SAMD9

Summary

SAMD9 (sterile alpha motif domain containing 9, HGNC:1348) is a protein-coding gene on chromosome 7q21.2, encoding Sterile alpha motif domain-containing protein 9 (Q5K651). Double-stranded nucleic acid binding that acts as an antiviral factor by playing an essential role in the formation of cytoplasmic antiviral granules.

This gene encodes a sterile alpha motif domain-containing protein. The encoded protein localizes to the cytoplasm and may play a role in regulating cell proliferation and apoptosis. Mutations in this gene are the cause of normophosphatemic familial tumoral calcinosis. Alternate splicing results in multiple transcript variants that encode the same protein.

Source: NCBI Gene 54809 — RefSeq curated summary.

At a glance

• Gene–disease (curated): SAMD9-related spectrum and myeloid neoplasm risk (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 2,604 total — 9 pathogenic, 23 likely-pathogenic
• Phenotypes (HPO): 59
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity unscored
• MANE Select transcript: NM_017654

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1348
Approved symbol	SAMD9
Name	sterile alpha motif domain containing 9
Location	7q21.2
Locus type	gene with protein product
Status	Approved
Aliases	KIAA2004, FLJ20073
Ensembl gene	ENSG00000205413
Ensembl biotype	protein_coding
OMIM	610456
Entrez	54809

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000379958, ENST00000446617, ENST00000620985

RefSeq mRNA: 2 — MANE Select: NM_017654 NM_001193307, NM_017654

CCDS: CCDS34680

Canonical transcript exons

ENST00000379958 — 3 exons

Exon	Start	End
ENSE00001483170	93099518	93106105
ENSE00001483172	93114795	93114895
ENSE00003850166	93117863	93117979

Expression profiles

Bgee: expression breadth ubiquitous, 247 present calls, max score 99.55.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.4611 / max 296.2582, expressed in 1215 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
84853	8.9504	1201
84854	0.3432	141
84852	0.1674	80

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
esophagus squamous epithelium	UBERON:0006920	99.55	gold quality
amniotic fluid	UBERON:0000173	98.58	gold quality
epithelium of esophagus	UBERON:0001976	97.20	gold quality
oral cavity	UBERON:0000167	96.81	gold quality
buccal mucosa cell	CL:0002336	96.35	gold quality
pharyngeal mucosa	UBERON:0000355	96.19	gold quality
gingiva	UBERON:0001828	94.58	gold quality
gingival epithelium	UBERON:0001949	94.12	gold quality
palpebral conjunctiva	UBERON:0001812	93.97	gold quality
squamous epithelium	UBERON:0006914	92.98	gold quality
decidua	UBERON:0002450	92.75	gold quality
epithelium of nasopharynx	UBERON:0001951	92.57	gold quality
trabecular bone tissue	UBERON:0002483	89.87	gold quality
visceral pleura	UBERON:0002401	89.09	gold quality
mucosa of sigmoid colon	UBERON:0004993	89.08	gold quality
colonic mucosa	UBERON:0000317	88.77	gold quality
germinal epithelium of ovary	UBERON:0001304	88.59	gold quality
parietal pleura	UBERON:0002400	88.50	gold quality
esophagus mucosa	UBERON:0002469	87.71	gold quality
pleura	UBERON:0000977	87.51	gold quality
leukocyte	CL:0000738	86.70	gold quality
monocyte	CL:0000576	86.69	gold quality
mononuclear cell	CL:0000842	86.49	gold quality
lower esophagus mucosa	UBERON:0035834	85.87	gold quality
sperm	CL:0000019	85.86	gold quality
bone marrow	UBERON:0002371	85.79	gold quality
tendon of biceps brachii	UBERON:0008188	85.78	gold quality
blood	UBERON:0000178	85.09	gold quality
calcaneal tendon	UBERON:0003701	85.02	gold quality
bone marrow cell	CL:0002092	84.75	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-53	yes	1708.02
E-MTAB-7052	yes	842.23
E-ANND-3	yes	4.62
E-MTAB-7249	no	170.11

