SMTNL2

Summary

SMTNL2 (smoothelin like 2, HGNC:24764) is a protein-coding gene on chromosome 17p13.2, encoding Smoothelin-like protein 2 (Q2TAL5).

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 105 total
• MANE Select transcript: NM_001114974

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24764
Approved symbol	SMTNL2
Name	smoothelin like 2
Location	17p13.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ42461
Ensembl gene	ENSG00000188176
Ensembl biotype	protein_coding
Entrez	342527

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 7 protein_coding, 1 retained_intron

ENST00000338859, ENST00000389313, ENST00000570526, ENST00000572951, ENST00000906960, ENST00000965180, ENST00000965181, ENST00000965182

RefSeq mRNA: 3 — MANE Select: NM_001114974 NM_001114974, NM_001375361, NM_198501

CCDS: CCDS11048, CCDS45583

Canonical transcript exons

ENST00000389313 — 8 exons

Exon	Start	End
ENSE00001367123	4597172	4597323
ENSE00001370771	4596860	4596977
ENSE00001372643	4592929	4593171
ENSE00001375908	4595145	4595327
ENSE00001378060	4607361	4608319
ENSE00001387116	4593822	4593897
ENSE00001505505	4584529	4585004
ENSE00003591779	4592361	4592448

Expression profiles

Bgee: expression breadth ubiquitous, 177 present calls, max score 99.00.

FANTOM5 (CAGE): breadth broad, TPM avg 1.8910 / max 214.2192, expressed in 375 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
158904	1.6102	313
158903	0.2331	139
158902	0.0476	18

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gastrocnemius	UBERON:0001388	99.00	gold quality
tibialis anterior	UBERON:0001385	98.73	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.44	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.03	gold quality
skeletal muscle tissue	UBERON:0001134	97.87	gold quality
quadriceps femoris	UBERON:0001377	97.87	gold quality
vastus lateralis	UBERON:0001379	97.72	gold quality
biceps brachii	UBERON:0001507	97.47	gold quality
muscle of leg	UBERON:0001383	97.40	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	96.40	gold quality
deltoid	UBERON:0001476	96.36	gold quality
muscle tissue	UBERON:0002385	94.54	gold quality
kidney epithelium	UBERON:0004819	94.51	gold quality
metanephros cortex	UBERON:0010533	91.60	gold quality
left ventricle myocardium	UBERON:0006566	90.46	silver quality
cardiac muscle of right atrium	UBERON:0003379	90.23	gold quality
body of tongue	UBERON:0011876	89.37	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.33	gold quality
adult mammalian kidney	UBERON:0000082	89.24	gold quality
kidney	UBERON:0002113	86.49	gold quality
renal medulla	UBERON:0000362	86.45	gold quality
apex of heart	UBERON:0002098	85.72	gold quality
heart left ventricle	UBERON:0002084	84.86	gold quality
metanephros	UBERON:0000081	84.66	gold quality
cardiac ventricle	UBERON:0002082	84.39	gold quality
cortex of kidney	UBERON:0001225	84.29	gold quality
tongue	UBERON:0001723	81.17	gold quality
left uterine tube	UBERON:0001303	80.02	gold quality
heart	UBERON:0000948	79.20	gold quality
parietal pleura	UBERON:0002400	79.17	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-9388	yes	5.75
E-MTAB-8060	no	39.77
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

48 targeting SMTNL2, 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-7110-3P	100.00	73.18	2486
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-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-1184	99.99	68.19	1458
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-5682	99.89	72.56	1005
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832

Literature-anchored findings (GeneRIF, showing 3)

• Study describes a novel JNK substrate that emerged from analysis of the human genome, the functionally uncharacterized protein smoothelin-like 2 (SMTNL2). SMTNL2 protein bound with high-affinity to multiple MAPKs including JNK1-3 and ERK2; SMTNL2 protein was expressed in many mammalian tissues, with a notably high expression in skeletal muscle. (PMID:23981301)
• Variants of SMTNL2 were associated with rheumatoid arthritis in an Arab population. (PMID:28118524)
• Smoothelin-like 2 Inhibits Coronin-1B to Stabilize the Apical Actin Cortex during Epithelial Morphogenesis. (PMID:33275893)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	smtnl	ENSDARG00000055632
mus_musculus	Smtnl2	ENSMUSG00000045667
rattus_norvegicus	Smtnl2	ENSRNOG00000015157
caenorhabditis_elegans		WBGENE00020530

Paralogs (36): SYNE2 (ENSG00000054654), SPTB (ENSG00000070182), ACTN1 (ENSG00000072110), ACTN2 (ENSG00000077522), DSP (ENSG00000096696), DRP2 (ENSG00000102385), SPTBN1 (ENSG00000115306), MACF1 (ENSG00000127603), FLNC (ENSG00000128591), ACTN4 (ENSG00000130402), SYNE1 (ENSG00000131018), MICAL2 (ENSG00000133816), DTNA (ENSG00000134769), MICAL1 (ENSG00000135596), FLNB (ENSG00000136068), SPTBN5 (ENSG00000137877), DTNB (ENSG00000138101), GAS2L3 (ENSG00000139354), DST (ENSG00000151914), UTRN (ENSG00000152818), SPTBN4 (ENSG00000160460), SPTA1 (ENSG00000163554), CLMN (ENSG00000165959), PKHD1 (ENSG00000170927), SPTBN2 (ENSG00000173898), SYNE3 (ENSG00000176438), PLEC (ENSG00000178209), FLNA (ENSG00000196924), SPTAN1 (ENSG00000197694), DMD (ENSG00000198947), PKHD1L1 (ENSG00000205038), DYTN (ENSG00000232125), MICAL3 (ENSG00000243156), ACTN3 (ENSG00000248746), EPPK1 (ENSG00000261150), GAS2L2 (ENSG00000270765)

Protein

Protein identifiers

Smoothelin-like protein 2 — Q2TAL5 (reviewed: Q2TAL5)

All UniProt accessions (2): Q2TAL5, I3L3R4

UniProt curated annotations — full annotation on UniProt →

Similarity. Belongs to the smoothelin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q2TAL5-1	1	yes
Q2TAL5-2	2

RefSeq proteins (3): NP_001108446, NP_001362290, NP_940903 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001715	CH_dom	Domain
IPR036872	CH_dom_sf	Homologous_superfamily
IPR050540	F-actin_Monoox_Mical	Family

Pfam: PF00307

UniProt features (22 total): modified residue 9, compositionally biased region 4, region of interest 3, sequence variant 2, chain 1, domain 1, splice variant 1, coiled-coil region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q2TAL5-F1	66.65	0.40

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 (9): 96, 101, 129, 134, 256, 269, 274, 278, 344

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 82 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, GCANCTGNY_MYOD_Q6, GGGTGGRR_PAX4_03, CATRRAGC_UNKNOWN, NKX62_Q2, NF1_Q6_01, WTGAAAT_UNKNOWN, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_DN, E12_Q6, LEE_AGING_CEREBELLUM_DN, TGGAAA_NFAT_Q4_01, YGCGYRCGC_UNKNOWN, ZF5_01, CDC5_01, MEISSNER_BRAIN_HCP_WITH_H3K4ME3_AND_H3K27ME3

GO Biological Process (0):

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

GO Cellular Component (0):

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	1

Protein interactions and networks

STRING

594 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SMTNL2	ZNHIT3	Q15649	591
SMTNL2	FAM110D	Q8TAY7	469
SMTNL2	EMC3	Q9P0I2	463
SMTNL2	ABLIM2	Q6H8Q1	461
SMTNL2	WDR37	Q9Y2I8	453
SMTNL2	TMEM14B	Q9NUH8	438
SMTNL2	RMND5A	Q9H871	437
SMTNL2	UTS2R	Q9UKP6	422
SMTNL2	RASL10B	Q96S79	419
SMTNL2	SCPEP1	Q9HB40	414
SMTNL2	ZNF483	Q8TF39	403
SMTNL2	CCDC74A	Q96AQ1	401
SMTNL2	LRCH3	Q96II8	397
SMTNL2	HAPLN2	Q9GZV7	396
SMTNL2	MESD	Q14696	382

IntAct

29 interactions, top by confidence:

A	B	Type	Score
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAQ	IGLC7	psi-mi:“MI:0914”(association)	0.530
NUP62	RGPD8	psi-mi:“MI:0914”(association)	0.530
SMTNL2	CCNA2	psi-mi:“MI:0914”(association)	0.530
PTPRD	SMTNL2	psi-mi:“MI:0407”(direct interaction)	0.440
SMTNL2	LRRK2	psi-mi:“MI:0407”(direct interaction)	0.440
SMTNL2	MFHAS1	psi-mi:“MI:0407”(direct interaction)	0.440
PPP1CA	ACO2	psi-mi:“MI:0914”(association)	0.350
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
YWHAG	C1orf226	psi-mi:“MI:0914”(association)	0.350
YWHAB	FOXO6	psi-mi:“MI:0914”(association)	0.350
YWHAG	FOXO6	psi-mi:“MI:0914”(association)	0.350
YWHAQ	FOXO6	psi-mi:“MI:0914”(association)	0.350
ENTHD1	C1orf226	psi-mi:“MI:0914”(association)	0.350
RIPPLY3	A2ML1	psi-mi:“MI:0914”(association)	0.350
ZNF154	A2ML1	psi-mi:“MI:0914”(association)	0.350
TSPAN6	IMPA2	psi-mi:“MI:0914”(association)	0.350
KRT7	NEFL	psi-mi:“MI:0914”(association)	0.350
S100A8	GOT1	psi-mi:“MI:0914”(association)	0.350
EGFL8	IGLC7	psi-mi:“MI:0914”(association)	0.350
APTX	A2ML1	psi-mi:“MI:0914”(association)	0.350
UPK1A	A2ML1	psi-mi:“MI:0914”(association)	0.350
FBXL16	STK25	psi-mi:“MI:0914”(association)	0.350
IL5RA	LETM1	psi-mi:“MI:0914”(association)	0.350
SMTNL2	ADCY9	psi-mi:“MI:0914”(association)	0.350
STRIP2	OXSR1	psi-mi:“MI:0914”(association)	0.350
SMTNL2	flaN	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (46): SMTNL2 (Affinity Capture-MS), CCNA2 (Affinity Capture-MS), SKP2 (Affinity Capture-MS), YWHAZ (Affinity Capture-MS), SMTNL2 (Affinity Capture-MS), YWHAG (Affinity Capture-MS), YWHAE (Affinity Capture-MS), YWHAH (Affinity Capture-MS), CDK2 (Affinity Capture-MS), YWHAB (Affinity Capture-MS), SFN (Affinity Capture-MS), YWHAQ (Affinity Capture-MS), SMTNL2 (Affinity Capture-MS), NLN (Affinity Capture-MS), CUL1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0U1RR37, A1L170, A1L1I3, A1L260, A2AMM0, A4IFJ0, B5G1P1, D3ZQL6, E7F5E1, G5BQH4, O08919, O54724, O60237, O75420, P06759, P33622, P53814, P85125, Q2KI85, Q2TAL5, Q3T044, Q3UMT1, Q4RTJ5, Q4V882, Q5I1X5, Q5U2R6, Q63312, Q6NZI2, Q75AS0, Q80VC9, Q8BG95, Q8BGT6, Q8C0J6, Q8CI12, Q8IV56, Q8K382, Q8N3F8, Q8TEH3, Q8WUF5, Q91VJ2

Diamond homologs: A5D7D1, A8MU46, D3ZEN0, D3ZHV2, D3ZQL6, D4A1F2, E1BBG2, E7F9T0, F1MF74, F1QH17, F1QWK4, F1RA39, F6QZ15, G3MWR8, G3V7L1, L7UZ85, M9MRD1, O13728, O15020, O43707, O76329, O88990, O94851, O97592, P05094, P05095, P11277, P11530, P11531, P11532, P11533, P12814, P15508, P18091, P20111, P30427, P35609, P46939, P53814, P57780

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 37 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
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	5	146.0×	4e-08
Cell Cycle Checkpoints	5	19.2×	2e-04
RHO GTPase Effectors	5	14.8×	3e-04
Transcriptional Regulation by TP53	5	13.5×	4e-04
Signaling by Rho GTPases	6	8.9×	5e-04
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	6	8.7×	5e-04
Cell Cycle	5	7.8×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
intracellular protein localization	5	15.4×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	96
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1666 predictions. Top by Δscore:

Variant	Effect	Δscore
17:4593818:ACAG:A	acceptor_loss	1.0000
17:4593819:C:G	acceptor_gain	1.0000
17:4593819:CA:C	acceptor_loss	1.0000
17:4593820:A:AG	acceptor_gain	1.0000
17:4593821:G:GC	acceptor_gain	1.0000
17:4593821:G:GT	acceptor_loss	1.0000
17:4593821:GA:G	acceptor_gain	1.0000
17:4593821:GAGAA:G	acceptor_gain	1.0000
17:4593895:TAGG:T	donor_loss	1.0000
17:4593897:GGT:G	donor_loss	1.0000
17:4593898:GTGA:G	donor_loss	1.0000
17:4593899:T:G	donor_loss	1.0000
17:4595328:G:GG	donor_gain	1.0000
17:4596975:CAGGT:C	donor_loss	1.0000
17:4596976:AGGT:A	donor_loss	1.0000
17:4596977:GGTG:G	donor_loss	1.0000
17:4596978:G:C	donor_loss	1.0000
17:4597168:GCAGC:G	acceptor_loss	1.0000
17:4597170:A:AG	acceptor_gain	1.0000
17:4597170:AG:A	acceptor_loss	1.0000
17:4597170:AGCAC:A	acceptor_gain	1.0000
17:4597171:G:GA	acceptor_gain	1.0000
17:4597171:GC:G	acceptor_gain	1.0000
17:4597171:GCA:G	acceptor_gain	1.0000
17:4597171:GCAC:G	acceptor_gain	1.0000
17:4597171:GCACG:G	acceptor_gain	1.0000
17:4597319:GCCGA:G	donor_gain	1.0000
17:4597320:CCGA:C	donor_gain	1.0000
17:4597321:CGA:C	donor_gain	1.0000
17:4597322:GA:G	donor_gain	1.0000

AlphaMissense

2988 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:4597202:T:A	W380R	1.000
17:4597202:T:C	W380R	1.000
17:4597204:G:C	W380C	1.000
17:4597204:G:T	W380C	1.000
17:4597212:G:T	G383V	1.000
17:4596948:T:A	W360R	0.999
17:4596948:T:C	W360R	0.999
17:4596950:G:C	W360C	0.999
17:4596950:G:T	W360C	0.999
17:4596953:C:G	C361W	0.999
17:4597189:C:A	N375K	0.999
17:4597189:C:G	N375K	0.999
17:4597190:T:C	F376L	0.999
17:4597191:T:C	F376S	0.999
17:4597192:C:A	F376L	0.999
17:4597192:C:G	F376L	0.999
17:4597199:A:C	S379R	0.999
17:4597201:C:A	S379R	0.999
17:4597201:C:G	S379R	0.999
17:4597203:G:C	W380S	0.999
17:4597211:G:C	G383R	0.999
17:4597211:G:T	G383C	0.999
17:4597212:G:A	G383D	0.999
17:4597221:T:C	F386S	0.999
17:4597227:C:A	A388D	0.999
17:4597310:T:C	F416L	0.999
17:4597311:T:C	F416S	0.999
17:4597312:C:A	F416L	0.999
17:4597312:C:G	F416L	0.999
17:4607438:T:A	V446D	0.999

dbSNP variants (sampled 300 via entrez): RS1000064013 (17:4582635 G>A), RS1000156122 (17:4587773 T>C), RS1000267080 (17:4599127 C>T), RS1000366820 (17:4592891 A>C,G), RS1000486716 (17:4593116 G>A,T), RS1000531767 (17:4597775 A>G), RS1000543955 (17:4598115 G>A), RS1000616526 (17:4587452 G>A), RS1000750810 (17:4603191 A>G), RS1000751976 (17:4602855 G>A), RS1000921554 (17:4590703 C>T), RS1000951492 (17:4594906 G>T), RS1001009918 (17:4583864 A>G), RS1001135580 (17:4608758 T>C), RS1001228062 (17:4588834 G>A)

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

4 associations (top):

Study	Trait	p-value
GCST003141_4	Proteinuria and chronic kidney disease	3.000000e-06
GCST004172_3	Rheumatoid arthritis	7.000000e-07
GCST004174_3	Rheumatoid arthritis (rheumatoid factor and/or anti-cyclic citrullinated peptide seropositive)	6.000000e-09
GCST005038_95	Allergic disease (asthma, hay fever or eczema)	2.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007791	rheumatoid factor seropositivity measurement
EFO:0007837	anti-citrullinated protein antibody seropositivity

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, increases methylation, affects expression	4
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation, increases methylation	3
Estradiol	affects binding, increases expression	2
methylmercuric chloride	decreases expression	1
trichostatin A	increases expression	1
dimethylselenide	increases expression, increases oxidation	1
butyraldehyde	increases expression	1
benzo(e)pyrene	decreases methylation	1
nutlin 3	affects cotreatment, increases expression	1
abrine	increases expression	1
jinfukang	increases expression, affects cotreatment	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Arsenic	affects methylation	1
Camptothecin	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Lead	affects expression	1
Methapyrilene	decreases methylation	1
Ozone	increases expression, increases oxidation	1
Plant Extracts	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	decreases expression	1
1-Methyl-4-phenylpyridinium	increases expression	1
Asbestos, Crocidolite	affects expression	1
Okadaic Acid	increases expression	1

Clinical trials (associated diseases)

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