SIM2

Summary

SIM2 (SIM bHLH transcription factor 2, HGNC:10883) is a protein-coding gene on chromosome 21q22.13, encoding Single-minded homolog 2 (Q14190). Transcription factor that may be a master gene of CNS development in cooperation with Arnt.

This gene represents a homolog of the Drosophila single-minded (sim) gene, which encodes a transcription factor that is a master regulator of neurogenesis. The encoded protein is ubiquitinated by RING-IBR-RING-type E3 ubiquitin ligases, including the parkin RBR E3 ubiquitin protein ligase. This gene maps within the so-called Down syndrome chromosomal region, and is thus thought to contribute to some specific Down syndrome phenotypes. Alternative splicing of this gene results in multiple transcript variants.

Source: NCBI Gene 6493 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 104 total — 1 likely-pathogenic
• Transcription factor: yes — 12 downstream targets (CollecTRI)
• MANE Select transcript: NM_005069

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10883
Approved symbol	SIM2
Name	SIM bHLH transcription factor 2
Location	21q22.13
Locus type	gene with protein product
Status	Approved
Aliases	MGC119447, bHLHe15
Ensembl gene	ENSG00000159263
Ensembl biotype	protein_coding
OMIM	600892
Entrez	6493

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000290399, ENST00000431229, ENST00000460783, ENST00000481185, ENST00000483178

RefSeq mRNA: 2 — MANE Select: NM_005069 NM_005069, NM_009586

CCDS: CCDS13646

Canonical transcript exons

ENST00000290399 — 11 exons

Exon	Start	End
ENSE00001044382	36747665	36749917
ENSE00001284595	36744728	36745136
ENSE00003458994	36743387	36743555
ENSE00003474390	36741717	36741864
ENSE00003558601	36723045	36723130
ENSE00003575917	36719821	36719929
ENSE00003579996	36699115	36699921
ENSE00003598947	36726119	36726318
ENSE00003621494	36731045	36731151
ENSE00003632648	36712533	36712622
ENSE00003635370	36709168	36709250

Expression profiles

Bgee: expression breadth ubiquitous, 135 present calls, max score 95.91.

FANTOM5 (CAGE): breadth broad, TPM avg 4.4001 / max 278.0239, expressed in 643 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
189003	2.8303	542
189002	0.9623	446
189004	0.3629	212
189005	0.1415	76
189006	0.0687	19
189007	0.0344	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
renal medulla	UBERON:0000362	95.91	gold quality
lower esophagus mucosa	UBERON:0035834	93.17	gold quality
esophagus squamous epithelium	UBERON:0006920	92.67	gold quality
buccal mucosa cell	CL:0002336	92.18	gold quality
metanephros cortex	UBERON:0010533	90.84	gold quality
esophagus mucosa	UBERON:0002469	90.60	gold quality
epithelium of esophagus	UBERON:0001976	90.25	gold quality
oral cavity	UBERON:0000167	80.15	gold quality
amniotic fluid	UBERON:0000173	79.50	gold quality
squamous epithelium	UBERON:0006914	79.22	gold quality
vastus lateralis	UBERON:0001379	78.91	silver quality
tongue squamous epithelium	UBERON:0006919	77.99	silver quality
adult mammalian kidney	UBERON:0000082	77.94	gold quality
superior surface of tongue	UBERON:0007371	77.49	gold quality
tibia	UBERON:0000979	77.14	gold quality
quadriceps femoris	UBERON:0001377	76.94	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.39	gold quality
kidney	UBERON:0002113	75.08	gold quality
triceps brachii	UBERON:0001509	74.55	gold quality
tongue	UBERON:0001723	74.47	gold quality
gluteal muscle	UBERON:0002000	73.63	gold quality
nipple	UBERON:0002030	73.03	gold quality
fundus of stomach	UBERON:0001160	72.61	gold quality
tendon of biceps brachii	UBERON:0008188	71.70	silver quality
body of stomach	UBERON:0001161	71.34	gold quality
stomach	UBERON:0000945	71.17	gold quality
cardia of stomach	UBERON:0001162	70.94	gold quality
muscle organ	UBERON:0001630	70.55	gold quality
medial globus pallidus	UBERON:0002477	70.22	silver quality
body of tongue	UBERON:0011876	69.63	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-119	yes	57.96
E-ANND-3	yes	10.20

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

12 targets.

Target	Regulation
ARNT
BCL2	Repression
CASP3	Activation
CSTB
EPO
HIF1A	Repression
MYOD1
MYOM2	Activation
PIAS1
PRKN	Unknown
SIM2
SNAI2	Unknown

Upstream regulators (CollecTRI, top): CTNNB1, MYB, MYC, SIM2

miRNA regulators (miRDB)

28 targeting SIM2, 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-3692-3P	99.98	70.27	2139
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-1260A	99.61	66.67	1098
HSA-MIR-1260B	99.61	66.67	1098
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-372-5P	99.41	69.11	2299
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-6770-5P	98.97	66.76	1853
HSA-MIR-1267	98.24	69.05	837
HSA-MIR-665	97.60	65.64	1781
HSA-MIR-6802-3P	97.29	65.42	613
HSA-MIR-4286	97.20	64.37	1587
HSA-MIR-3189-3P	96.80	66.34	896
HSA-MIR-552-3P	96.68	64.12	1026
HSA-MIR-7108-5P	96.42	66.17	598
HSA-MIR-6726-5P	95.97	63.72	841
HSA-MIR-920	95.97	63.95	811
HSA-MIR-4300	95.85	64.56	1003
HSA-MIR-5591-5P	95.85	64.76	1002
HSA-MIR-874-3P	95.02	65.66	806
HSA-MIR-6774-3P	89.14	65.20	68

Literature-anchored findings (GeneRIF, showing 32)

• Stage-specific expression of the sim2-short-form protein was seen in normal matched paraffin sections of the colon tumors. In a matched set of tissues of Benign Prostatic Hyperplasia (BPH) and prostate carcinomas, sim2-s expression was detected in the BPH (PMID:12530058)
• Isoform-specific expression of SIM2 short-form (SIM2-s) was seen selectively in colon, prostate, and pancreatic carcinomas. (PMID:12676991)
• Tissue- and tumor-specific expression of both SIM2 isoforms (SIM2-s and SIM2-l), but not SIM1, were detected in the pancreatic tumor models. (PMID:14550949)
• SIM1 and SIM2 have a novel nuclear localization signal (PMID:14697214)
• a novel NXF signaling system on neural gene promoter may be a molecular target of the adverse effects of Sim2 in the mental retardation of Down’s syndrome (PMID:14701734)
• Potential role of SIM2 in central nervous system development. SIM2 overexpression could participate in pathogenesis of mental retardation in Down syndrome. (PMID:15946822)
• provide a direct link between SIM2-s and differentiation, and may provide a model to identify SIM2-s targets (PMID:16129820)
• The expression of a splice variant of SIM2, SIM2s, is lost or reduced in human breast cancers. Inhibits growth and invasiveness of breast cancer cells upon ectopic expression. Represses MMP3 expression by direct binding to the MMP3 promoter. (PMID:16840439)
• Knockdown of SIM2s in MCF-7 breast cancer cells contributed to an epithelial-mesenchymal transition associated with increased MMP2 and slug levels. (PMID:18160708)
• Ha-Ras transformation of MCF10A cells leads to repression of Singleminded-2s through NOTCH and C/EBPbeta. (PMID:19169276)
• SIM2s’ functional interference with HIF1alpha activities on BNIP3 may indicate a novel role for SIM2s in promoting tumourigenesis. (PMID:19668230)
• The SIM2 is expressed in prostate cancer(PCa) and that anti-SIM2 antibodies are detectable in PCa patients’ sera implicate SIM2 as a PCa-associated antigen that is a suitable potential target for PCa immunotherapy. (PMID:19737960)
• Genetic variants of SIM2 gene may not be associated with the susceptibility to congenital scoliosis and different clinical phenotypes of CS in Chinese Han population. (PMID:20137643)
• Significantly lower frequency of SIM2 C-G haplotype (rs2073601-rs2073416) was noticed in individuals with Down syndrome (P value =0.01669) and their fathers (P value=0.01185) (PMID:22048266)
• These results suggest an involvement of SIM2 in key traits of prostate tumor cell biology. (PMID:22174909)
• role for SIM2s in promoting human breast tumor differentiation and maintaining epithelial integrity. (PMID:22777354)
• Altered expression of SIM2 and ETS2 could be one of the reasons for variable occurrence of different malignant conditions in Down syndrome. (PMID:23343470)
• miR-200a is downregulated in human glioma and inhibition of miR-200a caused upregulation of SIM2-s in T98G cells and promoted their motility. (PMID:24162743)
• a single peptide containing multiple SIM2 epitopes can be used to induce both a CD4 and CD8 T cell response, providing a peptide-based vaccine formulation for potential use in immunotherapy of various cancers. (PMID:24690990)
• Data suggest selected SIM1 variants exhibit poor dimerization with ARNT2 (aryl-hydrocarbon receptor nuclear translocator 2) and anomalous intracellular localization; data were used to predict spot in SIM1/SIM2 (residues 290-326) critical in function. (PMID:24814368)
• Data showed that SIM2 was highly expressed in human glioma tumors and cell lines and its short form might increase the invasion of glioma cells through the alteration of epithelial-mesenchymal transition. (PMID:24909296)
• In SH-SY5Y cells, ethanol exposure increased Sim2 expression in a manner similar to that of cleaved caspase 3. PKA activation was required for this. Sim2 might be involved in activating caspase 3 and ethanol-induced apoptosis in SH-SY5Y cells. (PMID:25319570)
• Two genes, OR51E2 and SIM2, and two miRNAs, miR-200c and miR-200b, showed significant association with prostate cancer. (PMID:28910345)
• attenuates resistance to hypoxia and tumor growth by transcriptional suppression of HIF1A in uterine cervical squamous cell carcinoma (PMID:29109451)
• SIM2 increases CRT sensitivity through tumor differentiation by cooperation with ARNT. (PMID:29427302)
• TMEM75 functions as an oncogene relying on activation of SIM2 in colorectal cancer. (PMID:29964097)
• SIM2s interacts with ATM and is stabilized through ATM-dependent phosphorylation in response to IR. (PMID:30531838)
• these results show a role for SIM2s in the resolution of replication stress and further characterize the necessity of SIM2s for effective RAD51 loading in response to DNA damage or stress, ultimately promoting genomic integrity and thus preventing the accumulation of cancer-promoting mutations. (PMID:31775907)
• These findings support a role for SIM2s in the prevention of breast cancer progression through its ability to repress PTGS2 expression via modulating the NFkappaB signaling pathway. (PMID:31783895)
• CD24 and CK4 are upregulated by SIM2, and are predictive biomarkers for chemoradiotherapy and surgery in esophageal cancer. (PMID:32124945)
• Long noncoding RNA CASC15 facilitates esophageal squamous cell carcinoma tumorigenesis via decreasing SIM2 stability via FTOmediated demethylation. (PMID:33650646)
• Characterization of functionally deficient SIM2 variants found in patients with neurological phenotypes. (PMID:35730699)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
mus_musculus	Sim2	ENSMUSG00000062713
rattus_norvegicus	Sim2	ENSRNOG00000054203
drosophila_melanogaster	trh	FBGN0262139
drosophila_melanogaster	sima	FBGN0266411
caenorhabditis_elegans		WBGENE00001851

Paralogs (7): HIF1A (ENSG00000100644), SIM1 (ENSG00000112246), EPAS1 (ENSG00000116016), HIF3A (ENSG00000124440), NPAS1 (ENSG00000130751), NPAS3 (ENSG00000151322), NPAS4 (ENSG00000174576)

Protein

Protein identifiers

Single-minded homolog 2 — Q14190 (reviewed: Q14190)

Alternative names: Class E basic helix-loop-helix protein 15

All UniProt accessions (3): Q14190, H7BZX8, V9GY04

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that may be a master gene of CNS development in cooperation with Arnt. It may have pleiotropic effects in the tissues expressed during development.

Subunit / interactions. Efficient DNA binding requires dimerization with another bHLH protein. Heterodimer of SIM2 and ARNT.

Subcellular location. Nucleus.

Isoforms (2)

UniProt ID	Names	Canonical?
Q14190-1	SIM2	yes
Q14190-2	SIM2S

RefSeq proteins (2): NP_005060, NP_033664 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000014	PAS	Domain
IPR001610	PAC	Repeat
IPR010578	SIM_C	Domain
IPR011598	bHLH_dom	Domain
IPR013655	PAS_fold_3	Domain
IPR013767	PAS_fold	Domain
IPR035965	PAS-like_dom_sf	Homologous_superfamily
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily

Pfam: PF00989, PF06621, PF08447, PF23171

UniProt features (36 total): mutagenesis site 18, domain 5, sequence conflict 3, region of interest 3, compositionally biased region 2, splice variant 2, chain 1, sequence variant 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14190-F1	63.05	0.36

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 (18):

Position	Phenotype
367	reduced nuclear translocation.
368	no effect on nuclear translocation.
369	no effect on nuclear translocation.
370	no effect on nuclear translocation.
371	no effect on nuclear translocation.
372	no effect on nuclear translocation.
373	reduced nuclear translocation.
375	no effect on nuclear translocation.
376	no effect on nuclear translocation.
377	no effect on nuclear translocation.
378	no effect on nuclear translocation.
379	no effect on nuclear translocation.
380	no effect on nuclear translocation.
381	no effect on nuclear translocation.
382	no effect on nuclear translocation.
383	no effect on nuclear translocation.
385	reduced nuclear translocation.
386	reduced nuclear translocation.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 138 (showing top): GCACCTT_MIR18A_MIR18B, BENPORATH_ES_WITH_H3K27ME3, MORF_MSH3, GCANCTGNY_MYOD_Q6, MODULE_16, MORF_RAD51L3, TANG_SENESCENCE_TP53_TARGETS_UP, GOBP_EMBRYONIC_PATTERN_SPECIFICATION, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_5, GOBP_RESPIRATORY_SYSTEM_DEVELOPMENT, GOBP_EMBRYO_DEVELOPMENT, MORF_ATF2, chr21q22, DANG_BOUND_BY_MYC, MORF_BCL2L11

GO Biological Process (9): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of transcription by RNA polymerase II (GO:0006357), nervous system development (GO:0007399), embryonic pattern specification (GO:0009880), cell differentiation (GO:0030154), lung development (GO:0030324), regulation of DNA-templated transcription (GO:0006355), negative regulation of DNA-templated transcription (GO:0045892), system development (GO:0048731)

GO Molecular Function (7): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein heterodimerization activity (GO:0046982), protein binding (GO:0005515), protein dimerization activity (GO:0046983)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), nuclear body (GO:0016604)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
DNA-templated transcription	2
transcription cis-regulatory region binding	2
cellular anatomical structure	2
negative regulation of DNA-templated transcription	1
system development	1
pattern specification process	1
embryo development	1
cellular developmental process	1
respiratory tube development	1
animal organ development	1
respiratory system development	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
negative regulation of RNA biosynthetic process	1
multicellular organism development	1
anatomical structure development	1
chromatin	1
RNA polymerase II transcription regulatory region sequence-specific DNA binding	1
DNA-binding transcription factor activity	1
nucleic acid binding	1
transcription regulator activity	1
protein dimerization activity	1
binding	1
protein binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
nucleoplasm	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

778 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SIM2	ARNT	P27540	601
SIM2	OTP	Q5XKR4	568
SIM2	THSD4	Q6ZMP0	529
SIM2	NPAS4	Q8IUM7	512
SIM2	PIAS1	O75925	508
SIM2	SIX3	O95343	502
SIM2	ACTB	P02570	490
SIM2	ARNT2	Q9HBZ2	485
SIM2	TRH	P20396	467
SIM2	CTSE	P14091	460
SIM2	SUMO1	P55856	448
SIM2	SUMO2	P55855	444
SIM2	HIF1A	Q16665	444
SIM2	TRIM5	Q9C035	443
SIM2	ROS1	P08922	422

IntAct

38 interactions, top by confidence:

A	B	Type	Score
SIM2	PTGES3	psi-mi:“MI:0915”(physical association)	0.570
FOXR2	NME2P1	psi-mi:“MI:0914”(association)	0.530
SIM2	Dlg4	psi-mi:“MI:0407”(direct interaction)	0.440
HSP90AB1	SIM2	psi-mi:“MI:0915”(physical association)	0.400
SIM2	FKBP5	psi-mi:“MI:0915”(physical association)	0.400
MLF1	SIM2	psi-mi:“MI:0915”(physical association)	0.400
Hacd3	SIM2	psi-mi:“MI:0915”(physical association)	0.400
MLF2	SIM2	psi-mi:“MI:0915”(physical association)	0.400
SIM2	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.400
SIM2	BAG4	psi-mi:“MI:0915”(physical association)	0.400
SIM2	NUDC	psi-mi:“MI:0915”(physical association)	0.400
BAG2	SIM2	psi-mi:“MI:0915”(physical association)	0.400
SIM2		psi-mi:“MI:0915”(physical association)	0.400
HSPB1	SIM2	psi-mi:“MI:0915”(physical association)	0.400
NUDCD3	SIM2	psi-mi:“MI:0915”(physical association)	0.400
	SIM2	psi-mi:“MI:0915”(physical association)	0.400
SIM2	PSMD2	psi-mi:“MI:0915”(physical association)	0.400
SGTA	SIM2	psi-mi:“MI:0915”(physical association)	0.400
SIM2	STIP1	psi-mi:“MI:0915”(physical association)	0.400
FKBPL	SIM2	psi-mi:“MI:0915”(physical association)	0.400
SIM2	STUB1	psi-mi:“MI:0915”(physical association)	0.400
CACYBP	SIM2	psi-mi:“MI:0915”(physical association)	0.400
SIM2	AIP	psi-mi:“MI:0915”(physical association)	0.400
AARSD1	SIM2	psi-mi:“MI:0915”(physical association)	0.400
SIM2	PPP5C	psi-mi:“MI:0915”(physical association)	0.400
SIM2	TTC1	psi-mi:“MI:0915”(physical association)	0.400
FOXN1	FOXN1	psi-mi:“MI:0914”(association)	0.350
SIM2	HSPA8	psi-mi:“MI:0914”(association)	0.350
ARNT2	FNTA	psi-mi:“MI:0914”(association)	0.350

BioGRID (52): SIM2 (Affinity Capture-MS), SIM2 (Affinity Capture-MS), SIM2 (Affinity Capture-MS), SIM2 (Affinity Capture-MS), ARNT (Affinity Capture-MS), ARNT2 (Affinity Capture-MS), MAGED1 (Affinity Capture-MS), MATR3 (Affinity Capture-MS), MAGED1 (Affinity Capture-Western), SIM2 (Affinity Capture-Western), SIM2 (Affinity Capture-Western), ARNT (FRET), MAGED1 (FRET), ARNT (Reconstituted Complex), ARNT2 (Reconstituted Complex)

ESM2 similar proteins: A1YFY6, A2T6X9, A6H7I8, B2RUJ5, F1M5F3, F1N2W9, O35430, O35431, O95487, O95628, O95644, P0C6S7, P14316, P17863, P22681, P22682, P23798, P23906, P35227, P81133, P98084, Q02410, Q0IHY4, Q13469, Q14190, Q14432, Q1L994, Q3UR85, Q52L14, Q5CD77, Q5RD33, Q60591, Q61045, Q61079, Q66JB6, Q69ZT9, Q6NRE7, Q6QB00, Q8BIZ1, Q8BT14

Diamond homologs: A1YFY6, A2T6X9, A9YTQ3, O09000, O35800, P05709, P81133, P97459, P97481, Q0PGG7, Q0VBL6, Q14190, Q16665, Q24119, Q24167, Q309Z6, Q61045, Q61079, Q61221, Q8IXF0, Q98SJ5, Q98SW2, Q99742, Q99814, Q9I8A9, Q9JHS1, Q9JHS2, Q9QZQ0, Q9XTA5, Q9Y2N7, Q9YIB9, E7FFX1, O02747, O44712, O57539, O61734, P30561, P35869, P41738, P70365

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
SIM2	“up-regulates activity”	ARNT	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 33 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	5	44.0×	8e-06
Cellular responses to stress	5	8.4×	4e-03
Cellular responses to stimuli	5	7.2×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein folding	10	35.6×	3e-11
protein stabilization	5	11.5×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	84
Likely benign	5
Benign	3

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1334899	NM_005069.6(SIM2):c.461A>G (p.Tyr154Cys)	Likely pathogenic

SpliceAI

2379 predictions. Top by Δscore:

Variant	Effect	Δscore
21:36699919:AAG:A	donor_loss	1.0000
21:36699921:GG:G	donor_loss	1.0000
21:36699923:T:A	donor_loss	1.0000
21:36712832:T:A	acceptor_gain	1.0000
21:36718661:G:GT	donor_gain	1.0000
21:36726117:A:AG	acceptor_gain	1.0000
21:36726117:AGG:A	acceptor_loss	1.0000
21:36726118:G:C	acceptor_loss	1.0000
21:36726118:G:GG	acceptor_gain	1.0000
21:36726314:TCCAG:T	donor_loss	1.0000
21:36726315:CCAG:C	donor_loss	1.0000
21:36726316:CAGG:C	donor_loss	1.0000
21:36726318:GGTG:G	donor_loss	1.0000
21:36726320:T:A	donor_loss	1.0000
21:36731147:CCTCC:C	donor_gain	1.0000
21:36731152:G:GG	donor_gain	1.0000
21:36741715:A:AG	acceptor_gain	1.0000
21:36741716:G:GG	acceptor_gain	1.0000
21:36741716:GT:G	acceptor_gain	1.0000
21:36741837:GCATC:G	donor_gain	1.0000
21:36741842:G:GG	donor_gain	1.0000
21:36747663:A:AG	acceptor_gain	1.0000
21:36747664:G:GG	acceptor_gain	1.0000
21:36747664:GC:G	acceptor_gain	1.0000
21:36712833:G:A	acceptor_gain	0.9900
21:36723043:A:AG	acceptor_gain	0.9900
21:36723044:G:GG	acceptor_gain	0.9900
21:36723044:GA:G	acceptor_gain	0.9900
21:36726118:GGTC:G	acceptor_gain	0.9900
21:36726258:AC:A	donor_gain	0.9900

AlphaMissense

4311 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:36699764:G:C	K6N	1.000
21:36699764:G:T	K6N	1.000
21:36699772:C:A	A9D	1.000
21:36699780:A:G	R12G	1.000
21:36699781:G:C	R12T	1.000
21:36699781:G:T	R12M	1.000
21:36699782:G:C	R12S	1.000
21:36699782:G:T	R12S	1.000
21:36699783:A:G	R13G	1.000
21:36699784:G:C	R13T	1.000
21:36699784:G:T	R13M	1.000
21:36699785:G:C	R13S	1.000
21:36699785:G:T	R13S	1.000
21:36699792:G:A	E16K	1.000
21:36699794:A:C	E16D	1.000
21:36699794:A:T	E16D	1.000
21:36699797:T:A	N17K	1.000
21:36699797:T:G	N17K	1.000
21:36699804:T:C	F20L	1.000
21:36699805:T:C	F20S	1.000
21:36699805:T:G	F20C	1.000
21:36699806:T:A	F20L	1.000
21:36699806:T:G	F20L	1.000
21:36699814:T:A	L23H	1.000
21:36699814:T:C	L23P	1.000
21:36699816:G:C	A24P	1.000
21:36699817:C:A	A24D	1.000
21:36699823:T:C	L26P	1.000
21:36699826:T:A	L27H	1.000
21:36699826:T:C	L27P	1.000

dbSNP variants (sampled 300 via entrez): RS1000030674 (21:36706578 G>A,T), RS1000120358 (21:36733228 C>A), RS1000134758 (21:36701851 C>T), RS1000159034 (21:36737822 G>A), RS1000209563 (21:36722257 A>G), RS1000212076 (21:36743916 C>T), RS1000285147 (21:36705742 C>A,T), RS1000314859 (21:36738086 G>A), RS1000321781 (21:36701354 T>C), RS1000387091 (21:36711566 G>A,T), RS1000408836 (21:36733001 C>T), RS1000441853 (21:36705942 T>C,G), RS1000538423 (21:36747280 T>C), RS1000588679 (21:36701161 T>A), RS1000607600 (21:36741994 T>C)

Disease associations

OMIM: gene MIM:600892 | 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
GCST002322_19	Asthma and hay fever	2.000000e-06
GCST003542_70	Night sleep phenotypes	1.000000e-06
GCST004601_205	Red blood cell count	2.000000e-11
GCST004604_2	Hematocrit	7.000000e-13
GCST004615_134	Hemoglobin concentration	2.000000e-11
GCST009203_14	Cerebellum cortex volume	9.000000e-06
GCST010083_63	Hemoglobin levels	2.000000e-21
GCST90000025_698	Appendicular lean mass	8.000000e-21
GCST90002383_321	Hematocrit	2.000000e-10
GCST90002384_490	Hemoglobin	1.000000e-09

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0007827	nighttime rest measurement
EFO:0004305	erythrocyte count
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0004980	appendicular lean mass

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, decreases expression, increases abundance, increases expression	4
bisphenol A	affects cotreatment, decreases methylation, increases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Nickel	decreases expression	2
Valproic Acid	affects cotreatment, decreases expression	2
geraniol	increases expression	1
ethyl-p-hydroxybenzoate	increases expression	1
trichostatin A	decreases expression	1
arsenite	increases methylation	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	increases expression	1
aflatoxin B2	increases methylation	1
cupric oxide	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Arsenic	increases abundance, increases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Clozapine	decreases expression	1
Estradiol	increases expression	1
Lipopolysaccharides	affects response to substance, increases expression	1
Methapyrilene	increases methylation	1
Silicon Dioxide	decreases expression	1
Smoke	increases expression	1
Vanadates	decreases expression	1
Particulate Matter	increases expression	1

Clinical trials (associated diseases)

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