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

93 targeting SAMD9, 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-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-129-5P	99.88	70.26	3273
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-3913-5P	99.78	67.26	968
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-567	99.63	68.57	1219

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 36)

• Mutation analysis revealed a homozygous mutation in the SAMD9 gene (K1495E), which was found to segregate with the disease in all families and to interfere with the protein expression. (PMID:16960814)
• SAMD9 and SAMD9L are a novel family of genes, which play a role regulating cell proliferation and suppressing the neoplastic phenotype; the human gene exists in rat, but is lost in mouse, due to a mouse specific rearrangement (PMID:17407603)
• PIvotal role in calcification and thus implicated in various hereditary diseases such as atherosclerosis, calcinosis and autoimmune diseases. (PMID:17507861)
• SAMD9 may have a role in the TNF-alpha signaling pathway and in the regulation of extra-osseous calcification (PMID:18094730)
• SAMD9 could be a key molecule to control cancer cell death by inactivated Sendai virus particle or IFN-beta treatment. (PMID:19830690)
• SAMD9, an IFN-gamma-responsive protein, interacts with RGL2 to diminish the expression of EGR1, a protein of direct relevance to the pathogenesis of ectopic calcification and inflammation. (PMID:21160498)
• M062 also binds and antagonizes cellular SAMD9 in human cells, suggesting that SAMD9 is a novel innate antiviral factor against poxviruses. (PMID:21248034)
• Over-expression of SAMD9 is correlated with the metastasis of esophageal squamous cell carcinoma (PMID:24721411)
• When SAMD9 is stimulated due to failure of the viral antagonism during infection, the resulting antiviral granules exhibit properties different from those of the canonical stress granules. (PMID:25428864)
• SAMD9 is down-regulated in non-small cell lung cancer. Knockdown of SAMD9 expression increased the invasion, migration and proliferation in H1299 cells in vitro and overexpression of SAMD9 suppressed proliferation and invasion in A549 cells. (PMID:25450373)
• Replication of the K1L(-)C7L(-) mutant vaccinia virus virus was enabled by multiple siRNAs to SAMD9 or WDR6. (PMID:26242627)
• SAMD9 mutation is associated with MIRAGE syndrome. (PMID:27182967)
• Progressive loss of mutated SAMD9 through the development of monosomy 7 (-7), deletions of 7q (7q-), and secondary somatic loss-of-function (nonsense and frameshift) mutations in SAMD9 rescued the growth-restricting effects of mutant SAMD9 proteins in bone marrow and was associated with increased length of survival. (PMID:28346228)
• findings establish SAMD9/SAMD9L mutations as a new class of germline lesions with variable clinical phenotypes, including familial MDS (PMID:28487541)
• Acquisition of a somatic nonsense SAMD9 mutation in the cells of the haematopoietic system might revert the cellular growth repression caused by the germline SAMD9 mutations (ie, second-site reversion mutations). Unexpected lack of haematological features in the two patients would be explained by the reversion mutations. (PMID:29175836)
