SACM1L

Summary

SACM1L (SAC1 like phosphatidylinositide phosphatase, HGNC:17059) is a protein-coding gene on chromosome 3p21.31, encoding Phosphatidylinositol-3-phosphatase SAC1 (Q9NTJ5). Phosphoinositide phosphatase which catalyzes the hydrolysis of phosphatidylinositol 4-phosphate (PtdIns(4)P). It is a common-essential gene (DepMap: required in 97.5% of cancer cell lines).

This gene encodes an integral membrane protein, which is localized to the endoplasmic reticulum, and functions as a phosphoinositide phosphatase that hydrolyzes phosphatidylinositol 3-phosphate, phosphatidylinositol 4-phosphate, and phosphatidylinositol 3,5-bisphosphate. Deletion of this gene in mouse results in preimplantation lethality. Other studies suggest that this gene is also involved in the organization of golgi membranes and mitotic spindles. Alternatively spliced transcript variants have been found for this gene. A C-terminally extended isoform is also predicted to be produced by the use of an alternative in-frame, downstream translation termination codon via a stop codon readthrough mechanism.

Source: NCBI Gene 22908 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 69 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 97.5% of screened cell lines (common-essential)
• MANE Select transcript: NM_014016

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17059
Approved symbol	SACM1L
Name	SAC1 like phosphatidylinositide phosphatase
Location	3p21.31
Locus type	gene with protein product
Status	Approved
Aliases	SAC1, KIAA0851
Ensembl gene	ENSG00000211456
Ensembl biotype	protein_coding
OMIM	606569
Entrez	22908

Gene structure

Transcript identifiers

Ensembl transcripts: 43 — 17 retained_intron, 12 protein_coding, 11 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

ENST00000389061, ENST00000418611, ENST00000433336, ENST00000438671, ENST00000441228, ENST00000445499, ENST00000455997, ENST00000463237, ENST00000463347, ENST00000463659, ENST00000464102, ENST00000464524, ENST00000471207, ENST00000478586, ENST00000485311, ENST00000672858, ENST00000706802, ENST00000706803, ENST00000706804, ENST00000706805, ENST00000706806, ENST00000706807, ENST00000706808, ENST00000706809, ENST00000706810, ENST00000706811, ENST00000706812, ENST00000706813, ENST00000706814, ENST00000706815, ENST00000706816, ENST00000706817, ENST00000706818, ENST00000706819, ENST00000706820, ENST00000706821, ENST00000706822, ENST00000706823, ENST00000706824, ENST00000706825, ENST00000706826, ENST00000972134, ENST00000972135

RefSeq mRNA: 4 — MANE Select: NM_014016 NM_001319071, NM_001319072, NM_001319073, NM_014016

CCDS: CCDS33745, CCDS82762, CCDS93257

Canonical transcript exons

ENST00000389061 — 20 exons

Exon	Start	End
ENSE00001939947	45743533	45745409
ENSE00003501750	45731301	45731380
ENSE00003507130	45739587	45739644
ENSE00003513395	45722000	45722085
ENSE00003524193	45738781	45738873
ENSE00003538945	45723475	45723543
ENSE00003540813	45722869	45722955
ENSE00003600558	45738578	45738671
ENSE00003607767	45719500	45719601
ENSE00003609599	45737583	45737652
ENSE00003640947	45737772	45737844
ENSE00003644747	45689396	45689497
ENSE00003646093	45732053	45732151
ENSE00003658823	45709498	45709647
ENSE00003666156	45735235	45735373
ENSE00003669053	45713137	45713196
ENSE00003673489	45714046	45714079
ENSE00003997035	45706780	45706907
ENSE00003997056	45703438	45703535
ENSE00003997059	45705135	45705209

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 99.11.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.2497 / max 229.6578, expressed in 1806 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
36391	11.6492	1762
36392	8.8435	1709
36389	0.4725	261
36390	0.2845	153

