NACA2

Summary

NACA2 (nascent polypeptide associated complex subunit alpha 2, HGNC:23290) is a protein-coding gene on chromosome 17q23.2, encoding Nascent polypeptide-associated complex subunit alpha-2 (Q9H009). Prevents inappropriate targeting of non-secretory polypeptides to the endoplasmic reticulum (ER). It is a selective cancer dependency (DepMap: 10.6% of cell lines).

Predicted to enable unfolded protein binding activity. Predicted to be involved in protein targeting to membrane. Predicted to be located in nucleus. Predicted to be part of nascent polypeptide-associated complex. Predicted to be active in cytoplasm.

Source: NCBI Gene 342538 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 29 total
• Cancer dependency (DepMap): dependent in 10.6% of screened cell lines
• MANE Select transcript: NM_199290

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23290
Approved symbol	NACA2
Name	nascent polypeptide associated complex subunit alpha 2
Location	17q23.2
Locus type	gene with protein product
Status	Approved
Aliases	MGC71999
Ensembl gene	ENSG00000253506
Ensembl biotype	protein_coding
OMIM	609274
Entrez	342538

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000521764

RefSeq mRNA: 2 — MANE Select: NM_199290 NM_001426702, NM_199290

CCDS: CCDS11630

Canonical transcript exons

ENST00000521764 — 1 exons

Exon	Start	End
ENSE00002104459	61590421	61591219

Expression profiles

Bgee: expression breadth ubiquitous, 129 present calls, max score 93.50.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.5803 / max 224.4737, expressed in 1767 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
167401	18.5803	1767

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	93.50	gold quality
right testis	UBERON:0004534	92.35	gold quality
testis	UBERON:0000473	90.77	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.43	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.35	gold quality
sperm	CL:0000019	82.34	gold quality
male germ cell	CL:0000015	80.41	gold quality
adult organism	UBERON:0007023	76.53	gold quality
lower lobe of lung	UBERON:0008949	58.28	silver quality
stromal cell of endometrium	CL:0002255	55.40	gold quality
mammary duct	UBERON:0001765	54.50	gold quality
epithelium of mammary gland	UBERON:0003244	54.28	gold quality
oviduct epithelium	UBERON:0004804	53.24	gold quality
oocyte	CL:0000023	53.14	gold quality
cranial nerve II	UBERON:0000941	52.36	silver quality
nasal cavity epithelium	UBERON:0005384	52.22	gold quality
pigmented layer of retina	UBERON:0001782	51.77	gold quality
pericardium	UBERON:0002407	51.58	gold quality
oral cavity	UBERON:0000167	51.25	gold quality
cortical plate	UBERON:0005343	51.16	gold quality
vermiform appendix	UBERON:0001154	51.06	gold quality
ganglionic eminence	UBERON:0004023	50.30	gold quality
ventricular zone	UBERON:0003053	49.92	gold quality
caecum	UBERON:0001153	49.71	gold quality
myocardium	UBERON:0002349	49.60	gold quality
quadriceps femoris	UBERON:0001377	49.38	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
hair follicle	UBERON:0002073	49.18	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	17.14

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

3 targeting NACA2, 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-101-3P	99.94	75.03	2230
HSA-MIR-6715B-3P	98.80	68.07	1204
HSA-MIR-495-5P	97.62	68.28	682

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 10.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 1)

• Alpha-nac is a potent inducer of a Th1 response via IL12 and TLR2. (PMID:23657466)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
drosophila_melanogaster	Hmr	FBGN0001206
drosophila_melanogaster	gNacalpha	FBGN0031296

Paralogs (2): NACAD (ENSG00000136274), NACA (ENSG00000196531)

Protein

Protein identifiers

Nascent polypeptide-associated complex subunit alpha-2 — Q9H009 (reviewed: Q9H009)

Alternative names: Alpha-NAC-like, Hom s 2.01, Nascent polypeptide-associated complex subunit alpha-like

All UniProt accessions (1): Q9H009

UniProt curated annotations — full annotation on UniProt →

Function. Prevents inappropriate targeting of non-secretory polypeptides to the endoplasmic reticulum (ER). Binds to nascent polypeptide chains as they emerge from the ribosome and blocks their interaction with the signal recognition particle (SRP), which normally targets nascent secretory peptides to the ER. Also reduces the inherent affinity of ribosomes for protein translocation sites in the ER membrane (M sites).

Subunit / interactions. Part of the nascent polypeptide-associated complex (NAC), consisting of NACA and BTF3. NAC associates with ribosomes through the BTF3 subunit. Both subunits can contact nascent polypeptide chains.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Expressed specifically in testis and skeletal muscle.

Miscellaneous. NACAL arose from a recent (40-63 million-year-old), anthropoid primate-specific retroduplication of NACA.

Similarity. Belongs to the NAC-alpha family.

RefSeq proteins (2): NP_001413631, NP_954984* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002715	Nas_poly-pep-assoc_cplx_dom	Domain
IPR016641	EGD2/NACA0like	Family
IPR038187	NAC_A/B_dom_sf	Homologous_superfamily
IPR044034	NAC-like_UBA	Domain

Pfam: PF01849, PF19026

UniProt features (16 total): modified residue 9, domain 2, chain 1, cross-link 1, sequence variant 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H009-F1	72.87	0.42

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 (10): 186, 191, 203, 214, 142, 43, 132, 142, 161, 166

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 29 (showing top): GOBP_PROTEIN_TARGETING, GOBP_PROTEIN_TARGETING_TO_MEMBRANE, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_MEMBRANE, GOBP_LOCALIZATION_WITHIN_MEMBRANE, NIKOLSKY_BREAST_CANCER_17Q21_Q25_AMPLICON, GOMF_UNFOLDED_PROTEIN_BINDING, chr17q23, JAK2_DN.V1_UP, GOCC_NASCENT_POLYPEPTIDE_ASSOCIATED_COMPLEX, MIR101_3P, GSE14000_TRANSLATED_RNA_VS_MRNA_16H_LPS_DC_DN, GSE1460_NAIVE_CD4_TCELL_ADULT_BLOOD_VS_THYMIC_STROMAL_CELL_UP, MANNO_MIDBRAIN_NEUROTYPES_BASAL, MURARO_PANCREAS_ACINAR_CELL, DESCARTES_FETAL_CEREBELLUM_VASCULAR_ENDOTHELIAL_CELLS

GO Biological Process (2): protein targeting to membrane (GO:0006612), protein transport (GO:0015031)

GO Molecular Function (1): obsolete unfolded protein binding (GO:0051082)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), nascent polypeptide-associated complex (GO:0005854)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein targeting	1
establishment of protein localization to membrane	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1
cytoplasm	1
protein-containing complex	1

Protein interactions and networks

STRING

1240 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NACA2	GMCL2	Q8NEA9	432
NACA2	TXLNG	Q9NUQ3	409
NACA2	OR2Z1	Q8NG97	348
NACA2	TIPRL	O75663	325
NACA2	CNOT4	O95628	323
NACA2	CDC14B	O60729	305
NACA2	CDIP1	Q9H305	305
NACA2	ZNF705EP	A8MWA4	305
NACA2	TXLNB	Q8N3L3	304
NACA2	APOBEC1	P41238	290
NACA2	CORO6	Q6QEF8	289
NACA2	CDC14C	A4D256	284
NACA2	WDR44	Q5JSH3	274
NACA2	RBMXL1	Q96E39	271
NACA2	CABP7	Q86V35	270

IntAct

8 interactions, top by confidence:

A	B	Type	Score
BTF3L4	TXLNA	psi-mi:“MI:0914”(association)	0.780
BTF3L4	PRIM1	psi-mi:“MI:0914”(association)	0.530
BTF3	HSPA8	psi-mi:“MI:0914”(association)	0.350
BTF3	NACAD	psi-mi:“MI:0914”(association)	0.350
BTF3L4	NACAD	psi-mi:“MI:0914”(association)	0.350
BTF3	VPS37C	psi-mi:“MI:0914”(association)	0.350
KCNJ2	ELAPOR2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (27): NACA2 (Co-fractionation), NACA2 (Co-fractionation), NACA2 (Co-fractionation), NACA2 (Co-fractionation), NACA2 (Co-fractionation), NACA2 (Co-fractionation), NACA2 (Co-fractionation), NACA2 (Co-fractionation), NACA2 (Co-fractionation), NACA2 (Co-fractionation), NACA2 (Co-fractionation), NACA2 (Affinity Capture-MS), NACA2 (Affinity Capture-MS), NACA2 (Affinity Capture-MS), NACA2 (Affinity Capture-RNA)

ESM2 similar proteins: A1C4X0, A1CKI4, A1CZU9, A2QDB9, A2QUR1, A4R6K8, A5DEQ9, A6QT51, A6R641, A6S3N2, A6SFG0, A7ENU3, A7EXH9, B2B763, B8NL00, G0S5Q0, O94305, P0CR44, P0CR45, P26642, P40075, P40796, P45816, P53860, P55876, Q0C7M4, Q0CE43, Q0V0B0, Q1DSY1, Q26457, Q2GLX8, Q2UA18, Q2UKX8, Q40680, Q4P2B6, Q4WEP0, Q4WXA1, Q56WK6, Q56ZI2, Q5ATZ7

Diamond homologs: A1CMF8, A1DLM0, A2R4V1, A3GHD3, A4RC89, A5DGN9, A5DXK7, A6R641, A6SB28, A6ZT99, A7EIZ1, A7TG43, E9PAV3, O15069, P0C2C7, P0CP06, P0CP07, P38879, P70670, P87147, Q0UKB5, Q13765, Q1DHR3, Q2H4Z2, Q2U955, Q45FF9, Q4I2J8, Q4P341, Q4WD81, Q5ANP2, Q5AYK0, Q5E9A1, Q5R9I9, Q5SWP3, Q60817, Q61UX1, Q68F90, Q6BSN9, Q6CDH0, Q6CWG6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	29
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

248 predictions. Top by Δscore:

Variant	Effect	Δscore
17:61590859:T:TC	acceptor_gain	0.7500
17:61590687:T:A	donor_gain	0.6800
17:61590987:CCGA:C	donor_gain	0.6600
17:61590859:T:C	acceptor_gain	0.6300
17:61590807:T:TA	donor_gain	0.6100
17:61590808:C:A	donor_gain	0.6100
17:61590569:A:AC	donor_gain	0.5800
17:61590914:TGTA:T	donor_gain	0.5800
17:61590486:G:C	donor_gain	0.5700
17:61590572:A:AC	donor_gain	0.5700
17:61590573:C:CC	donor_gain	0.5700
17:61590597:G:GA	donor_gain	0.5600
17:61590627:A:AC	donor_gain	0.5500
17:61590855:A:T	acceptor_gain	0.5500
17:61590498:C:CA	donor_gain	0.5400
17:61590944:AG:A	donor_gain	0.5400
17:61591118:AG:A	donor_gain	0.5400
17:61591137:T:TA	donor_gain	0.5400
17:61590648:A:C	donor_gain	0.5200
17:61590917:A:T	donor_gain	0.5200
17:61590642:T:TA	donor_gain	0.5100
17:61590668:G:GT	donor_gain	0.5100
17:61590918:ACCTG:A	acceptor_gain	0.5100
17:61590990:A:AC	donor_gain	0.5100
17:61590991:C:CC	donor_gain	0.5100
17:61590675:T:A	donor_gain	0.5000
17:61590852:T:TA	donor_gain	0.5000
17:61590666:T:C	donor_gain	0.4900
17:61590919:CCTGT:C	acceptor_gain	0.4900
17:61591078:CTGAT:C	donor_gain	0.4900

AlphaMissense

1395 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:61590869:A:C	F104L	0.764
17:61590869:A:T	F104L	0.764
17:61590871:A:G	F104L	0.764
17:61590752:G:C	F143L	0.737
17:61590752:G:T	F143L	0.737
17:61590754:A:G	F143L	0.737
17:61590812:A:C	F123L	0.713
17:61590812:A:T	F123L	0.713
17:61590814:A:G	F123L	0.713
17:61590630:A:T	V184D	0.589

dbSNP variants (sampled 300 via entrez): RS1000383930 (17:61591115 C>T), RS1002817552 (17:61592696 T>C), RS1003538931 (17:61591584 T>G), RS1003847190 (17:61591283 G>A,C,T), RS1003918306 (17:61590797 G>C), RS1007747540 (17:61592312 TAAG>T), RS1008115589 (17:61592153 G>A), RS1010421770 (17:61590550 T>C), RS1012352909 (17:61591469 T>C), RS1012489852 (17:61592898 G>A), RS1012969746 (17:61592641 T>C,G), RS1013351142 (17:61592233 G>A), RS1014420576 (17:61591255 C>T), RS1015224727 (17:61591669 T>C), RS1016194043 (17:61590074 G>A)

Disease associations

OMIM: gene MIM:609274 | 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
GCST000175_44	Height	6.000000e-08
GCST002155_3	Osteoarthritis (hip)	8.000000e-06
GCST002647_153	Height	4.000000e-10
GCST007001_13	Cerebrospinal AB1-42 levels in normal cognition	2.000000e-08
GCST009391_85	Metabolite levels	6.000000e-06
GCST010002_127	Refractive error	3.000000e-21
GCST90013466_20	Height	9.000000e-10
GCST90013466_39	Height	2.000000e-13
GCST90013467_8	Height	7.000000e-08
GCST90013468_5	Height	5.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004670	beta-amyloid 1-42 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

4 total (human), top 4 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
CGP 52608	affects binding, increases reaction	1
ICG 001	increases expression	1
Dronabinol	decreases expression	1
Aflatoxin B1	increases methylation	1

Clinical trials (associated diseases)

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