• Here we describe one patient with a novel de novo mutation p.R824Q in SAMD9 and provide functional evidence of its pathogenicity. We also review a second patient with a previously described p.R1293Q mutation with special attention to dysmorphology and findings that could aid in recognition of the disorder. (PMID:29266745)
• describe the first patient to present with congenital amegakaryocytic thrombocytopenia secondary to MIRAGE syndrome and describe a novel disease-causing SAMD9 allele (c.2462A>T; p.K821M). (PMID:29365320)
• In humans, both SAMD9 and SAMD9L are poxvirus restriction factors, although the latter requires interferon induction in many cell types. (PMID:29447249)
• REVIEW: expert-based recommendations regarding diagnosis, follow-up, and treatment of mutation carriers. (PMID:29535429)
• SAMD9 and SAMD9L germline loss-of-function variants exist in 3% of adult myelodysplastic syndromes and are located more in the N terminus relative to pediatric germline loss-of-function variants, which exist more in the C terminus. (PMID:30322869)
• Somatic mosaic monosomy 7 and UPD7q in a child with MIRAGE syndrome caused by a novel SAMD9 mutation. (PMID:30565860)
• SAMD9 expression is (epi-) genetically regulated, and significantly upregulated in PBMCs in RA patients and in activated T cells in vitro. SAMD9 might serve as a T cell activation marker but act as an anti-inflammatory factor. (PMID:30715670)
• A novel SAMD9 variant identified in patient with MIRAGE syndrome: Further defining syndromic phenotype and review of previous cases. (PMID:30900330)
• Homeobox B8 Targets Sterile Alpha Motif Domain-Containing Protein 9 and Drives Glioma Progression. (PMID:31646435)
• In trans early mosaic mutational escape and novel phenotypic features of germline SAMD9 mutation. (PMID:31900929)
• Prevalence of germline GATA2 and SAMD9/9L variants in paediatric haematological disorders with monosomy 7. (PMID:32770553)
• Germline predisposition in myeloid neoplasms: Unique genetic and clinical features of GATA2 deficiency and SAMD9/SAMD9L syndromes. (PMID:33038986)
• Pediatric MDS and bone marrow failure-associated germline mutations in SAMD9 and SAMD9L impair multiple pathways in primary hematopoietic cells. (PMID:33731850)
• SAMD9 Is Relating With M2 Macrophage and Remarkable Malignancy Characters in Low-Grade Glioma. (PMID:33936093)
• Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes. (PMID:34621053)
• Emerging phenotypes linked to variants in SAMD9 and MIRAGE syndrome. (PMID:36060959)
• SAMD9 Promotes Postoperative Recurrence of Esophageal Squamous Cell Carcinoma by Stimulating MYH9-Mediated GSK3beta/beta-Catenin Signaling. (PMID:36757050)
• Viral host range factors antagonize pathogenic SAMD9 and SAMD9L variants. (PMID:36894052)
• [Pancytopenia in children caused by SAMD9/9L mutation: 5 cases report and literature review]. (PMID:37357006)
• PARP14 correlates with GBM proliferation and poor prognosis by elevating expression of SAMD/SAMD9L. (PMID:37612499)
• Overexpression of human SAMD9 inhibits protein translation and alters MYC signaling resulting in cell cycle arrest. (PMID:38848876)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
danio_rerio	SAMD9	ENSDARG00000102729
rattus_norvegicus	Samd9	ENSRNOG00000052444