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.11	gold quality
oocyte	CL:0000023	99.03	gold quality
Brodmann (1909) area 23	UBERON:0013554	97.97	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.84	gold quality
substantia nigra pars reticulata	UBERON:0001966	97.15	gold quality
endothelial cell	CL:0000115	97.14	gold quality
substantia nigra pars compacta	UBERON:0001965	96.92	gold quality
choroid plexus epithelium	UBERON:0003911	96.72	gold quality
visceral pleura	UBERON:0002401	96.69	gold quality
lower lobe of lung	UBERON:0008949	96.46	gold quality
renal medulla	UBERON:0000362	96.41	gold quality
skin of hip	UBERON:0001554	96.36	gold quality
epithelium of nasopharynx	UBERON:0001951	96.17	gold quality
germinal epithelium of ovary	UBERON:0001304	96.14	gold quality
trigeminal ganglion	UBERON:0001675	96.14	gold quality
cerebellar vermis	UBERON:0004720	96.08	gold quality
pleura	UBERON:0000977	95.81	gold quality
tibia	UBERON:0000979	95.81	gold quality
dorsal root ganglion	UBERON:0000044	95.66	gold quality
mucosa of paranasal sinus	UBERON:0005030	95.61	gold quality
upper leg skin	UBERON:0004262	95.54	gold quality
cardia of stomach	UBERON:0001162	95.47	gold quality
hair follicle	UBERON:0002073	95.43	gold quality
superficial temporal artery	UBERON:0001614	95.37	gold quality
renal glomerulus	UBERON:0000074	95.34	gold quality
palpebral conjunctiva	UBERON:0001812	95.34	gold quality
pigmented layer of retina	UBERON:0001782	95.30	gold quality
parietal pleura	UBERON:0002400	95.30	gold quality
jejunal mucosa	UBERON:0000399	95.29	gold quality
lateral globus pallidus	UBERON:0002476	95.21	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	13.88

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

117 targeting SACM1L, 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-5692A	100.00	74.40	6850
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 97.5% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 7)

• the enzymatic function of hSAC1 provides a switch for accessibility of the COPI interaction motif (PMID:14527956)
• Sac1 executes an essential household function in mammals that involves organization of both Golgi membranes and mitotic spindles (PMID:18480408)
• data suggest a model in which the 14-3-3 protein mediates SAC1 traffic from the ER through direct interaction with a sorting signal and COPII (PMID:26056309)
• results demonstrate that Sac1 expression in either the ER or Golgi apparatus has a minimal impact on the PI-4P that regulates OSBP activity or recruitment to contact sites (PMID:28471037)
• the component proteins of the machinery, OSBP, VAP, SAC1, and PITPNB, are all essential host factors for AiV replication. Importantly, the machinery is directly recruited to the RNA replication sites through previously unknown interactions of VAP/OSBP/SAC1 with the AiV proteins and with ACBD3. (PMID:29367253)
• The activity of Sac1 across ER-TGN contact sites requires the four-phosphate-adaptor-protein-1. (PMID:30659099)
• Sac1 phosphatidylinositol 4-phosphate phosphatase is a novel host cell factor regulating hepatitis B virus particles assembly and release. (PMID:35816160)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	sacm1la	ENSDARG00000015290
danio_rerio	sacm1lb	ENSDARG00000059806
mus_musculus	Sacm1l	ENSMUSG00000025240
rattus_norvegicus	Sacm1l	ENSRNOG00000005149
drosophila_melanogaster	Sac1	FBGN0283500
caenorhabditis_elegans	sacm-1L	WBGENE00009264

Paralogs (13): SYNJ2 (ENSG00000078269), FIG4 (ENSG00000112367), OCRL (ENSG00000122126), INPP5K (ENSG00000132376), INPP5E (ENSG00000148384), SYNJ1 (ENSG00000159082), INPPL1 (ENSG00000165458), INPP5D (ENSG00000168918), SH2D1A (ENSG00000183918), INPP5J (ENSG00000185133), SH2D1B (ENSG00000198574), INPP5F (ENSG00000198825), INPP5B (ENSG00000204084)

Protein

Protein identifiers

Phosphatidylinositol-3-phosphatase SAC1 — Q9NTJ5 (reviewed: Q9NTJ5)

Alternative names: Phosphatidylinositol-4-phosphate phosphatase, Suppressor of actin mutations 1-like protein

