NHSL2

Summary

NHSL2 (NHS like 2, HGNC:33737) is a protein-coding gene on chromosome Xq13.1, encoding NHS-like protein 2 (Q5HYW2).

Predicted to enable calcium ion binding activity. Predicted to be involved in cell differentiation. Predicted to be active in cytoplasm.

Source: NCBI Gene 340527 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 282 total
• MANE Select transcript: NM_001013627

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:33737
Approved symbol	NHSL2
Name	NHS like 2
Location	Xq13.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000204131
Ensembl biotype	protein_coding
OMIM	301093
Entrez	340527

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 4 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000373677, ENST00000510661, ENST00000623354, ENST00000631375, ENST00000631833, ENST00000632230, ENST00000633930

RefSeq mRNA: 1 — MANE Select: NM_001013627 NM_001013627

CCDS: CCDS87759

Canonical transcript exons

ENST00000633930 — 8 exons

Exon	Start	End
ENSE00003521799	72134509	72134704
ENSE00003776016	72132079	72132234
ENSE00003776254	72137094	72137225
ENSE00003777256	72143253	72153286
ENSE00003778350	71910845	71911367
ENSE00003778796	72134091	72134218
ENSE00003782430	72138441	72140771
ENSE00003791558	72142232	72142364

Expression profiles

Bgee: expression breadth ubiquitous, 199 present calls, max score 89.64.

FANTOM5 (CAGE): breadth broad, TPM avg 2.8681 / max 81.1340, expressed in 827 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
196708	1.0719	452
196719	0.4491	201
196716	0.2418	75
196721	0.2241	145
196714	0.2226	140
196709	0.1703	79
196717	0.1076	38
196718	0.1019	59
196720	0.0839	45
196715	0.0787	45

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	89.64	gold quality
blood	UBERON:0000178	88.10	gold quality
monocyte	CL:0000576	85.37	gold quality
leukocyte	CL:0000738	85.37	gold quality
saphenous vein	UBERON:0007318	84.43	gold quality
cerebellar vermis	UBERON:0004720	82.83	gold quality
cerebellum	UBERON:0002037	82.28	gold quality
cerebellar cortex	UBERON:0002129	81.96	gold quality
cerebellar hemisphere	UBERON:0002245	81.83	gold quality
colonic epithelium	UBERON:0000397	81.32	gold quality
right hemisphere of cerebellum	UBERON:0014890	80.90	gold quality
granulocyte	CL:0000094	80.88	gold quality
adrenal tissue	UBERON:0018303	80.83	gold quality
smooth muscle tissue	UBERON:0001135	80.00	gold quality
layer of synovial tissue	UBERON:0007616	78.88	gold quality
tibialis anterior	UBERON:0001385	78.11	silver quality
calcaneal tendon	UBERON:0003701	78.11	gold quality
seminal vesicle	UBERON:0000998	77.43	gold quality
tendon	UBERON:0000043	76.81	gold quality
bone marrow cell	CL:0002092	76.29	gold quality
lower esophagus muscularis layer	UBERON:0035833	76.15	gold quality
lower esophagus	UBERON:0013473	76.09	gold quality
gall bladder	UBERON:0002110	75.81	gold quality
skin of hip	UBERON:0001554	75.38	gold quality
right coronary artery	UBERON:0001625	75.24	gold quality
tendon of biceps brachii	UBERON:0008188	75.08	silver quality
descending thoracic aorta	UBERON:0002345	74.89	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	74.88	gold quality
tibial artery	UBERON:0007610	74.83	gold quality
nucleus accumbens	UBERON:0001882	74.81	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.89

Regulation

Is transcription factor: no

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	nhsl2	ENSDARG00000089066
danio_rerio	si:ch73-362m14.2	ENSDARG00000090164
mus_musculus	Nhsl2	ENSMUSG00000079481
rattus_norvegicus	Nhsl2	ENSRNOG00000037951

Paralogs (3): NHSL1 (ENSG00000135540), NHSL3 (ENSG00000162522), NHS (ENSG00000188158)

Protein

Protein identifiers

NHS-like protein 2 — Q5HYW2 (reviewed: Q5HYW2)

All UniProt accessions (3): A0A0J9YW69, A0A0J9YY72, Q5HYW2

UniProt curated annotations — full annotation on UniProt →

Similarity. Belongs to the NHS family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q5HYW2-1	1	yes
Q5HYW2-2	2

RefSeq proteins (1): NP_001013649* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR024845	NHS-like	Family

Pfam: PF15273

UniProt features (30 total): compositionally biased region 13, region of interest 9, modified residue 4, splice variant 2, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5HYW2-F1	48.33	0.06

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 (4): 500, 576, 691, 1054

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 115 (showing top): RNGTGGGC_UNKNOWN, GCANCTGNY_MYOD_Q6, AREB6_03, IVANOVA_HEMATOPOIESIS_MATURE_CELL, RACCACAR_AML_Q6, CAGCTG_AP4_Q5, ATGTTAA_MIR302C, CEBP_Q2, FREAC3_01, RAMALHO_STEMNESS_DN, WTGAAAT_UNKNOWN, ARGGGTTAA_UNKNOWN, CYTAGCAAY_UNKNOWN, HTF_01, TCCAGAT_MIR5165P

GO Biological Process (1): cell differentiation (GO:0030154)

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
cellular developmental process	1
binding	1

Protein interactions and networks

STRING

374 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NHSL2	POLR2M	P0CAP2	482
NHSL2	AP1AR	Q63HQ0	436
NHSL2	OR2T4	Q8NH00	419
NHSL2	ABHD12B	Q7Z5M8	409
NHSL2	RTP1	P59025	407
NHSL2	SAMD10	Q9BYL1	406
NHSL2	CMTM4	Q8IZR5	395
NHSL2	MMRN2	Q9H8L6	390
NHSL2	ARFGEF1	Q9Y6D6	381
NHSL2	RAPGEF5	Q92565	374
NHSL2	BRK1	Q8WUW1	370
NHSL2	COMMD6	Q7Z4G1	364
NHSL2	OR8U1	Q8NH10	348
NHSL2	THSD7A	Q9UPZ6	335
NHSL2	FKBP11	Q9NYL4	335

IntAct

106 interactions, top by confidence:

A	B	Type	Score
NCK2	NHSL2	psi-mi:“MI:0915”(physical association)	0.740
BRK1	HSBP1	psi-mi:“MI:0914”(association)	0.740
NHSL2	NCK1	psi-mi:“MI:0915”(physical association)	0.670
NHSL2	ABI2	psi-mi:“MI:0915”(physical association)	0.670
NHSL2	ABI3	psi-mi:“MI:0915”(physical association)	0.670
NCK1	NHSL2	psi-mi:“MI:0915”(physical association)	0.670
NCK2	SH3PXD2B	psi-mi:“MI:0914”(association)	0.640
NHSL2	PLK1	psi-mi:“MI:0915”(physical association)	0.560
NHSL2	CLIC1	psi-mi:“MI:0915”(physical association)	0.560
MAPK9	NHSL2	psi-mi:“MI:0915”(physical association)	0.560
TRAF2	NHSL2	psi-mi:“MI:0915”(physical association)	0.560
TP53BP2	NHSL2	psi-mi:“MI:0915”(physical association)	0.560
SORBS3	NHSL2	psi-mi:“MI:0915”(physical association)	0.560
NHSL2	PPP1R13B	psi-mi:“MI:0915”(physical association)	0.560
CTTN	NHSL2	psi-mi:“MI:0915”(physical association)	0.560
NHSL2	MTUS2	psi-mi:“MI:0915”(physical association)	0.560
DYNLT1	NHSL2	psi-mi:“MI:0915”(physical association)	0.560
MYO15B	NHSL2	psi-mi:“MI:0915”(physical association)	0.560
NHSL2	ABI1	psi-mi:“MI:0915”(physical association)	0.560
ATXN1	NHSL2	psi-mi:“MI:0915”(physical association)	0.560
YWHAG	NHSL2	psi-mi:“MI:0915”(physical association)	0.560
HSF2BP	NHSL2	psi-mi:“MI:0915”(physical association)	0.560
	NHSL2	psi-mi:“MI:0915”(physical association)	0.560
NHSL2	BTRC	psi-mi:“MI:0915”(physical association)	0.560
INCA1	NHSL2	psi-mi:“MI:0915”(physical association)	0.560
NHSL2	PIH1D2	psi-mi:“MI:0915”(physical association)	0.560
ARID4B	NHSL2	psi-mi:“MI:0915”(physical association)	0.560

ESM2 similar proteins: A0A096MK47, A0JNH1, A6H5Y1, A6NCI8, A6NFA0, A6NGG8, B2RQL2, D3Z1D3, D3ZMK9, E9Q286, E9Q309, M0RD54, O14513, P51816, Q01613, Q03172, Q05860, Q2M2Z5, Q32LN6, Q3MHH3, Q3UXL4, Q3V0A6, Q569L8, Q571I4, Q5DTX6, Q5FW52, Q5HYW2, Q5R9I1, Q5VT06, Q5VWP3, Q60988, Q66HG9, Q68DA7, Q6P1W5, Q6P9P0, Q6PAC4, Q6PG16, Q711Q0, Q7TP36, Q7TSA6

Diamond homologs: B1AXH1, Q5HYW2, Q5SYE7, Q8CAF4, Q1LWM5

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 44 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
RHO GTPases Activate WASPs and WAVEs	6	63.4×	9e-08
Parasite infection	5	57.7×	6e-07
Leishmania phagocytosis	5	57.7×	6e-07
Fcgamma receptor (FCGR) dependent phagocytosis	5	46.4×	2e-06
Signaling by VEGF	6	43.9×	3e-07
FCGR3A-mediated phagocytosis	6	37.4×	4e-07
Regulation of actin dynamics for phagocytic cup formation	6	36.8×	4e-07
VEGFA-VEGFR2 Pathway	7	32.5×	2e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	219
Likely benign	18
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2819 predictions. Top by Δscore:

Variant	Effect	Δscore
X:71911358:G:GT	donor_gain	1.0000
X:71911364:C:G	donor_gain	1.0000
X:72140756:G:T	donor_gain	1.0000
X:72142225:T:G	acceptor_gain	1.0000
X:72142228:CTAG:C	acceptor_loss	1.0000
X:72142229:TAGG:T	acceptor_loss	1.0000
X:72142230:A:T	acceptor_loss	1.0000
X:72142230:AG:A	acceptor_gain	1.0000
X:72142230:AGG:A	acceptor_gain	1.0000
X:72142231:G:T	acceptor_loss	1.0000
X:72142231:GG:G	acceptor_gain	1.0000
X:72142231:GGG:G	acceptor_gain	1.0000
X:72142231:GGGA:G	acceptor_gain	1.0000
X:72142357:A:AG	donor_gain	1.0000
X:72142363:AGGT:A	donor_loss	1.0000
X:72142364:GGT:G	donor_loss	1.0000
X:72142365:G:T	donor_loss	1.0000
X:72142366:T:A	donor_loss	1.0000
X:72143447:G:GT	donor_gain	1.0000
X:72143447:G:T	donor_gain	1.0000
X:71911363:GCTAG:G	donor_gain	0.9900
X:71911364:CTAG:C	donor_loss	0.9900
X:71911365:TAG:T	donor_loss	0.9900
X:71911366:AG:A	donor_loss	0.9900
X:71911367:GG:G	donor_loss	0.9900
X:71911368:GT:G	donor_loss	0.9900
X:71911369:T:A	donor_loss	0.9900
X:72009506:T:TA	donor_gain	0.9900
X:72009507:A:AA	donor_gain	0.9900
X:72009561:G:GG	donor_gain	0.9900

AlphaMissense

7919 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:72142358:T:A	I1117K	1.000
X:72143258:A:T	K1121I	1.000
X:72143259:A:C	K1121N	1.000
X:72143259:A:T	K1121N	1.000
X:72139697:A:C	S717R	0.999
X:72139699:C:A	S717R	0.999
X:72139699:C:G	S717R	0.999
X:72142348:T:C	F1114L	0.999
X:72142349:T:C	F1114S	0.999
X:72142350:T:A	F1114L	0.999
X:72142350:T:G	F1114L	0.999
X:72142358:T:C	I1117T	0.999
X:72142358:T:G	I1117R	0.999
X:72142360:C:G	H1118D	0.999
X:72143262:G:C	R1122S	0.999
X:72143262:G:T	R1122S	0.999
X:71911206:T:C	L40P	0.998
X:72139685:A:C	S713R	0.998
X:72139687:T:A	S713R	0.998
X:72139687:T:G	S713R	0.998
X:72140031:T:C	L828P	0.998
X:72142346:T:C	L1113S	0.998
X:72142349:T:G	F1114C	0.998
X:72143254:T:C	S1120P	0.998
X:72143261:G:C	R1122T	0.998
X:72143423:T:C	F1176S	0.998
X:72143489:T:C	L1198P	0.998
X:72143492:T:C	L1199P	0.998
X:72139689:G:A	G714D	0.997
X:72139691:T:C	Y715H	0.997

dbSNP variants (sampled 300 via entrez): RS1000007468 (X:72027949 G>A), RS1000012553 (X:72032708 A>T), RS1000066424 (X:71949246 A>G), RS1000069807 (X:72119276 G>T), RS1000128175 (X:72033006 G>A), RS1000133573 (X:71947815 A>G), RS1000138278 (X:72107967 C>T), RS1000150820 (X:72079695 C>T), RS1000155228 (X:71997233 C>G,T), RS1000187453 (X:71922836 T>A), RS1000188211 (X:71989456 A>T), RS1000198084 (X:72076493 C>G), RS1000202938 (X:71984643 A>T), RS1000210142 (X:72148299 G>A), RS1000218666 (X:72151139 C>T)

Disease associations

OMIM: gene MIM:301093 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST90002400_3	Plateletcrit	1.000000e-09
GCST90002402_516	Platelet count	4.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007985	platelet crit
EFO:0004309	platelet count

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
bisphenol A	decreases methylation, increases expression, affects cotreatment, increases methylation	2
sodium arsenite	affects binding, increases reaction, affects cotreatment, decreases expression, increases abundance	2
Arsenic	affects cotreatment, decreases expression, increases abundance, affects methylation	2
Benzo(a)pyrene	affects methylation	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
sotorasib	decreases expression, affects cotreatment	1
triphenyl phosphate	affects expression	1
butyraldehyde	decreases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	decreases methylation	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression	1
di-n-butylphosphoric acid	affects expression	1
2-palmitoylglycerol	increases expression	1
trametinib	decreases expression, affects cotreatment	1
(+)-JQ1 compound	affects expression, increases reaction	1
NVP-BKM120	affects cotreatment, decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Panobinostat	affects expression, increases reaction	1
Air Pollutants, Occupational	decreases expression	1
Cadmium	decreases expression, increases abundance	1
Doxorubicin	decreases expression	1
Estradiol	increases expression	1
Lipopolysaccharides	increases expression, decreases reaction	1
Manganese	decreases expression, increases abundance, affects cotreatment	1
Methapyrilene	increases methylation	1
Nickel	decreases expression	1
Smoke	decreases expression	1
Aflatoxin B1	increases methylation	1
Okadaic Acid	increases expression	1

Clinical trials (associated diseases)

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