SCML4

Summary

SCML4 (Scm polycomb group protein like 4, HGNC:21397) is a protein-coding gene on chromosome 6q21, encoding Sex comb on midleg-like protein 4 (Q8N228). Putative Polycomb group (PcG) protein.

Predicted to enable chromatin binding activity and histone binding activity. Predicted to be involved in negative regulation of DNA-templated transcription. Predicted to be active in nucleus.

Source: NCBI Gene 256380 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 75 total
• MANE Select transcript: NM_198081

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21397
Approved symbol	SCML4
Name	Scm polycomb group protein like 4
Location	6q21
Locus type	gene with protein product
Status	Approved
Aliases	dJ47M23.1
Ensembl gene	ENSG00000146285
Ensembl biotype	protein_coding
Entrez	256380

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 9 protein_coding, 4 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000369020, ENST00000369022, ENST00000369025, ENST00000426221, ENST00000440927, ENST00000459992, ENST00000463507, ENST00000473515, ENST00000476798, ENST00000479803, ENST00000909485, ENST00000909486, ENST00000909487, ENST00000909488, ENST00000909489

RefSeq mRNA: 3 — MANE Select: NM_198081 NM_001286408, NM_001286409, NM_198081

CCDS: CCDS5060, CCDS69163, CCDS75500

Canonical transcript exons

ENST00000369020 — 8 exons

Exon	Start	End
ENSE00001448615	107772172	107772386
ENSE00001448631	107707866	107708011
ENSE00001894257	107702154	107705325
ENSE00003475930	107746689	107746889
ENSE00003493212	107720703	107720993
ENSE00003633436	107749684	107749813
ENSE00003786544	107744949	107745143
ENSE00003844249	107824126	107824313

Expression profiles

Bgee: expression breadth ubiquitous, 173 present calls, max score 87.43.

FANTOM5 (CAGE): breadth broad, TPM avg 3.6941 / max 269.0466, expressed in 216 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
74936	2.0118	164
74939	0.5826	60
74933	0.3195	64
74929	0.2584	72
74937	0.1763	68
74935	0.0823	45
74938	0.0823	53
74940	0.0729	28
74932	0.0714	22
74934	0.0365	22

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	87.43	gold quality
blood	UBERON:0000178	86.95	gold quality
jejunal mucosa	UBERON:0000399	83.02	gold quality
lymph node	UBERON:0000029	82.71	gold quality
thymus	UBERON:0002370	82.51	gold quality
duodenum	UBERON:0002114	80.57	gold quality
vermiform appendix	UBERON:0001154	79.33	gold quality
spleen	UBERON:0002106	78.91	gold quality
small intestine Peyer’s patch	UBERON:0003454	77.06	gold quality
small intestine	UBERON:0002108	76.17	gold quality
caecum	UBERON:0001153	75.97	gold quality
mucosa of transverse colon	UBERON:0004991	73.59	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	72.37	gold quality
bone marrow cell	CL:0002092	72.16	gold quality
bone marrow	UBERON:0002371	70.57	gold quality
superficial temporal artery	UBERON:0001614	70.37	gold quality
colonic epithelium	UBERON:0000397	70.12	gold quality
tonsil	UBERON:0002372	69.15	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	68.89	gold quality
rectum	UBERON:0001052	68.64	gold quality
left testis	UBERON:0004533	68.57	gold quality
right lobe of liver	UBERON:0001114	68.29	gold quality
jejunum	UBERON:0002115	68.19	gold quality
gall bladder	UBERON:0002110	67.60	gold quality
right testis	UBERON:0004534	67.57	gold quality
epithelium of nasopharynx	UBERON:0001951	66.74	gold quality
amniotic fluid	UBERON:0000173	66.70	gold quality
testis	UBERON:0000473	66.16	gold quality
upper lobe of left lung	UBERON:0008952	64.29	gold quality
upper lobe of lung	UBERON:0008948	64.08	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-CURD-46	yes	29.83
E-CURD-122	yes	28.82
E-ANND-3	yes	13.07
E-MTAB-9067	yes	5.45
E-MTAB-7606	no	893.91

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

96 targeting SCML4, 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-3120-5P	100.00	65.56	965
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-10395-5P	99.86	67.35	676
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-3663-3P	99.84	70.39	798
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-3133	99.81	70.92	3506

Literature-anchored findings (GeneRIF, showing 1)

• SCML4 and THSD7A are identified as novel susceptibility genes for coronary artery disease. (PMID:29472232)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	scml4	ENSDARG00000017266
mus_musculus	Scml4	ENSMUSG00000044770
rattus_norvegicus	Scml4	ENSRNOG00000026110
drosophila_melanogaster	l(3)mbt	FBGN0002441
drosophila_melanogaster	Sfmbt	FBGN0032475
caenorhabditis_elegans	lin-61	WBGENE00003041
caenorhabditis_elegans	mbtr-1	WBGENE00021661

Paralogs (18): SCMH1 (ENSG00000010803), MBTD1 (ENSG00000011258), SCML1 (ENSG00000047634), L3MBTL2 (ENSG00000100395), SCML2 (ENSG00000102098), PHC1 (ENSG00000111752), THAP10 (ENSG00000129028), PHC2 (ENSG00000134686), SAMD1 (ENSG00000141858), L3MBTL4 (ENSG00000154655), SFMBT1 (ENSG00000163935), PHC3 (ENSG00000173889), L3MBTL1 (ENSG00000185513), SAMD7 (ENSG00000187033), SAMD11 (ENSG00000187634), SFMBT2 (ENSG00000198879), L3MBTL3 (ENSG00000198945), SAMD13 (ENSG00000203943)

Protein

Protein identifiers

Sex comb on midleg-like protein 4 — Q8N228 (reviewed: Q8N228)

All UniProt accessions (3): Q8N228, A0A0B4J1S9, Q5T0T5

UniProt curated annotations — full annotation on UniProt →

Function. Putative Polycomb group (PcG) protein. PcG proteins act by forming multiprotein complexes, which are required to maintain the transcriptionally repressive state of homeotic genes throughout development.

Subcellular location. Nucleus.

Similarity. Belongs to the SCM family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8N228-1	1	yes
Q8N228-2	2
Q8N228-3	3

RefSeq proteins (3): NP_001273337, NP_001273338, NP_932347* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001660	SAM	Domain
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR021987	SLED	Domain
IPR033763	SCML2_RBR	Domain
IPR038348	SLED_sf	Homologous_superfamily
IPR047531	SAM_Scm-like	Domain
IPR050548	PcG_chromatin_remod_factors	Family

Pfam: PF00536, PF12140, PF17208

UniProt features (13 total): splice variant 4, compositionally biased region 3, modified residue 2, chain 1, domain 1, sequence variant 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N228-F1	69.85	0.43

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 (2): 55, 65

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 189 (showing top): NKX25_02, TGCTGAY_UNKNOWN, GATA1_01, HP1SITEFACTOR_Q6, OCT1_07, ZHOU_INFLAMMATORY_RESPONSE_LIVE_DN, YY1_01, IK3_01, OCT1_B, GOMF_CHROMATIN_BINDING, ZHENG_BOUND_BY_FOXP3, MARSON_BOUND_BY_FOXP3_UNSTIMULATED, ZHENG_FOXP3_TARGETS_IN_T_LYMPHOCYTE_DN, GOMF_HISTONE_BINDING, E4BP4_01

GO Biological Process (1): negative regulation of DNA-templated transcription (GO:0045892)

GO Molecular Function (3): chromatin binding (GO:0003682), histone binding (GO:0042393), protein binding (GO:0005515)

GO Cellular Component (1): nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
protein binding	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

506 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SCML4	LRRC61	Q9BV99	475
SCML4	MCC	P23508	438
SCML4	NWD2	Q9ULI1	428
SCML4	GGA3	Q9NZ52	419
SCML4	QRSL1	Q9H0R6	405
SCML4	RTN4IP1	Q8WWV3	404
SCML4	PXYLP1	Q8TE99	397
SCML4	BEND3	Q5T5X7	395
SCML4	TSC22D2	O75157	376
SCML4	ZNF367	Q7RTV3	372
SCML4	AP5M1	Q9H0R1	371
SCML4	NEK10	Q6ZWH5	371
SCML4	ATAD2B	Q9ULI0	369
SCML4	MEX3A	A1L020	364
SCML4	OSTM1	Q86WC4	362

IntAct

2 interactions, top by confidence:

A	B	Type	Score
SCML4	KDM5C	psi-mi:“MI:0914”(association)	0.350

BioGRID (12): UBR1 (Affinity Capture-MS), FBXO11 (Affinity Capture-MS), KDM5C (Affinity Capture-MS), UBR1 (Affinity Capture-MS), KDM5C (Affinity Capture-MS), FBXO11 (Affinity Capture-MS), SCML4 (Two-hybrid), CLIC3 (Two-hybrid), FBXO11 (Affinity Capture-MS), UBR1 (Affinity Capture-MS), KDM5C (Affinity Capture-MS), CHCHD3 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A0G2JTY4, A2VD01, A5PMU4, A8E4V2, D2HNW6, E1BEQ5, O54972, O95644, P16236, P59281, P70365, P97305, Q12968, Q13191, Q13469, Q13905, Q15788, Q1LY51, Q2VPU4, Q3LRZ1, Q3TTA7, Q3U182, Q4PJW2, Q4VCS5, Q60591, Q61122, Q66IV1, Q68FF7, Q6DFR2, Q6GQL0, Q6NYU6, Q6ZNC4, Q80TM6, Q80VG1, Q8HWS3, Q8IXK0, Q8IY63, Q8K4S7, Q8N228, Q8VHG2

Diamond homologs: B0FZN7, B0FZN8, B0FZN9, B0FZP0, B0FZP1, B0FZP2, B0FZP3, P78364, Q5DTW2, Q5VUG0, Q64028, Q80VG1, Q8CHP6, Q8K214, Q8N228, Q8NDX5, Q8QHL5, Q96GD3, Q9JMD1, Q9JMD2, Q9UHJ3, Q9UN30, Q9UQR0, Q9VHA0, Q9VK33, Q29L50, Q4V7W5, Q8IXK0, Q9QWH1, A2A5N8, B1B1A0, D3YUG0, D3YXK1, D3ZWK4, E1C2V1, P39769, P59178, P70047, Q05BQ5, Q1JQD9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	59
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

2361 predictions. Top by Δscore:

Variant	Effect	Δscore
6:107705341:C:CT	acceptor_gain	1.0000
6:107705342:A:T	acceptor_gain	1.0000
6:107707854:CCA:C	donor_gain	1.0000
6:107707864:A:AC	donor_gain	1.0000
6:107707865:C:CC	donor_gain	1.0000
6:107707865:CGTG:C	donor_gain	1.0000
6:107708007:TGAGG:T	acceptor_gain	1.0000
6:107708010:GG:G	acceptor_gain	1.0000
6:107708011:GC:G	acceptor_loss	1.0000
6:107708012:C:CA	acceptor_loss	1.0000
6:107708012:C:CC	acceptor_gain	1.0000
6:107708013:T:C	acceptor_loss	1.0000
6:107744943:GCCTA:G	donor_loss	1.0000
6:107744944:CCTA:C	donor_loss	1.0000
6:107744945:CTA:C	donor_loss	1.0000
6:107744946:TA:T	donor_loss	1.0000
6:107744947:ACC:A	donor_loss	1.0000
6:107744948:CCT:C	donor_loss	1.0000
6:107744966:T:TA	donor_gain	1.0000
6:107745139:CGAGA:C	acceptor_gain	1.0000
6:107745143:AC:A	acceptor_loss	1.0000
6:107745144:C:CC	acceptor_gain	1.0000
6:107745144:C:CG	acceptor_loss	1.0000
6:107746703:C:CT	donor_gain	1.0000
6:107746710:AGC:A	donor_gain	1.0000
6:107746719:TG:T	donor_gain	1.0000
6:107789432:T:A	donor_gain	1.0000
6:107705321:ATCTC:A	acceptor_gain	0.9900
6:107705323:CTC:C	acceptor_gain	0.9900
6:107705324:TC:T	acceptor_gain	0.9900

AlphaMissense

2676 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:107705315:C:T	G377D	1.000
6:107705240:A:G	L402P	0.999
6:107705242:T:A	K401N	0.999
6:107705242:T:G	K401N	0.999
6:107705246:A:G	L400P	0.999
6:107705264:A:G	L394P	0.999
6:107705297:A:G	L383P	0.999
6:107705306:A:G	L380P	0.999
6:107705315:C:A	G377V	0.999
6:107705316:C:A	G377C	0.999
6:107705321:A:C	I375S	0.999
6:107705321:A:T	I375N	0.999
6:107707876:A:G	F370S	0.999
6:107707949:A:G	W346R	0.999
6:107707949:A:T	W346R	0.999
6:107746772:A:T	V135D	0.999
6:107705240:A:T	L402H	0.998
6:107705256:C:G	G397R	0.998
6:107705256:C:T	G397R	0.998
6:107705306:A:T	L380Q	0.998
6:107705309:G:T	A379D	0.998
6:107705316:C:G	G377R	0.998
6:107705318:T:A	D376V	0.998
6:107705321:A:G	I375T	0.998
6:107707923:A:C	F354L	0.998
6:107707923:A:T	F354L	0.998
6:107707925:A:G	F354L	0.998
6:107707947:C:A	W346C	0.998
6:107707947:C:G	W346C	0.998
6:107705219:A:G	L409P	0.997

dbSNP variants (sampled 300 via entrez): RS1000016891 (6:107724991 T>C), RS1000023065 (6:107745769 C>T), RS1000037291 (6:107767252 G>A), RS1000044536 (6:107772651 G>A), RS1000047788 (6:107836528 C>A,T), RS1000062463 (6:107830355 C>T), RS1000137320 (6:107817906 T>G), RS1000155766 (6:107702529 G>A), RS1000160889 (6:107750943 A>C), RS1000177747 (6:107708365 G>A,C), RS1000196184 (6:107733662 C>T), RS1000197444 (6:107817302 A>G), RS1000212740 (6:107751206 G>A,T), RS1000236297 (6:107792028 G>A), RS1000245776 (6:107823818 T>C)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST004627_31	Lymphocyte count	3.000000e-09
GCST004632_52	Lymphocyte percentage of white cells	2.000000e-10
GCST004633_122	Neutrophil percentage of white cells	4.000000e-09
GCST005094_8	Iris color (L* coordinate)	7.000000e-06
GCST005582_2	Coronary artery disease	4.000000e-11
GCST90002388_1	Lymphocyte count	3.000000e-32
GCST90002388_100	Lymphocyte count	2.000000e-09
GCST90002389_330	Lymphocyte percentage of white cells	1.000000e-24
GCST90002389_331	Lymphocyte percentage of white cells	1.000000e-10
GCST90002399_301	Neutrophil percentage of white cells	3.000000e-13
GCST90002399_302	Neutrophil percentage of white cells	4.000000e-09

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004587	lymphocyte count
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0007990	neutrophil percentage of leukocytes
EFO:0003949	eye color

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	decreases expression	2
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation	2
Aflatoxin B1	decreases methylation, increases methylation	2
triphenyl phosphate	affects expression	1
benzo(e)pyrene	increases methylation	1
cylindrospermopsin	decreases expression	1
entinostat	decreases expression	1
Vorinostat	decreases expression	1
Acetaminophen	increases expression	1
Lead	increases expression	1
Methapyrilene	increases methylation	1
Nickel	increases expression	1
Rotenone	decreases expression	1
Tretinoin	decreases expression	1
1-Methyl-4-phenylpyridinium	decreases expression	1
Cyclosporine	decreases expression	1
Antirheumatic Agents	decreases expression	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

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