All UniProt accessions (18): Q9NTJ5, A0A5F9ZHN7, A0A9L9PXB9, A0A9L9PXC7, A0A9L9PXJ1, A0A9L9PXJ6, A0A9L9PXK1, A0A9L9PXW1, A0A9L9PXW5, A0A9L9PXW9, A0A9L9PXY7, A0A9L9PXZ2, A0A9L9PYD2, A0A9L9PYD8, C9J3E3, E9PGZ4, F8WCQ2, F8WDN7

UniProt curated annotations — full annotation on UniProt →

Function. Phosphoinositide phosphatase which catalyzes the hydrolysis of phosphatidylinositol 4-phosphate (PtdIns(4)P). Can also catalyze the hydrolysis of phosphatidylinositol 3-phosphate (PtdIns(3)P) and has low activity towards phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2). Shows a very robust PtdIns(4)P phosphatase activity when it binds PtdIns(4)P in a ‘cis’ configuration in the cellular environment, with much less activity seen when it binds PtdIns(4)P in ’trans’ configuration. PtdIns(4)P phosphatase activity (when it binds PtdIns(4)P in ’trans’ configuration) is enhanced in the presence of PLEKHA3.

Subunit / interactions. Interacts with TMEM39A. Interacts with SEC23A and SEC24A; this interaction is reduced in the absence of TMEM39A. Interacts with PLEKHA3 and VAPA and/or VAPB to form a ternary complex.

Subcellular location. Endoplasmic reticulum membrane. Golgi apparatus membrane.

Tissue specificity. Detected in heart, brain, lung, liver, kidney, pancreas and testis.

Activity regulation. Inhibited by bis-peroxovanadates and hydrogen peroxide.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NTJ5-1	1	yes
Q9NTJ5-2	2

RefSeq proteins (4): NP_001306000, NP_001306001, NP_001306002, NP_054735* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002013	SAC_dom	Domain

Pfam: PF02383

Catalyzed reactions (Rhea), 2 shown:

• a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3-phosphate) + H2O = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol) + phosphate (RHEA:12316)
• a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol 4-phosphate) + H2O = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol) + phosphate (RHEA:55652)

UniProt features (15 total): topological domain 3, splice variant 2, sequence conflict 2, transmembrane region 2, chain 1, sequence variant 1, mutagenesis site 1, domain 1, region of interest 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NTJ5-F1	90.83	0.71

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): 456

Mutagenesis-validated functional residues (1):

Position	Phenotype
389	loss of phosphatidylinositol-4-phosphate phosphatase activity.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-1483248	Synthesis of PIPs at the ER membrane
R-HSA-1660514	Synthesis of PIPs at the Golgi membrane
R-HSA-1430728	Metabolism
R-HSA-1483255	PI Metabolism
R-HSA-1483257	Phospholipid metabolism
R-HSA-556833	Metabolism of lipids

MSigDB gene sets: 232 (showing top): GOBP_LIPID_MODIFICATION, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, GOBP_PHOSPHOLIPID_DEPHOSPHORYLATION, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP, IVANOVA_HEMATOPOIESIS_MATURE_CELL, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_VESICLE_MEDIATED_TRANSPORT, CHX10_01, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, GOBP_PHOSPHOLIPID_BIOSYNTHETIC_PROCESS, GOBP_GLYCEROLIPID_METABOLIC_PROCESS, GOBP_EXOCYTOSIS, MILI_PSEUDOPODIA_HAPTOTAXIS_UP

GO Biological Process (5): phosphatidylinositol biosynthetic process (GO:0006661), phosphatidylinositol dephosphorylation (GO:0046856), exocytic insertion of neurotransmitter receptor to postsynaptic membrane (GO:0098967), vesicle-mediated transport in synapse (GO:0099003), lipid metabolic process (GO:0006629)

GO Molecular Function (6): phosphatidylinositol-3-phosphate phosphatase activity (GO:0004438), phosphatase activity (GO:0016791), phosphatidylinositol phosphate 4-phosphatase activity (GO:0034596), phosphatidylinositol-4-phosphate phosphatase activity (GO:0043812), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (8): Golgi membrane (GO:0000139), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), AMPA glutamate receptor complex (GO:0032281), glutamatergic synapse (GO:0098978), endoplasmic reticulum-plasma membrane contact site (GO:0140268), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
PI Metabolism	2
Phospholipid metabolism	1
Metabolism of lipids	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
phosphatidylinositol metabolic process	2
synapse	2
phosphatidylinositol monophosphate phosphatase activity	2
cytoplasm	2
endomembrane system	2
intracellular membrane-bounded organelle	2
biosynthetic process	1
phospholipid dephosphorylation	1
exocytosis	1
neurotransmitter receptor transport to postsynaptic membrane	1
regulation of postsynaptic membrane neurotransmitter receptor levels	1
vesicle-mediated transport	1
primary metabolic process	1
phosphoric ester hydrolase activity	1
phosphatidylinositol phosphate phosphatase activity	1
phosphatidylinositol phosphate 4-phosphatase activity	1
binding	1
catalytic activity	1
Golgi apparatus	1
bounding membrane of organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
ionotropic glutamate receptor complex	1
organelle membrane contact site	1
cellular anatomical structure	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

246 interactions, top by confidence:

A	B	Type	Score
COPG1	COPB2	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
SLC7A1	SACM1L	psi-mi:“MI:0915”(physical association)	0.670
COPG1	COPE	psi-mi:“MI:0914”(association)	0.640
CREB3L1	SACM1L	psi-mi:“MI:0915”(physical association)	0.600
SACM1L	TMX2	psi-mi:“MI:0915”(physical association)	0.560
SACM1L	ODF4	psi-mi:“MI:0915”(physical association)	0.560
SACM1L	HSD17B13	psi-mi:“MI:0915”(physical association)	0.560
MFF	SACM1L	psi-mi:“MI:0915”(physical association)	0.560
RTN3	SACM1L	psi-mi:“MI:0915”(physical association)	0.560
FMO3	SACM1L	psi-mi:“MI:0915”(physical association)	0.560
FFAR2	SACM1L	psi-mi:“MI:0915”(physical association)	0.560
GPR152	SACM1L	psi-mi:“MI:0915”(physical association)	0.560
RNF19B	SACM1L	psi-mi:“MI:0915”(physical association)	0.560
JAGN1	SACM1L	psi-mi:“MI:0915”(physical association)	0.560
MTERF2	SACM1L	psi-mi:“MI:0915”(physical association)	0.560
ZFYVE27	SACM1L	psi-mi:“MI:0915”(physical association)	0.560
ACKR2	SACM1L	psi-mi:“MI:0915”(physical association)	0.560
GPR151	SACM1L	psi-mi:“MI:0915”(physical association)	0.560
SACM1L	DHRS7	psi-mi:“MI:0915”(physical association)	0.560
ARL13B	SACM1L	psi-mi:“MI:0915”(physical association)	0.560
CD79A	SACM1L	psi-mi:“MI:0915”(physical association)	0.560
AQP6	SACM1L	psi-mi:“MI:0915”(physical association)	0.560
	SACM1L	psi-mi:“MI:0915”(physical association)	0.560
SLC10A1	SACM1L	psi-mi:“MI:0915”(physical association)	0.560
SLC10A6	SACM1L	psi-mi:“MI:0915”(physical association)	0.560
SACM1L	SCN3B	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (230): SACM1L (Affinity Capture-MS), SACM1L (Affinity Capture-MS), SACM1L (Affinity Capture-MS), SACM1L (Affinity Capture-MS), SACM1L (Affinity Capture-MS), SACM1L (Two-hybrid), SACM1L (Affinity Capture-MS), SACM1L (Affinity Capture-MS), SACM1L (Affinity Capture-MS), SACM1L (Affinity Capture-MS), SACM1L (Affinity Capture-MS), SACM1L (Affinity Capture-MS), SACM1L (Affinity Capture-RNA), SACM1L (Two-hybrid), SACM1L (Affinity Capture-MS)

ESM2 similar proteins: A1L244, A4VCH0, A6QL88, F4JIN3, G5ECL2, I1R9A6, I1S489, O13943, O14127, O15056, O18964, O43001, O43426, O55207, O60162, P0C9C0, P0C9C1, P0C9C2, P32368, P34203, P34260, P40559, P46580, P50942, P91133, Q00942, Q09600, Q12271, Q18891, Q55AW9, Q5R921, Q60V75, Q62910, Q6GM29, Q7X911, Q7XVN7, Q8CHC4, Q8RW97, Q8TGA2, Q94A27

Diamond homologs: A1L244, A4VCH0, A6QL88, A8E7C5, O14127, O15056, O18964, O43001, O43426, O55207, O60162, P32368, P42837, P50942, Q12271, Q55AW9, Q5R921, Q62910, Q6GM29, Q7X911, Q7Z9H9, Q8CDA1, Q8CHC4, Q96328, Q9C5G5, Q9D2G5, Q9EP69, Q9ES21, Q9NTJ5, Q9W0I6, Q9Y2H2, A8MR21, D3ZGS3, D7PF45, G5ECL2, P32019, P59644, Q01968, Q0WQ41, Q0WT19

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
SACM1L	“down-regulates quantity”	“phosphatidylinositol 4-phosphate”	“chemical modification”
SACM1L	down-regulates	“Receptor_mediated_ endocytosis”
TFEB	“up-regulates quantity by expression”	SACM1L	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 160 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
intra-Golgi vesicle-mediated transport	6	23.2×	8e-05
phospholipase C-activating G protein-coupled receptor signaling pathway	9	8.7×	2e-04
positive regulation of cytosolic calcium ion concentration	10	8.6×	8e-05
endoplasmic reticulum to Golgi vesicle-mediated transport	7	7.0×	8e-03
G protein-coupled receptor signaling pathway	17	4.5×	8e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	53
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2976 predictions. Top by Δscore:

Variant	Effect	Δscore
3:45689495:GCT:G	donor_gain	1.0000
3:45703432:TCTTA:T	acceptor_loss	1.0000
3:45703433:CTTA:C	acceptor_loss	1.0000
3:45703434:TTAGG:T	acceptor_loss	1.0000
3:45703435:TA:T	acceptor_loss	1.0000
3:45703436:A:AC	acceptor_loss	1.0000
3:45703436:A:AG	acceptor_gain	1.0000
3:45703437:G:GG	acceptor_gain	1.0000
3:45703437:GGC:G	acceptor_gain	1.0000
3:45703437:GGCAT:G	acceptor_gain	1.0000
3:45705131:A:AG	acceptor_gain	1.0000
3:45705132:A:AG	acceptor_gain	1.0000
3:45705133:A:G	acceptor_gain	1.0000
3:45705134:G:GA	acceptor_gain	1.0000
3:45705134:GT:G	acceptor_gain	1.0000
3:45705134:GTC:G	acceptor_gain	1.0000
3:45705134:GTCA:G	acceptor_gain	1.0000
3:45705134:GTCAA:G	acceptor_gain	1.0000
3:45705207:CAGG:C	donor_loss	1.0000
3:45705209:GGTA:G	donor_loss	1.0000
3:45705210:G:T	donor_loss	1.0000
3:45705211:T:A	donor_loss	1.0000
3:45706903:TTCAG:T	donor_loss	1.0000
3:45706904:TCAG:T	donor_loss	1.0000
3:45706905:CAG:C	donor_loss	1.0000
3:45706906:AGGTA:A	donor_loss	1.0000
3:45706907:GG:G	donor_loss	1.0000
3:45706908:GT:G	donor_loss	1.0000
3:45706909:T:A	donor_loss	1.0000
3:45709495:TAGT:T	acceptor_loss	1.0000

AlphaMissense

3897 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:45713155:T:A	W168R	1.000
3:45713155:T:C	W168R	1.000
3:45719560:G:C	R213T	1.000
3:45719560:G:T	R213M	1.000
3:45719561:G:C	R213S	1.000
3:45719561:G:T	R213S	1.000
3:45722028:C:A	N236K	1.000
3:45722028:C:G	N236K	1.000
3:45722893:T:A	W264R	1.000
3:45722893:T:C	W264R	1.000
3:45735301:C:G	C389W	1.000
3:45735305:G:C	D391H	1.000
3:45735315:A:C	D394A	1.000
3:45735315:A:T	D394V	1.000
3:45735316:T:A	D394E	1.000
3:45735316:T:G	D394E	1.000
3:45737774:T:A	W438R	1.000
3:45737774:T:C	W438R	1.000
3:45738661:G:A	G489E	1.000
3:45743571:T:A	W556R	1.000
3:45743571:T:C	W556R	1.000
3:45705188:G:C	G62R	0.999
3:45709598:G:C	R145P	0.999
3:45713149:T:C	F166L	0.999
3:45713151:T:A	F166L	0.999
3:45713151:T:G	F166L	0.999
3:45713160:T:A	N169K	0.999
3:45713160:T:G	N169K	0.999
3:45714077:G:A	G192D	0.999
3:45719559:A:G	R213G	0.999

dbSNP variants (sampled 300 via entrez): RS1000015452 (3:45735415 C>A,T), RS1000018687 (3:45697465 C>G,T), RS1000026516 (3:45744046 G>A,T), RS1000069255 (3:45735019 TC>T), RS1000079694 (3:45729776 C>G), RS1000086545 (3:45717905 G>T), RS1000178461 (3:45721581 C>A,T), RS1000238584 (3:45691136 G>A), RS1000244949 (3:45742478 CTGTA>C), RS1000252261 (3:45710253 T>C), RS1000307615 (3:45710666 G>A,T), RS1000422436 (3:45721879 A>G), RS1000453146 (3:45724341 A>G), RS1000561993 (3:45688672 A>C,G), RS1000570153 (3:45724032 A>G)

Disease associations

OMIM: gene MIM:606569 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST001308_3	Response to anti-depressant treatment in major depressive disorder	5.000000e-07
GCST002481_7	Acne (severe)	3.000000e-06
GCST010698_35	Subcortical volume (min-P)	2.000000e-35
GCST010699_82	Brain morphology (min-P)	3.000000e-15
GCST010701_19	Cortical surface area (MOSTest)	5.000000e-08
GCST010702_119	Subcortical volume (MOSTest)	2.000000e-09
GCST010703_230	Brain morphology (MOSTest)	1.000000e-12
GCST012020_93	Serum metabolite levels	9.000000e-11
GCST012251_14	Macular telangiectasia type 2	1.000000e-09
GCST012252_5	Macular telangiectasia type 2	6.000000e-10

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006322	antidepressant-induced sexual dysfunction
EFO:0004346	neuroimaging measurement
EFO:1002009	macular telangiectasia type 2

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067218 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

8 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1969624	Toxicity	3	bupropion	Major Depressive Disorder
rs2245705	Toxicity	3	bupropion	Major Depressive Disorder
rs2251954	Toxicity	3	bupropion	Major Depressive Disorder
rs2742390	Toxicity	3	bupropion	Major Depressive Disorder
rs2742417	Toxicity	3	bupropion	Major Depressive Disorder
rs2742421	Toxicity	3	bupropion	Major Depressive Disorder
rs2742423	Toxicity	3	bupropion	Major Depressive Disorder
rs2742435	Toxicity	3	bupropion	Major Depressive Disorder

PharmGKB variants

8 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1969624	SACM1L	3	0.00	1	bupropion
rs2245705	SACM1L	3	0.00	1	bupropion
rs2251954	SACM1L	3	0.00	1	bupropion
rs2742390	SACM1L	3	0.00	1	bupropion
rs2742417	SACM1L	3	0.00	1	bupropion
rs2742421	SACM1L	3	0.00	1	bupropion
rs2742423	SACM1L	3	0.00	1	bupropion
rs2742435	SACM1L	3	0.00	1	bupropion

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
7.36	Kd	44.1	nM	CHEMBL5653589
7.36	ED50	44.1	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149336: Binding affinity to human SACM1L incubated for 45 mins by Kinobead based pull down assay	kd	0.0441	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol F	increases expression, affects cotreatment, decreases expression	2
sodium arsenite	increases expression, decreases expression	2
Valproic Acid	affects expression, decreases methylation	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
arsenite	affects binding, decreases reaction	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
nickel sulfate	decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
bisphenol B	increases expression	1
abrine	decreases expression, increases expression	1
jinfukang	decreases expression	1
LDN 193189	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Antimycin A	decreases expression	1
Dexamethasone	decreases expression, affects cotreatment	1
Diazinon	increases methylation	1
Ethyl Methanesulfonate	decreases expression	1
Formaldehyde	decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Ivermectin	decreases expression	1
Methapyrilene	increases methylation	1
Methyl Methanesulfonate	decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Ribonucleotides	affects binding	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
CHEMBL5652378	Binding	Binding affinity to human SACM1L incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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