Paralogs (1): SAMD9L (ENSG00000177409)

Protein

Protein identifiers

Sterile alpha motif domain-containing protein 9 — Q5K651 (reviewed: Q5K651)

All UniProt accessions (2): C9JKF1, Q5K651

UniProt curated annotations — full annotation on UniProt →

Function. Double-stranded nucleic acid binding that acts as an antiviral factor by playing an essential role in the formation of cytoplasmic antiviral granules. May play a role in the inflammatory response to tissue injury and the control of extra-osseous calcification, acting as a downstream target of TNF signaling. Involved in the regulation of EGR1, in coordination with RGL2. May be involved in endosome fusion.

Subunit / interactions. Interacts with RGL2. Interacts with EEA1. (Microbial infection) Interacts with myxoma virus protein M062.

Subcellular location. Cytoplasm.

Tissue specificity. Widely expressed. Very low levels are detected in skeletal muscle. Not detected in brain. Down-regulated in aggressive fibromatosis, as well as in breast and colon cancers. Up-regulated in fibroblasts from patients with normophosphatemic tumoral calcinosis (NFTC).

Disease relevance. Tumoral calcinosis, normophosphatemic, familial (NFTC) [MIM:610455] An uncommon, life-threatening disorder characterized by progressive deposition of calcified masses in cutaneous and subcutaneous tissues. Serum phosphate levels are normal. Clinical features include painful calcified ulcerative lesions and massive calcium deposition in the mid- and lower dermis, severe skin and bone infections, erythematous papular skin eruption in infancy, conjunctivitis, and gingivitis. NFTC shows a striking resemblance to acquired dystrophic calcinosis, in which tissue calcification occurs as a consequence of tissue injury/inflammation. The disease is caused by variants affecting the gene represented in this entry. MIRAGE syndrome (MIRAGE) [MIM:617053] A form of syndromic adrenal hypoplasia characterized by myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy. The disease is caused by variants affecting the gene represented in this entry. Monosomy 7 myelodysplasia and leukemia syndrome 2 (M7MLS2) [MIM:619041] A hematologic disorder manifesting in early childhood and characterized by bone marrow dyspoiesis, pancytopenia, myelodysplastic syndrome or acute myelogenous leukemia, associated with monosomy 7 in the bone marrow. Disease severity is highly variable. Inheritance is autosomal dominant with incomplete penetrance. The disease is caused by variants affecting the gene represented in this entry. Germline mutations in SAMD9 with a suppressive effect on the cell cycle are associated with somatic loss of the chromosome 7 harboring the mutant allele. This results in the deletion of several genes and predisposes to the development of myelodysplastic syndrome and acute myelogenous leukemia.

Induction. Up-regulated by TNF through p38 MAPKs and NF-kappa-B. Up-regulated by osmotic shock. Induced by IFNG.

RefSeq proteins (2): NP_001180236, NP_060124* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001660	SAM	Domain
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR027417	P-loop_NTPase	Homologous_superfamily

Pfam: PF00536

UniProt features (35 total): sequence variant 13, strand 8, helix 5, mutagenesis site 3, chain 1, domain 1, region of interest 1, sequence conflict 1, turn 1, compositionally biased region 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
9ZJR	ELECTRON MICROSCOPY	2.53
9ZJU	ELECTRON MICROSCOPY	2.6
7KSP	X-RAY DIFFRACTION	2.8
9ZJW	ELECTRON MICROSCOPY	2.8
9ZJZ	ELECTRON MICROSCOPY	2.87
9ZJS	ELECTRON MICROSCOPY	3.04
9ZJV	ELECTRON MICROSCOPY	3.13

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5K651-F1	83.79	0.50

Functional residue map

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

Mutagenesis-validated functional residues (3):

Position	Phenotype
198	no defect in double-stranded nucleic acid binding but defective at inhibiting viral replication.
214	no defect in double-stranded nucleic acid binding but defective at inhibiting viral replication.
257	no defect in double-stranded nucleic acid binding but defective at inhibiting viral replication.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 0 (showing top):

GO Biological Process (3): endosomal vesicle fusion (GO:0034058), innate immune response (GO:0045087), immune system process (GO:0002376)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (2): cytoplasm (GO:0005737), cytosol (GO:0005829)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
vesicle fusion	1
immune response	1
defense response to symbiont	1
biological_process	1
binding	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

1262 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SAMD9	RGL2	O15211	798
SAMD9	GALNT3	Q14435	710
SAMD9	WDR6	Q9NNW5	688
SAMD9	HEPACAM2	A8MVW5	550
SAMD9	FGF23	Q9GZV9	519
SAMD9	ISG15	P05161	512
SAMD9	LEF1	Q9UJU2	501
SAMD9	EPHB2	P29323	496
SAMD9	ERCC6L2	Q5T890	480
SAMD9	ANKRD26	Q9UPS8	479
SAMD9	RIGI	O95786	476
SAMD9	GATA2	P23769	451
SAMD9	PARP9	Q8IXQ6	449
SAMD9	DDX41	Q9UJV9	445
SAMD9	DDX60	Q8IY21	432

IntAct

15 interactions, top by confidence:

A	B	Type	Score
Cdc20	BUB1	psi-mi:“MI:0914”(association)	0.560
EEA1	SAMD9	psi-mi:“MI:0915”(physical association)	0.520
Tor1aip1	PEX10	psi-mi:“MI:0914”(association)	0.350
RSRP1	DMWD	psi-mi:“MI:0914”(association)	0.350
Rcc1	WDR46	psi-mi:“MI:0914”(association)	0.350
SAMD9	TRAPPC13	psi-mi:“MI:0914”(association)	0.350
WTAP	DDX39A	psi-mi:“MI:0914”(association)	0.350
CDKN2A	NHERF1	psi-mi:“MI:0914”(association)	0.350
ATG16L1		psi-mi:“MI:0914”(association)	0.350
MAGEA9	CIBAR1	psi-mi:“MI:0914”(association)	0.350
SRRT	A2ML1	psi-mi:“MI:0914”(association)	0.350
FNDC5	A2ML1	psi-mi:“MI:0914”(association)	0.350
SAMD9		psi-mi:“MI:0915”(physical association)	0.000

BioGRID (39): SAMD9 (Affinity Capture-RNA), SAMD9 (Co-fractionation), SAMD9 (Co-fractionation), SAMD9 (Co-fractionation), SAMD9 (Co-fractionation), SAMD9 (Co-fractionation), SAMD9 (Affinity Capture-MS), TRAPPC13 (Affinity Capture-MS), EOGT (Affinity Capture-MS), SAMD9 (Affinity Capture-MS), SAMD9 (Affinity Capture-MS), SAMD9 (Affinity Capture-MS), SAMD9 (Affinity Capture-MS), SAMD9 (Protein-RNA), SAMD9 (Proximity Label-MS)

ESM2 similar proteins: A0A1B0GW35, A6QNM3, B0R034, B1ANS9, B9EK06, D2KC46, D3ZY60, F1MS15, F1P065, F1REV3, O00522, O15091, O75747, P10911, P58069, Q008S8, Q14449, Q14D04, Q15283, Q32NR9, Q45GW3, Q4R366, Q4R6T7, Q5H9U9, Q5K651, Q5PQS3, Q5XGX5, Q5XIZ9, Q5ZLD2, Q60862, Q63713, Q69Z37, Q6DCF6, Q6S5J6, Q6TNJ1, Q75PQ8, Q80W71, Q86VD1, Q86YR7, Q8C5W4

Diamond homologs: A1A5G4, A5PKA5, A8JQ65, A8MUH7, B3LXF2, B3NYS4, B4I4Y1, B4JHJ7, B4K6T8, B4PRE2, B4R0A5, B7WN72, D3YXJ0, D3YZU1, E9PUQ8, O14745, P18160, Q16760, Q28619, Q3SZK8, Q3T0X8, Q3UHD6, Q4ACU6, Q4R6G4, Q52KW0, Q5F488, Q5K651, Q5RCF7, Q5T2W1, Q5TCQ9, Q7Z6J2, Q80Z38, Q86XP1, Q8IZD0, Q8K4V4, Q8R4H2, Q96L92, Q9BYB0, Q9EQJ9, Q9JJ40

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

2604 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	23
Uncertain significance	1705
Likely benign	755
Benign	13

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1229	NM_017654.4(SAMD9):c.4483A>G (p.Lys1495Glu)	Pathogenic
1343336	NM_017654.4(SAMD9):c.2471G>A (p.Arg824Gln)	Pathogenic
1708316	NM_017654.4(SAMD9):c.4008_4011dup (p.Ala1338fs)	Pathogenic
253151	NM_017654.4(SAMD9):c.1376G>A (p.Arg459Gln)	Pathogenic
253152	NM_017654.4(SAMD9):c.2305G>A (p.Asp769Asn)	Pathogenic
253153	NM_017654.4(SAMD9):c.3877C>T (p.Arg1293Trp)	Pathogenic
521232	NM_017654.4(SAMD9):c.2920G>A (p.Glu974Lys)	Pathogenic
988626	NM_017654.4(SAMD9):c.3406G>C (p.Glu1136Gln)	Pathogenic
988627	NM_017654.4(SAMD9):c.2026A>G (p.Lys676Glu)	Pathogenic
1029633	NM_017654.4(SAMD9):c.2795C>T (p.Thr932Ile)	Likely pathogenic
1338259	NM_017654.4(SAMD9):c.1853T>C (p.Ile618Thr)	Likely pathogenic
1513631	NM_017654.4(SAMD9):c.2300C>A (p.Thr767Lys)	Likely pathogenic
1695195	NM_017654.4(SAMD9):c.2644T>G (p.Phe882Val)	Likely pathogenic
1803127	NM_017654.4(SAMD9):c.2414A>G (p.Asp805Gly)	Likely pathogenic
1805947	NM_017654.4(SAMD9):c.4532T>C (p.Leu1511Ser)	Likely pathogenic
2231044	NM_017654.4(SAMD9):c.1228T>G (p.Tyr410Asp)	Likely pathogenic
2441798	NM_017654.4(SAMD9):c.4690G>A (p.Gly1564Ser)	Likely pathogenic
2504158	NM_017654.4(SAMD9):c.2195T>G (p.Ile732Ser)	Likely pathogenic
2505033	NM_017654.4(SAMD9):c.1792C>T (p.Gln598Ter)	Likely pathogenic
2663808	NM_017654.4(SAMD9):c.2603A>C (p.Lys868Thr)	Likely pathogenic
2671833	NM_017654.4(SAMD9):c.976del (p.Gln326fs)	Likely pathogenic
3068441	NM_017654.4(SAMD9):c.1922T>G (p.Leu641Arg)	Likely pathogenic
3254866	NM_017654.4(SAMD9):c.2200C>G (p.His734Asp)	Likely pathogenic
3366302	NM_017654.4(SAMD9):c.4696A>G (p.Ser1566Gly)	Likely pathogenic
3900228	NM_017654.4(SAMD9):c.2248A>T (p.Ile750Phe)	Likely pathogenic
3901292	NM_017654.4(SAMD9):c.2809C>A (p.Gln937Lys)	Likely pathogenic
4056163	NM_017654.4(SAMD9):c.1940A>C (p.Asp647Ala)	Likely pathogenic
4056191	NM_017654.4(SAMD9):c.4057A>G (p.Lys1353Glu)	Likely pathogenic
4819928	NM_017654.4(SAMD9):c.2483C>G (p.Pro828Arg)	Likely pathogenic
556683	NM_017654.4(SAMD9):c.132del (p.Val45fs)	Likely pathogenic

SpliceAI

319 predictions. Top by Δscore:

Variant	Effect	Δscore
7:93106105:CCTA:C	acceptor_loss	1.0000
7:93106106:C:CC	acceptor_gain	1.0000
7:93106103:TAC:T	acceptor_gain	0.9900
7:93106110:A:AC	acceptor_gain	0.9900
7:93106110:A:C	acceptor_gain	0.9900
7:93106112:G:C	acceptor_gain	0.9900
7:93106112:G:GC	acceptor_gain	0.9900
7:93117861:A:AC	donor_gain	0.9900
7:93117861:AC:A	donor_gain	0.9900
7:93117862:C:CC	donor_gain	0.9900
7:93117862:CC:C	donor_gain	0.9900
7:93106102:ATAC:A	acceptor_gain	0.9800
7:93106104:AC:A	acceptor_gain	0.9800
7:93106104:ACCT:A	acceptor_gain	0.9800
7:93106105:CC:C	acceptor_gain	0.9800
7:93106108:A:C	acceptor_gain	0.9800
7:93117859:TTAC:T	donor_loss	0.9800
7:93117860:TACCC:T	donor_loss	0.9800
7:93117861:ACCCA:A	donor_loss	0.9800
7:93117862:C:CT	donor_loss	0.9800
7:93117862:CCCA:C	donor_gain	0.9800
7:93106101:GATAC:G	acceptor_gain	0.9700
7:93106108:A:AC	acceptor_gain	0.9700
7:93117861:ACC:A	donor_gain	0.9700
7:93117862:CCC:C	donor_gain	0.9700
7:93106102:ATACC:A	acceptor_gain	0.9600
7:93106103:TACCT:T	acceptor_gain	0.9600
7:93106105:CCT:C	acceptor_gain	0.9600
7:93106106:C:A	acceptor_gain	0.9600
7:93114794:CCAAA:C	donor_gain	0.9600

AlphaMissense

10622 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:93102773:C:G	A1109P	0.995
7:93104561:A:G	W513R	0.994
7:93104561:A:T	W513R	0.994
7:93102623:C:G	A1159P	0.993
7:93102829:C:G	R1090T	0.993
7:93104627:A:G	W491R	0.993
7:93104627:A:T	W491R	0.993
7:93101780:A:G	W1440R	0.992
7:93101780:A:T	W1440R	0.992
7:93102609:G:C	F1163L	0.992
7:93102609:G:T	F1163L	0.992
7:93102611:A:G	F1163L	0.992
7:93102622:G:T	A1159D	0.991
7:93102727:C:T	G1124D	0.991
7:93104559:C:A	W513C	0.991
7:93104559:C:G	W513C	0.991
7:93102714:T:A	K1128N	0.990
7:93102714:T:G	K1128N	0.990
7:93102782:C:G	A1106P	0.990
7:93102828:T:A	R1090S	0.990
7:93102828:T:G	R1090S	0.990
7:93103711:A:G	L796P	0.990
7:93101371:A:G	F1576S	0.988
7:93102728:C:G	G1124R	0.988
7:93102840:T:A	Q1086H	0.988
7:93102840:T:G	Q1086H	0.988
7:93103816:G:T	A761D	0.988
7:93101382:A:C	F1572L	0.987
7:93101382:A:T	F1572L	0.987
7:93101384:A:G	F1572L	0.987

dbSNP variants (sampled 300 via entrez): RS1000155477 (7:93108258 C>T), RS1000172105 (7:93107127 G>C), RS1000194549 (7:93102990 G>C), RS1000492168 (7:93107014 A>C,G), RS1000716447 (7:93099666 T>C), RS1000786814 (7:93115648 G>A), RS1000790750 (7:93101157 T>C), RS1000870397 (7:93099739 G>C,T), RS1001082548 (7:93111389 T>A,G), RS1001212487 (7:93099403 A>C), RS1001221002 (7:93118829 C>T), RS1001342207 (7:93119062 C>G), RS1001412969 (7:93117403 A>G), RS1001474508 (7:93111584 G>A,C), RS1001506863 (7:93101534 T>C,G)

Disease associations

OMIM: gene MIM:610456 | disease phenotypes: MIM:617053, MIM:619041, MIM:610455, MIM:607086, MIM:614286, MIM:159550

GenCC curated gene-disease

Disease	Classification	Inheritance
MIRAGE syndrome	Definitive	Autosomal dominant
normophosphatemic familial tumoral calcinosis	Strong	Autosomal recessive
monosomy 7 myelodysplasia and leukemia syndrome 2	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
normophosphatemic familial tumoral calcinosis	Limited	AR
SAMD9-related spectrum and myeloid neoplasm risk	Definitive	AD

Mondo (9): intellectual disability (MONDO:0001071), MIRAGE syndrome (MONDO:0014888), monosomy 7 myelodysplasia and leukemia syndrome 2 (MONDO:0030801), normophosphatemic familial tumoral calcinosis (MONDO:0012502), familial thoracic aortic aneurysm and aortic dissection (MONDO:0019625), myelodysplastic syndrome (MONDO:0018881), hereditary neoplastic syndrome (MONDO:0015356), diffuse midline glioma, H3 K27-altered (MONDO:1060171), ataxia-pancytopenia syndrome (MONDO:0008038)

Orphanet (8): MIRAGE syndrome (Orphanet:494433), Familial normophosphatemic tumoral calcinosis (Orphanet:306658), Familial tumoral calcinosis (Orphanet:53715), Familial thoracic aortic aneurysm and aortic dissection (Orphanet:91387), Myelodysplastic syndrome (Orphanet:52688), Inherited cancer-predisposing syndrome (Orphanet:140162), Ataxia-pancytopenia syndrome (Orphanet:2585), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

