SMS

Summary

SMS (spermine synthase, HGNC:11123) is a protein-coding gene on chromosome Xp22.11, encoding Spermine synthase (P52788). Catalyzes the production of spermine from spermidine and decarboxylated S-adenosylmethionine (dcSAM). It is a selective cancer dependency (DepMap: 14.5% of cell lines).

This gene encodes a protein belonging to the spermidine/spermin synthase family and catalyzes the production of spermine from spermidine. Pseudogenes of this gene are located on chromosomes 1, 5, 6 and X. Mutations in this gene cause an X-linked intellectual disability called Snyder-Robinson Syndrome (SRS). Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 6611 — RefSeq curated summary.

At a glance

• Gene–disease (curated): syndromic X-linked intellectual disability Snyder type (Definitive, ClinGen)
• Clinical variants (ClinVar): 252 total — 12 pathogenic, 19 likely-pathogenic
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 14.5% of screened cell lines
• MANE Select transcript: NM_004595

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11123
Approved symbol	SMS
Name	spermine synthase
Location	Xp22.11
Locus type	gene with protein product
Status	Approved
Aliases	SPMSY, SpS, MRSR
Ensembl gene	ENSG00000102172
Ensembl biotype	protein_coding
OMIM	300105
Entrez	6611

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000379404, ENST00000404933, ENST00000457085, ENST00000478094, ENST00000853888, ENST00000853889, ENST00000955899

RefSeq mRNA: 2 — MANE Select: NM_004595 NM_001258423, NM_004595

CCDS: CCDS14203, CCDS59161

Canonical transcript exons

ENST00000404933 — 11 exons

Exon	Start	End
ENSE00000666726	21984304	21984418
ENSE00000666728	21985144	21985223
ENSE00000666729	21992597	21992712
ENSE00001434921	21978877	21978966
ENSE00001436366	21977960	21978114
ENSE00001656038	21971897	21971990
ENSE00001899777	21940709	21940873
ENSE00001899895	21994312	21994837
ENSE00003546822	21967196	21967316
ENSE00003665825	21972507	21972571
ENSE00003673242	21977061	21977236

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 98.55.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 112.0783 / max 1817.1032, expressed in 1826 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
195730	106.3363	1826
195728	4.4165	1568
195731	1.1648	672
195729	0.1608	54

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	98.55	gold quality
placenta	UBERON:0001987	98.38	gold quality
ganglionic eminence	UBERON:0004023	98.26	gold quality
adrenal tissue	UBERON:0018303	97.83	gold quality
right adrenal gland cortex	UBERON:0035827	97.23	gold quality
right adrenal gland	UBERON:0001233	97.18	gold quality
left adrenal gland	UBERON:0001234	97.05	gold quality
adrenal gland	UBERON:0002369	96.80	gold quality
left adrenal gland cortex	UBERON:0035825	96.80	gold quality
adult mammalian kidney	UBERON:0000082	96.76	gold quality
endometrium	UBERON:0001295	96.72	gold quality
ventricular zone	UBERON:0003053	96.58	gold quality
islet of Langerhans	UBERON:0000006	96.47	gold quality
ovary	UBERON:0000992	96.42	gold quality
kidney	UBERON:0002113	96.39	gold quality
left ovary	UBERON:0002119	96.38	gold quality
anterior cingulate cortex	UBERON:0009835	96.36	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	96.25	gold quality
superior frontal gyrus	UBERON:0002661	96.06	gold quality
prostate gland	UBERON:0002367	96.05	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.03	gold quality
cortex of kidney	UBERON:0001225	96.01	gold quality
right ovary	UBERON:0002118	95.83	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.79	gold quality
monocyte	CL:0000576	95.72	gold quality
cerebellar cortex	UBERON:0002129	95.69	gold quality
cerebellum	UBERON:0002037	95.68	gold quality
cerebellar hemisphere	UBERON:0002245	95.66	gold quality
calcaneal tendon	UBERON:0003701	95.64	gold quality
amygdala	UBERON:0001876	95.59	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-GEOD-124472	yes	1465.35
E-GEOD-114530	yes	640.56
E-MTAB-6701	yes	119.47
E-GEOD-134144	yes	26.56
E-HCAD-10	yes	17.65
E-CURD-114	yes	12.41
E-MTAB-7008	no	1298.67
E-MTAB-8271	no	699.25
E-MTAB-7037	no	463.33
E-MTAB-8205	no	421.79
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

49 targeting SMS, 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-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-1250-3P	99.96	70.04	4038
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-651-3P	99.94	73.48	5177
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-148A-3P	99.74	73.77	1700
HSA-MIR-148B-3P	99.74	73.75	1700
HSA-MIR-152-3P	99.74	73.75	1703
HSA-MIR-889-3P	99.40	69.76	2103
HSA-MIR-130A-5P	99.33	70.26	2623

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 14.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 17)

• Study reports the identification of a novel mutation at a highly conserved residue within the N-terminal region of spermine synthase (SMS) in a second family with Snyder-Robinson X-linked mental retardation syndrome. (PMID:18550699)
• A missense mutation, p. V132G, in the X-linked SMS gene causes Snyder-Robinson syndrome. (PMID:19206178)
• Data suggest that disruption of spermine synthase function may negatively affect regional brain volumes that subserve cognitive and motor abilities. (PMID:19277733)
• the genetic and epigenetic factors examined in this study show little influence on the expression level of SMS in suicide completers. (PMID:20059804)
• each gene was associated with at least one main outcome: anxiety (SAT1, SMS), mood disorders (SAT1, SMOX), and suicide attempts (SAT1, OATL1). (PMID:21152090)
• Mutations in the spermine synthase have been shown to be responsible for an X-linked intellectual disability condition known as Snyder-Robinson syndrome. (PMID:21318891)
• the mutability of spermine synthase (PMID:21647366)
• spermine synthase activity and the resulting elevation of the spermine:spermidine ratio does not alter susceptibility to tumor development initiated by c-Ha-Ras mutation or Apc loss (PMID:22258329)
• This observation is used to demonstrate, computationally and experimentally, that a particular condition, Snyder-Robinson syndrome caused by the G56S spermine synthase mutation, might be ameliorated by small molecule binding. (PMID:23408511)
• Studied human spermine synthase activity by engineered mutations. (PMID:23468611)
• Results show that p.Y328C, a missense mutation in SMS is responsible for the patients having a mild form of Snyder-Robinson syndrome. (PMID:23696453)
• Missense mutations causing Snyder-Robinson Syndrome resulting in dysfunctional spermine synthase cause the destabilization of the protein. (PMID:26761001)
• Spermine synthase (SMS) localized together with myosin Va (MyoVa) in cytoplasmic vesicles of breast cancer MCF-7 and neuroblastoma SH-SY5Y cell lines, known to produce exosomes, supporting a role for MyoVa in SMS expression and targeting. (PMID:30733278)
• Spermine synthase and MYC cooperate to maintain colorectal cancer cell survival by repressing Bim expression. (PMID:32591507)
• Whole-exome sequencing identifies a novel mutation in spermine synthase gene (SMS) associated with Snyder-Robinson Syndrome. (PMID:32838743)
• Effects of Spermine Synthase Deficiency in Mesenchymal Stromal Cells Are Rescued by Upstream Inhibition of Ornithine Decarboxylase. (PMID:38473716)
• Reduction of spermine synthase enhances autophagy to suppress Tau accumulation. (PMID:38740758)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	sms	ENSDARG00000008155
mus_musculus	Sms	ENSMUSG00000071708
rattus_norvegicus	Sms	ENSRNOG00000007688
rattus_norvegicus	AABR07021734.1	ENSRNOG00000059957
rattus_norvegicus		ENSRNOG00000091204
drosophila_melanogaster	Sms	FBGN0036272

Paralogs (1): SRM (ENSG00000116649)

Protein

Protein identifiers

Spermine synthase — P52788 (reviewed: P52788)

Alternative names: Spermidine aminopropyltransferase

All UniProt accessions (2): P52788, H7C2R7

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the production of spermine from spermidine and decarboxylated S-adenosylmethionine (dcSAM).

Subunit / interactions. Homodimer. Dimerization is mediated through the N-terminal domain and seems to be required for activity as deletion of the N-terminal domain causes complete loss of activity.

Disease relevance. Intellectual developmental disorder, X-linked, syndromic, Snyder-Robinson type (MRXSSR) [MIM:309583] An X-linked intellectual disability syndrome characterized by a collection of clinical features including facial asymmetry, marfanoid habitus, hypertonia, osteoporosis and unsteady gait. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Composed of 3 domains: the N-terminal domain has structural similarity to S-adenosylmethionine decarboxylase, the central domain is made up of four beta strands and the C-terminal domain is similar in structure to spermidine synthase. The N- and C-terminal domains are both required for activity.

Pathway. Amine and polyamine biosynthesis; spermine biosynthesis; spermine from spermidine: step 1/1.

Similarity. Belongs to the spermidine/spermine synthase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P52788-1	1	yes
P52788-2	2

RefSeq proteins (2): NP_001245352, NP_004586* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR015576	Spermine_synthase_animal	Family
IPR029063	SAM-dependent_MTases_sf	Homologous_superfamily
IPR030373	PABS_CS	Conserved_site
IPR030374	PABS	Domain
IPR035246	Spermidine_synt_N	Domain
IPR037163	Spermidine_synt_N_sf	Homologous_superfamily
IPR040900	SpmSyn_N	Domain

Pfam: PF01564, PF17284, PF17950

Enzyme classification (BRENDA):

• EC 2.5.1.22 — spermine synthase (BRENDA: 19 organisms, 27 substrates, 49 inhibitors, 18 Km, 10 kcat entries)

Substrate kinetics (BRENDA)

7 substrates with measured Km, best-characterized 7. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
SPERMIDINE	0.006–0.8	6
S-ADENOSYLMETHIONINAMINE	0.0001–0.005	4
S-ADENOSYL 3-(METHYLTHIO)PROPYLAMINE	0.0005–0.0009	2
6,6-DIFLUOROSPERMIDINE	0.458	1
6-MONOFLUOROSPERMIDINE	0.093	1
7,7-DIFLUOROSPERMIDINE	0.0005	1
7-MONOFLUOROSPERMIDINE	0.0011	1

Catalyzed reactions (Rhea), 1 shown:

• S-adenosyl 3-(methylsulfanyl)propylamine + spermidine = spermine + S-methyl-5’-thioadenosine + H(+) (RHEA:19973)

UniProt features (56 total): strand 19, helix 10, binding site 7, sequence variant 6, mutagenesis site 3, turn 3, modified residue 2, initiator methionine 1, chain 1, splice variant 1, domain 1, sequence conflict 1, active site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3C6K	X-RAY DIFFRACTION	1.95
3C6M	X-RAY DIFFRACTION	2.45

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P52788-F1	95.09	0.89

Functional residue map

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

Catalytic / active sites (1): 276 (proton acceptor)

Ligand- & substrate-binding residues (7): 353; 148; 177; 201; 220; 255–256; 351

Post-translational modifications (2): 2, 57

Mutagenesis-validated functional residues (3):

Position	Phenotype
201	100,000-fold decrease in catalytic efficiency.
276	200,000-fold decrease in catalytic efficiency.
353	800-fold decrease in catalytic efficiency.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-351202	Metabolism of polyamines
R-HSA-1430728	Metabolism
R-HSA-71291	Metabolism of amino acids and derivatives

MSigDB gene sets: 397 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, TGGTGCT_MIR29A_MIR29B_MIR29C, LEE_NEURAL_CREST_STEM_CELL_DN, GGGNRMNNYCAT_UNKNOWN, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, KEGG_CYSTEINE_AND_METHIONINE_METABOLISM, MODULE_16, GOBP_POLYAMINE_METABOLIC_PROCESS, RUTELLA_RESPONSE_TO_CSF2RB_AND_IL4_UP, HOWLIN_PUBERTAL_MAMMARY_GLAND, BACH2_01, BROWNE_HCMV_INFECTION_14HR_DN, MARTIN_VIRAL_GPCR_SIGNALING_DN

GO Biological Process (5): L-methionine metabolic process (GO:0006555), polyamine metabolic process (GO:0006595), spermine biosynthetic process (GO:0006597), polyamine biosynthetic process (GO:0006596), spermine metabolic process (GO:0008215)

GO Molecular Function (2): spermine synthase activity (GO:0016768), transferase activity (GO:0016740)

GO Cellular Component (2): cytosol (GO:0005829), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metabolism of amino acids and derivatives	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
polyamine metabolic process	2
sulfur amino acid metabolic process	1
L-amino acid metabolic process	1
proteinogenic amino acid metabolic process	1
biogenic amine metabolic process	1
polyamine biosynthetic process	1
spermine metabolic process	1
biogenic amine biosynthetic process	1
transferase activity, transferring alkyl or aryl (other than methyl) groups	1
catalytic activity	1
cytoplasm	1
cellular anatomical structure	1
extracellular vesicle	1

Protein interactions and networks

STRING

1848 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SMS	ODC1	P11926	968
SMS	PAOX	Q6QHF9	837
SMS	SMOX	Q9NWM0	819
SMS	PHEX	P78562	814
SMS	SAT1	P21673	782
SMS	AZIN2	Q96A70	737
SMS	AGMAT	Q9BSE5	710
SMS	DHPS	P49366	667
SMS	OAT	P04181	665
SMS	ARG2	P78540	657
SMS	MTAP	Q13126	641
SMS	ASS1	P00966	625
SMS	DOHH	Q9BU89	625
SMS	ARG1	P05089	605
SMS	SRM	P19623	599

IntAct

23 interactions, top by confidence:

A	B	Type	Score
IGBP1	PPP6C	psi-mi:“MI:0914”(association)	0.940
MNT	SMS	psi-mi:“MI:0915”(physical association)	0.400
SMS		psi-mi:“MI:0915”(physical association)	0.370
SMS	MAPK6	psi-mi:“MI:0915”(physical association)	0.370
SMS	MAPK8IP2	psi-mi:“MI:0915”(physical association)	0.370
MAPKAPK3	SMS	psi-mi:“MI:0915”(physical association)	0.370
RPS6KA3	SMS	psi-mi:“MI:0915”(physical association)	0.370
SMS	BAP1	psi-mi:“MI:0914”(association)	0.350
PRNP	CARNS1	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350
IMMP2L	ANKHD1-EIF4EBP3	psi-mi:“MI:0914”(association)	0.350
LAGE3	HYKK	psi-mi:“MI:0914”(association)	0.350
LAGE3	PPIAL4C	psi-mi:“MI:0914”(association)	0.350
OSGEP	POTEF	psi-mi:“MI:0914”(association)	0.350
SLC22A11	CNOT1	psi-mi:“MI:0914”(association)	0.350
TP53RK	SMS	psi-mi:“MI:0914”(association)	0.350
CDH5	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
TFE3	SMS	psi-mi:“MI:0915”(physical association)	0.000
FTSJ1	SMS	psi-mi:“MI:0915”(physical association)	0.000
EZH2	SMS	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (134): ENOPH1 (Co-fractionation), HDLBP (Co-fractionation), MTRR (Co-fractionation), SMS (Co-fractionation), UCHL3 (Co-fractionation), SMS (Affinity Capture-MS), XIAP (Affinity Capture-MS), ATP6V1C1 (Affinity Capture-MS), ETFA (Affinity Capture-MS), SMS (Affinity Capture-MS), STXBP2 (Affinity Capture-MS), BAP1 (Affinity Capture-MS), PPP1R13L (Affinity Capture-MS), HEATR3 (Affinity Capture-MS), PDRG1 (Affinity Capture-MS)

ESM2 similar proteins: A0A075D5I4, A0A075D654, A0A075D657, A0A075D6M1, A0A1D6NER6, A0A482NB13, A0A8X8M4T9, A0A8X8M4W6, A0A8X8M501, A0A8X8M505, A4GNA8, A6ZRD1, C8YTM5, O74529, O94634, P32643, P34254, P49915, P50135, P52788, P97355, Q09580, Q10170, Q16KN5, Q22993, Q29LW1, Q3SZA5, Q3THK7, Q4V7C6, Q55DH6, Q5PP70, Q5R7C3, Q5RA96, Q6C3P4, Q6DC37, Q6DW73, Q83WC3, Q8IDQ9, Q8VYX1, Q93V78

Diamond homologs: A1A7G7, A1WZR2, A2C5F4, A2CDX0, A3DDA0, A3PFH4, A4W6M6, A4WHN0, A4XKM9, A5N219, A6TRI3, A7ZHL0, A7ZW70, A8ALG8, A9MZR2, B0K172, B0K9I5, B1I5Z0, B1IQL9, B1LGS2, B1XC96, B2TMY2, B2V328, B4SU91, B4TJD2, B4TXL7, B5BL97, B5F815, B5FIB4, B5R2R5, B5RHA5, B5YZF6, B6HZ96, B7LFY8, B7LVY5, B7M162, B7MBA4, B7MNY3, B7N7Z1, B7NI81

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	19
Uncertain significance	90
Likely benign	22
Benign	32

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
11623	NM_004595.5(SMS):c.329+5G>A	Pathogenic
11624	NM_004595.5(SMS):c.166G>A (p.Gly56Ser)	Pathogenic
11625	NM_004595.5(SMS):c.395T>G (p.Val132Gly)	Pathogenic
3366861	NM_004595.5(SMS):c.661-13A>C	Pathogenic
4813567	NM_004595.5(SMS):c.954T>G (p.Cys318Trp)	Pathogenic
626916	NM_004595.5(SMS):c.908_911del (p.Met303fs)	Pathogenic
65677	NM_004595.5(SMS):c.200G>A (p.Gly67Glu)	Pathogenic
65679	NM_004595.5(SMS):c.443A>G (p.Gln148Arg)	Pathogenic
816629	NM_004595.5(SMS):c.388C>T (p.Arg130Cys)	Pathogenic
827761	NM_004595.5(SMS):c.608G>A (p.Gly203Asp)	Pathogenic
88767	NM_004595.5(SMS):c.983A>G (p.Tyr328Cys)	Pathogenic
973097	NM_004595.5(SMS):c.905C>T (p.Ser302Leu)	Pathogenic
1013359	NM_004595.5(SMS):c.350G>T (p.Gly117Val)	Likely pathogenic
1191854	NM_004595.5(SMS):c.1045C>A (p.Pro349Thr)	Likely pathogenic
1526148	NM_004595.5(SMS):c.865+2T>C	Likely pathogenic
1695523	NM_004595.5(SMS):c.875G>T (p.Trp292Leu)	Likely pathogenic
1879754	NM_004595.5(SMS):c.697A>G (p.Met233Val)	Likely pathogenic
2444331	NM_004595.5(SMS):c.335C>A (p.Pro112Gln)	Likely pathogenic
2500736	NM_004595.5(SMS):c.674T>C (p.Val225Ala)	Likely pathogenic
2630815	NM_004595.5(SMS):c.200G>T (p.Gly67Val)	Likely pathogenic
3061643	NM_004595.5(SMS):c.661-1C>T	Likely pathogenic
421087	NM_004595.5(SMS):c.831G>T (p.Leu277Phe)	Likely pathogenic
4279691	NM_004595.5(SMS):c.442C>G (p.Gln148Glu)	Likely pathogenic
441113	NM_004595.5(SMS):c.665A>T (p.Asp222Val)	Likely pathogenic
4537919	NM_004595.5(SMS):c.400T>C (p.Tyr134His)	Likely pathogenic
4819344	NM_004595.5(SMS):c.608G>T (p.Gly203Val)	Likely pathogenic
520793	NM_004595.5(SMS):c.638C>A (p.Pro213Gln)	Likely pathogenic
620039	NM_004595.5(SMS):c.581T>G (p.Val194Gly)	Likely pathogenic
916028	NM_004595.5(SMS):c.410A>G (p.Asp137Gly)	Likely pathogenic
973506	NM_004595.5(SMS):c.328C>G (p.Arg110Gly)	Likely pathogenic

SpliceAI

2062 predictions. Top by Δscore:

Variant	Effect	Δscore
X:21942329:GGTT:G	donor_gain	1.0000
X:21971989:GT:G	donor_gain	1.0000
X:21977056:TCCA:T	acceptor_gain	1.0000
X:21977056:TCCAG:T	acceptor_loss	1.0000
X:21977057:CCAGA:C	acceptor_gain	1.0000
X:21977058:CAG:C	acceptor_gain	1.0000
X:21977059:A:AC	acceptor_gain	1.0000
X:21977059:A:AG	acceptor_gain	1.0000
X:21977059:A:T	acceptor_loss	1.0000
X:21977060:G:C	acceptor_gain	1.0000
X:21977060:G:GT	acceptor_gain	1.0000
X:21977060:GA:G	acceptor_gain	1.0000
X:21977060:GAT:G	acceptor_gain	1.0000
X:21977060:GATT:G	acceptor_gain	1.0000
X:21977060:GATTA:G	acceptor_gain	1.0000
X:21977233:GTTA:G	donor_gain	1.0000
X:21977234:TTA:T	donor_gain	1.0000
X:21977234:TTAG:T	donor_loss	1.0000
X:21977235:TA:T	donor_gain	1.0000
X:21977236:AG:A	donor_loss	1.0000
X:21977237:G:GG	donor_gain	1.0000
X:21977237:GTA:G	donor_loss	1.0000
X:21977238:TAA:T	donor_loss	1.0000
X:21977239:AA:A	donor_loss	1.0000
X:21978872:C:CA	acceptor_gain	1.0000
X:21978873:G:A	acceptor_gain	1.0000
X:21984298:T:A	acceptor_gain	1.0000
X:21984299:G:A	acceptor_gain	1.0000
X:21940869:CAAAG:C	donor_loss	0.9900
X:21940870:AAAG:A	donor_loss	0.9900

AlphaMissense

2407 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:21978047:G:A	G198E	1.000
X:21978056:A:T	D201V	1.000
X:21978059:G:A	G202E	1.000
X:21984380:A:C	D276A	1.000
X:21984380:A:G	D276G	1.000
X:21984380:A:T	D276V	1.000
X:21984381:T:A	D276E	1.000
X:21984381:T:G	D276E	1.000
X:21992694:T:A	V348D	1.000
X:21977207:G:T	G159V	0.999
X:21977216:T:A	L162H	0.999
X:21977216:T:C	L162P	0.999
X:21977222:T:C	L164P	0.999
X:21977961:T:A	N169K	0.999
X:21977961:T:G	N169K	0.999
X:21977966:C:A	A171E	0.999
X:21977974:G:C	D174H	0.999
X:21977974:G:T	D174Y	0.999
X:21977975:A:T	D174V	0.999
X:21977983:T:C	Y177H	0.999
X:21978038:T:C	L195P	0.999
X:21978046:G:A	G198R	0.999
X:21978046:G:C	G198R	0.999
X:21978047:G:T	G198V	0.999
X:21978053:G:A	G200E	0.999
X:21978053:G:T	G200V	0.999
X:21978055:G:C	D201H	0.999
X:21978056:A:C	D201A	0.999
X:21978059:G:T	G202V	0.999
X:21978881:A:T	D222V	0.999

dbSNP variants (sampled 300 via entrez): RS1000017374 (X:21947541 A>G), RS1000196125 (X:21961739 C>T), RS1000211368 (X:21990013 A>G), RS1000245670 (X:21989554 C>T), RS1000246958 (X:21958734 T>A), RS1000259964 (X:21968135 G>T), RS1000306696 (X:21953980 T>G), RS1000344283 (X:21960988 T>C), RS1000502566 (X:21983755 G>A), RS1000551879 (X:21987497 A>G), RS1000582970 (X:21986609 T>C), RS1000689429 (X:21962684 G>A), RS1000840854 (X:21979185 ATTC>A), RS1000843878 (X:21983516 C>G), RS1000918424 (X:21991053 C>G,T)

Disease associations

OMIM: gene MIM:300105 | disease phenotypes: MIM:309583, MIM:182290

GenCC curated gene-disease

Disease	Classification	Inheritance
syndromic X-linked intellectual disability Snyder type	Strong	X-linked

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
syndromic X-linked intellectual disability Snyder type	Definitive	XL

Mondo (3): syndromic X-linked intellectual disability Snyder type (MONDO:0010664), Smith-Magenis syndrome (MONDO:0008434), intellectual disability (MONDO:0001071)

Orphanet (3): X-linked intellectual disability, Snyder type (Orphanet:3063), Smith-Magenis syndrome (Orphanet:819), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

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

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D058496	Smith-Magenis Syndrome	C10.281.900; C16.131.077.879; C16.131.260.887; C16.320.180.887
C536678	Snyder Robinson syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4934 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.70	IC50	20	nM	CHEMBL315995
7.30	IC50	50	nM	CHEMBL330673

PubChem BioAssay actives

2 with measured affinity, of 2 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S,3S,4R,5R)-2-[[1-amino-8-(3-aminopropylamino)octan-3-yl]sulfanylmethyl]-5-(6-aminopurin-9-yl)oxolane-3,4-diol	226564: Inhibitory activity against spermine synthase	ic50	0.0200	uM
(2R,3R,4S,5S)-2-(6-aminopurin-9-yl)-5-(1,8-diaminooctan-3-ylsulfanylmethyl)oxolane-3,4-diol	226564: Inhibitory activity against spermine synthase	ic50	0.0500	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression, affects cotreatment	6
Tobacco Smoke Pollution	decreases expression, increases expression, increases methylation	3
chloropicrin	affects expression, decreases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Fluorouracil	increases expression, affects reaction, decreases expression	2
Dihydrotestosterone	increases expression	2
aristolochic acid I	decreases expression, increases expression	1
bismuth tripotassium dicitrate	increases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
sodium arsenate	decreases expression	1
tetrahydropalmatine	decreases expression	1
sodium arsenite	affects methylation	1
aflatoxin B2	affects methylation	1
CGP 52608	affects binding, increases reaction	1
nutlin 3	affects cotreatment, increases secretion	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
abrine	increases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
incobotulinumtoxinA	decreases expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	increases expression	1
Atrazine	increases expression	1
Azathioprine	decreases expression	1
Dactinomycin	affects cotreatment, increases secretion	1
Dichlorodiphenyl Dichloroethylene	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL845254	Binding	Inhibitory activity against spermine synthase	Terminally alkylated polyamine analogues as chemotherapeutic agents. — J Med Chem

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1LD	Abcam Jurkat SMS KO	Cancer cell line	Male
CVCL_D1QM	Abcam K-562 SMS KO	Cancer cell line	Female
CVCL_D2M8	Abcam Raji SMS KO	Cancer cell line	Male
CVCL_TP71	HAP1 SMS (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT06457906	PHASE3	RECRUITING	SRS/SRT/Hypo-RT Versus HA-WBRT for No More Than 10 Brain Metastases in SCLC
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT04180501	PHASE2	UNKNOWN	SRS Sequential Sindilimab in Brain Metastasis of NSLSC
NCT04899908	PHASE2	ACTIVE_NOT_RECRUITING	Stereotactic Brain-directed Radiation With or Without Aguix Gadolinium-Based Nanoparticles in Brain Metastases
NCT07162246	PHASE2	RECRUITING	Combined Gamma Knife/Linac Radiosurgery for Large Brain Tumors / Metastases
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT02776215	PHASE1	COMPLETED	Study of the Pharmacokinetics and Safety of Tasimelteon in Children and Adolescents
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03915106	Not specified	RECRUITING	Quality of Life (HRQoL) of AIS Patients Who Require Bracing or Surgery Using SRS-22 Questionnaire
NCT06466720	Not specified	ACTIVE_NOT_RECRUITING	Measuring and Mapping Cognitive Decline After Brain Radiosurgery
NCT06852001	Not specified	NOT_YET_RECRUITING	Efficacy of the RayerKnife X Stereotactic Radiotherapy System in the Treatment of Brain Metastases
NCT07405112	Not specified	COMPLETED	Impact of Curve Magnitude on Pain and Body Image in Patients With Adolescents Idiopathic Scoliosis
NCT02231008	PHASE2/PHASE3	COMPLETED	Evaluating the Effects of Tasimelteon vs Placebo on Sleep Disturbances in SMS
NCT00004351	Not specified	COMPLETED	Study of Phenotype and Genotype Correlations in Patients With Contiguous Gene Deletion Syndromes
NCT00013559	Not specified	ACTIVE_NOT_RECRUITING	Natural History Study of Smith-Magenis Syndrome
NCT01837121	Not specified	COMPLETED	a Trial of Using SMS Reminder Among Diabetic Retinopathy Patients in Rural China
NCT02180451	Not specified	UNKNOWN	Observational Study to Investigate the Melatonin and Cortisol Circadian Rhythms of Individuals With Smith-Magenis Syndrome (SMS)
NCT02400671	Not specified	COMPLETED	Mobile Strategies for Women’s and Children’s Health: Optimizing Adherence and Efficacy of PMTCT/ART
NCT03346616	Not specified	COMPLETED	Text4Peds: Short Message Service Evaluating Medical Student Education
NCT03379467	Not specified	COMPLETED	Use of SMS and Interactive Reminders to Improve Timely Immunization Coverage
NCT03492970	Not specified	COMPLETED	Melatonin in Adults With SMS
NCT03836300	Not specified	ENROLLING_BY_INVITATION	Parent and Infant Inter(X)Action Intervention (PIXI)
NCT04768803	Not specified	UNKNOWN	Ghrelin in Patients With a Rare Disease Associated With Intellectual Disability, and Hyperphagia, and/or Overweight, and/or Obesity
NCT05116904	Not specified	RECRUITING	Smith Magenis Syndrome and Autism Spectrum Disorders
NCT06247852	Not specified	COMPLETED	Persistent Pain After Cesarean Delivery - A Danish Multicenter Cohort Study
NCT07510971	Not specified	NOT_YET_RECRUITING	mHealth Intervention for Improving Vaccination Coverage in Bangladesh
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation