G	acceptor_gain	1.0000
22:40404556:GCTGT:G	acceptor_gain	1.0000
22:40404661:GCAG:G	donor_gain	1.0000

AlphaMissense

4883 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:40404336:T:C	F83L	1.000
22:40404338:C:A	F83L	1.000
22:40404338:C:G	F83L	1.000
22:40405154:T:C	L163P	1.000
22:40405217:T:C	L184P	1.000
22:40406101:T:A	W280R	1.000
22:40406101:T:C	W280R	1.000
22:40406477:T:C	F334L	1.000
22:40406479:C:A	F334L	1.000
22:40406479:C:G	F334L	1.000
22:40407546:T:C	F501S	1.000
22:40407822:G:T	G520W	1.000
22:40408073:T:A	W528R	1.000
22:40408073:T:C	W528R	1.000
22:40408077:T:C	F529S	1.000
22:40408412:T:A	W589R	1.000
22:40408412:T:C	W589R	1.000
22:40404318:T:A	W77R	0.999
22:40404318:T:C	W77R	0.999
22:40404337:T:C	F83S	0.999
22:40404369:T:A	W94R	0.999
22:40404369:T:C	W94R	0.999
22:40404560:T:A	W124R	0.999
22:40404560:T:C	W124R	0.999
22:40405150:G:C	D162H	0.999
22:40405151:A:C	D162A	0.999
22:40405151:A:G	D162G	0.999
22:40405151:A:T	D162V	0.999
22:40405152:C:A	D162E	0.999
22:40405152:C:G	D162E	0.999

dbSNP variants (sampled 300 via entrez): RS1000023417 (22:40381739 G>A), RS1000183806 (22:40370381 A>C), RS1000297489 (22:40388445 G>A,T), RS1000327904 (22:40394818 T>C), RS1000399379 (22:40369948 G>A,C), RS1000434653 (22:40402951 T>C), RS1000501591 (22:40400672 C>T), RS1000514659 (22:40368637 A>G), RS1000539656 (22:40402465 C>T), RS1000572847 (22:40410278 G>A,C), RS1000722731 (22:40375130 C>G,T), RS1000884035 (22:40382204 A>G), RS1000986738 (22:40382466 T>C), RS1001092687 (22:40369522 T>G), RS1001174628 (22:40410065 T>A,C)

Disease associations

OMIM: gene MIM:610440 | disease phenotypes: MIM:620401, MIM:209850

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Strong	Autosomal recessive
intellectual disability	Limited	Autosomal recessive

Mondo (4): intellectual developmental disorder, autosomal recessive 84 (MONDO:0980746), autism (MONDO:0005260), neurodevelopmental disorder (MONDO:0700092), intellectual disability (MONDO:0001071)

Orphanet (0):

HPO phenotypes

58 total (30 of 58 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000054	Micropenis
HP:0000126	Hydronephrosis
HP:0000252	Microcephaly
HP:0000268	Dolichocephaly
HP:0000278	Retrognathia
HP:0000316	Hypertelorism
HP:0000348	High forehead
HP:0000369	Low-set ears
HP:0000463	Anteverted nares
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000540	Hypermetropia
HP:0000718	Aggressive behavior
HP:0000737	Irritability
HP:0000739	Anxiety
HP:0000744	Low frustration tolerance
HP:0000750	Delayed speech and language development
HP:0000821	Hypothyroidism
HP:0000822	Hypertension
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability
HP:0001273	Abnormal corpus callosum morphology
HP:0001276	Hypertonia
HP:0001397	Hepatic steatosis
HP:0001508	Failure to thrive
HP:0001561	Polyhydramnios
HP:0001712	Left ventricular hypertrophy

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST000431_3	Height	4.000000e-06
GCST002667_12	Mammographic density (dense area)	2.000000e-13
GCST003837_14	Chronotype	5.000000e-06
GCST003838_13	Morning vs. evening chronotype	4.000000e-08
GCST005951_24	Body mass index	2.000000e-08
GCST006655_11	Breast size	7.000000e-07
GCST006921_10	Regular attendance at a pub or social club	3.000000e-10
GCST010002_83	Refractive error	2.000000e-27

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0005941	mammographic density measurement
EFO:0006503	dense area measurement
EFO:0004340	body mass index
EFO:0009592	social interaction measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
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

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, decreases expression, increases abundance	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, increases expression	2
Arsenic	decreases expression, increases abundance, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Smoke	decreases expression, increases abundance, increases expression	2
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
licochalcone B	increases expression	1
jinfukang	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Decitabine	decreases expression	1
Sunitinib	decreases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation	1
Caffeine	decreases phosphorylation	1
Carbamazepine	affects expression	1
Cisplatin	affects cotreatment, increases expression	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1
Plant Extracts	affects cotreatment, increases expression	1
Selenium	affects cotreatment, increases expression	1
Vitamin E	affects cotreatment, increases expression	1
Aflatoxin B1	increases methylation	1
Sodium Selenite	increases expression	1
Cadmium Chloride	increases expression	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
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,
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT00409747	PHASE4	COMPLETED	Minocycline to Treat Childhood Regressive Autism
NCT00576732	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder
NCT00844753	PHASE4	COMPLETED	Atomoxetine, Placebo and Parent Management Training in Autism
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01098383	PHASE4	UNKNOWN	Treatment With Acetyl-Choline Esterase Inhibitors in Children With 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
NCT02069977	PHASE4	UNKNOWN	Study to Evaluate the Efficacy and Safety of Aripiprazole
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02199925	PHASE4	UNKNOWN	An Open-Label Study to Evaluate the Efficacy of High-Dose Gammaplex in Children on the Autism Spectrum
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02255565	PHASE4	COMPLETED	Dose Response Effects of Quillivant XR in Children With ADHD and Autism: A Pilot Study
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
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT00036231	PHASE3	TERMINATED	Synthetic Human Secretin in Children With Autism and Gastrointestinal Dysfunction
NCT00036244	PHASE3	COMPLETED	Synthetic Human Secretin in Children With Autism
NCT00065884	PHASE3	UNKNOWN	Valproate Response in Aggressive Autistic Adolescents
NCT00065962	PHASE3	COMPLETED	Secretin for the Treatment of Autism
NCT00252603	PHASE3	COMPLETED	Galantamine Versus Placebo in Childhood Autism