59 total (30 of 59 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000049	Shawl scrotum
HP:0000230	Gingivitis
HP:0000238	Hydrocephalus
HP:0000509	Conjunctivitis
HP:0000815	Hypergonadotropic hypogonadism
HP:0000835	Adrenal hypoplasia
HP:0000846	Adrenal insufficiency
HP:0000967	Petechiae
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001511	Intrauterine growth retardation
HP:0001643	Patent ductus arteriosus
HP:0001762	Talipes equinovarus
HP:0001838	Rocker bottom foot
HP:0001873	Thrombocytopenia
HP:0001875	Decreased total neutrophil count
HP:0001876	Pancytopenia
HP:0001882	Decreased total leukocyte count
HP:0001888	Decreased total lymphocyte count
HP:0001903	Anemia
HP:0001943	Hypoglycemia
HP:0002020	Gastroesophageal reflux
HP:0002028	Chronic diarrhea
HP:0002043	Esophageal stricture

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST005667_13	Central corneal thickness	5.000000e-08
GCST005993_38	Mean corpuscular hemoglobin	9.000000e-12
GCST006011_70	Mean corpuscular volume	9.000000e-16
GCST008595_187	Cognitive ability, years of educational attainment or schizophrenia (pleiotropy)	1.000000e-09
GCST009524_148	Household income (MTAG)	2.000000e-12
GCST011155_6	Nontraumatic osteonecrosis of the femoral head	2.000000e-07

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0005213	central corneal thickness
EFO:0004527	mean corpuscular hemoglobin
EFO:0004337	intelligence
EFO:0004784	self reported educational attainment
EFO:0009695	household income
EFO:1001930	idiopathic osteonecrosis of the femoral head

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
C563233	Myelocerebellar Disorder (supp.)
C566473	Tumoral Calcinosis, Normophosphatemic, Familial (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression	3
Estradiol	affects cotreatment, increases expression	3
Nickel	decreases expression, increases expression	3
triphenyl phosphate	affects expression, increases expression	2
sodium arsenite	affects expression, decreases expression	2
potassium chromate(VI)	affects cotreatment, decreases expression	2
chromium hexavalent ion	increases abundance, increases expression, decreases expression	2
perfluorooctane sulfonic acid	decreases expression	2
Air Pollutants	decreases expression, increases abundance	2
Lipopolysaccharides	affects expression, increases expression, affects reaction, affects response to substance	2
Plant Extracts	increases expression, affects expression, affects reaction	2
Tetrachlorodibenzodioxin	affects cotreatment, increases expression	2
Tretinoin	increases expression	2
Particulate Matter	increases expression, decreases expression, increases abundance	2
GSK-J4	decreases expression	1
propionaldehyde	increases expression	1
bisphenol A	affects cotreatment, increases methylation	1
sodium arsenate	increases abundance, decreases expression	1
pyrogallol 1,3-dimethyl ether	affects localization, decreases expression, increases expression, affects cotreatment	1
arsenite	affects binding, decreases reaction	1
2-bromopalmitate	increases palmitoylation, decreases reaction, increases abundance	1
perfluorooctanoic acid	decreases expression	1
zinc chromate	increases expression, increases abundance	1
ferrous chloride	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
diallyl trisulfide	decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
avobenzone	decreases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1

Cellosaurus cell lines

7 cell lines: 4 induced pluripotent stem cell, 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1HE	Abcam A-549 SAMD9 KO 2	Cancer cell line	Male
CVCL_B2PX	Abcam A-549 SAMD9 KO 1	Cancer cell line	Male
CVCL_C1PT	ESi086-A-3	Induced pluripotent stem cell	Male
CVCL_IT59	CUBi001-A	Induced pluripotent stem cell	Male
CVCL_IT60	CUBi002-B	Induced pluripotent stem cell	Male
CVCL_TJ99	HAP1 SAMD9 (-)	Cancer cell line	Male
CVCL_XJ86	CUBi002-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

199 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
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
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
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)
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
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders