NACAD

Summary

NACAD (NAC alpha domain containing, HGNC:22196) is a protein-coding gene on chromosome 7p13, encoding NAC-alpha domain-containing protein 1 (O15069). May prevent inappropriate targeting of non-secretory polypeptides to the endoplasmic reticulum (ER).

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 23148 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 286 total — 1 pathogenic, 1 likely-pathogenic
• MANE Select transcript: NM_001146334

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:22196
Approved symbol	NACAD
Name	NAC alpha domain containing
Location	7p13
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0363
Ensembl gene	ENSG00000136274
Ensembl biotype	protein_coding
OMIM	619419
Entrez	23148

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 retained_intron, 1 protein_coding

ENST00000460409, ENST00000490531

RefSeq mRNA: 1 — MANE Select: NM_001146334 NM_001146334

CCDS: CCDS47582

Canonical transcript exons

ENST00000490531 — 8 exons

Exon	Start	End
ENSE00000924235	45080640	45080762
ENSE00000924236	45080876	45081022
ENSE00000924237	45081117	45081263
ENSE00000924238	45081601	45081672
ENSE00000924239	45081755	45081867
ENSE00001176370	45082108	45086112
ENSE00001794697	45088828	45088969
ENSE00001928433	45080437	45080523

Expression profiles

Bgee: expression breadth ubiquitous, 203 present calls, max score 98.30.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.1883 / max 311.7857, expressed in 996 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
83932	6.0881	996
83930	0.0631	40
83931	0.0371	27

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
inferior vagus X ganglion	UBERON:0005363	98.30	gold quality
middle frontal gyrus	UBERON:0002702	97.53	gold quality
dorsal root ganglion	UBERON:0000044	96.48	gold quality
superior vestibular nucleus	UBERON:0007227	96.41	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	96.37	gold quality
subthalamic nucleus	UBERON:0001906	96.36	gold quality
spinal cord	UBERON:0002240	96.17	gold quality
medulla oblongata	UBERON:0001896	96.11	gold quality
globus pallidus	UBERON:0001875	96.07	gold quality
substantia nigra pars reticulata	UBERON:0001966	96.07	gold quality
medial globus pallidus	UBERON:0002477	95.98	gold quality
substantia nigra pars compacta	UBERON:0001965	95.88	gold quality
lateral globus pallidus	UBERON:0002476	95.68	gold quality
ventral tegmental area	UBERON:0002691	95.65	gold quality
dorsal plus ventral thalamus	UBERON:0001897	95.34	gold quality
pons	UBERON:0000988	95.15	gold quality
Brodmann (1909) area 10	UBERON:0013541	95.04	gold quality
paraflocculus	UBERON:0005351	94.89	gold quality
inferior olivary complex	UBERON:0002127	94.63	gold quality
lateral nuclear group of thalamus	UBERON:0002736	94.36	gold quality
midbrain	UBERON:0001891	94.08	gold quality
substantia nigra	UBERON:0002038	93.85	gold quality
frontal pole	UBERON:0002795	93.76	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.71	gold quality
cerebellar hemisphere	UBERON:0002245	93.08	gold quality
cerebellar cortex	UBERON:0002129	93.03	gold quality
right frontal lobe	UBERON:0002810	92.91	gold quality
cerebellum	UBERON:0002037	92.29	gold quality
hypothalamus	UBERON:0001898	91.91	gold quality
prefrontal cortex	UBERON:0000451	91.90	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	9.62
E-MTAB-7303	no	1658.86
E-ANND-3	no	1.57

Regulation

Is transcription factor: no

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	nacad	ENSDARG00000012347
mus_musculus	Nacad	ENSMUSG00000041073
rattus_norvegicus	Nacad	ENSRNOG00000053875
drosophila_melanogaster	Nacalpha	FBGN0086904

Paralogs (2): NACA (ENSG00000196531), NACA2 (ENSG00000253506)

Protein

Protein identifiers

NAC-alpha domain-containing protein 1 — O15069 (reviewed: O15069)

All UniProt accessions (1): O15069

UniProt curated annotations — full annotation on UniProt →

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

Subcellular location. Cytoplasm. Nucleus.

Similarity. Belongs to the NAC-alpha family.

RefSeq proteins (1): NP_001139806* (*=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
IPR041907	NACAD_UBA	Domain
IPR044034	NAC-like_UBA	Domain

Pfam: PF01849, PF19026

UniProt features (34 total): compositionally biased region 16, region of interest 8, sequence variant 5, modified residue 2, chain 1, domain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15069-F1	40.13	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 (2): 1068, 1354

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 67 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, MODULE_255, GOBP_PROTEIN_TARGETING, MODULE_317, BROWNE_HCMV_INFECTION_16HR_UP, GOBP_PROTEIN_TARGETING_TO_MEMBRANE, MODULE_301, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_MEMBRANE, MORF_EPHA7, chr7p13, MORF_WNT1, MODULE_188, GOBP_LOCALIZATION_WITHIN_MEMBRANE, MORF_IL9, XU_GH1_EXOGENOUS_TARGETS_DN

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

GO Molecular Function (2): obsolete unfolded protein binding (GO:0051082), protein binding (GO:0005515)

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
binding	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

1660 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NACAD	XIRP1	Q702N8	533
NACAD	NET1	Q7Z628	530
NACAD	SENP6	Q9GZR1	414
NACAD	PHACTR4	Q8IZ21	401
NACAD	CMYA5	Q8N3K9	389
NACAD	SERHL2	Q9H4I8	379
NACAD	ZNF687	Q8N1G0	336
NACAD	IGFN1	Q86VF2	311
NACAD	R3HCC1	Q9Y3T6	302
NACAD	NBEAL2	Q6ZNJ1	300
NACAD	CSMD2	Q7Z408	299
NACAD	RSF1	Q96T23	290
NACAD	COL24A1	Q17RW2	270
NACAD	YIPF3	Q9GZM5	264
NACAD	LTN1	O94822	263

IntAct

45 interactions, top by confidence:

A	B	Type	Score
VAPB	FAM83G	psi-mi:“MI:0914”(association)	0.730
VAPA	FAM83G	psi-mi:“MI:0914”(association)	0.640
VAPA	PITPNM1	psi-mi:“MI:0914”(association)	0.640
ERCC8	NACAD	psi-mi:“MI:0915”(physical association)	0.560
GRN	NACAD	psi-mi:“MI:0915”(physical association)	0.560
NACAD	HTT	psi-mi:“MI:0915”(physical association)	0.560
EPB41L3	AP3B1	psi-mi:“MI:0914”(association)	0.530
NACAD	STAT3	psi-mi:“MI:0915”(physical association)	0.370
NACAD	AGTR1	psi-mi:“MI:0915”(physical association)	0.370
NACAD	YAE1	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (27): NACAD (Affinity Capture-MS), NACAD (Affinity Capture-MS), NACAD (Two-hybrid), NACAD (Affinity Capture-MS), NACAD (Affinity Capture-MS), NACAD (Affinity Capture-MS), NACAD (Two-hybrid), NACAD (Affinity Capture-MS), NACAD (Affinity Capture-MS), NACAD (Affinity Capture-MS), NACAD (Affinity Capture-MS), NACAD (Affinity Capture-MS), NACAD (Affinity Capture-MS), NACAD (Affinity Capture-MS), NACAD (Affinity Capture-MS)

ESM2 similar proteins: A0A0J9YWL9, A0A0J9YY54, A5D7L8, A6NEF3, A6NI86, B2KFW1, B4DH59, D3YZV8, E9Q6E9, F1LWT0, F6QRE9, H0YKK7, O15069, P17040, P17564, P21263, P51843, P62521, P79386, Q0P6D6, Q13342, Q2EG98, Q2KI51, Q3BBV2, Q4VC44, Q5F378, Q5QGU6, Q63560, Q6ITT4, Q6P5H2, Q6ZQX7, Q86T75, Q8CHD8, Q8IWY8, Q8N660, Q8N693, Q99PG2, Q9BE18, Q9BG93, Q9BG94

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

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	242
Likely benign	37
Benign	0

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
584080	NC_000007.14:g.(?45027705)(45086112_?)del	Pathogenic
979754	GRCh37/hg19 7p13(chr7:45057188-45135918)x1	Likely pathogenic

SpliceAI

1014 predictions. Top by Δscore:

Variant	Effect	Δscore
7:45080523:CCT:C	acceptor_loss	1.0000
7:45080524:C:CC	acceptor_gain	1.0000
7:45080524:CT:C	acceptor_loss	1.0000
7:45080634:A:AC	donor_gain	1.0000
7:45080635:C:CA	donor_gain	1.0000
7:45080635:CT:C	donor_gain	1.0000
7:45080635:CTCA:C	donor_gain	1.0000
7:45080636:TCA:T	donor_loss	1.0000
7:45080637:CA:C	donor_loss	1.0000
7:45080638:A:AC	donor_gain	1.0000
7:45080638:AC:A	donor_gain	1.0000
7:45080639:C:CG	donor_gain	1.0000
7:45080639:CC:C	donor_gain	1.0000
7:45080639:CCA:C	donor_gain	1.0000
7:45080639:CCAT:C	donor_gain	1.0000
7:45080639:CCATG:C	donor_gain	1.0000
7:45080758:TCCAC:T	acceptor_gain	1.0000
7:45080759:CCAC:C	acceptor_gain	1.0000
7:45080759:CCACC:C	acceptor_gain	1.0000
7:45080760:CAC:C	acceptor_gain	1.0000
7:45080760:CACC:C	acceptor_gain	1.0000
7:45080761:ACCT:A	acceptor_loss	1.0000
7:45080763:C:CA	acceptor_loss	1.0000
7:45080763:C:CC	acceptor_gain	1.0000
7:45080768:G:GC	acceptor_gain	1.0000
7:45080769:T:C	acceptor_gain	1.0000
7:45080769:T:TC	acceptor_gain	1.0000
7:45080872:T:TA	donor_gain	1.0000
7:45080872:TCAC:T	donor_loss	1.0000
7:45080874:ACCTC:A	donor_loss	1.0000

AlphaMissense

9927 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:45080644:A:T	I1557N	1.000
7:45080725:A:G	L1530P	1.000
7:45081127:C:A	G1465V	1.000
7:45081127:C:T	G1465D	1.000
7:45081128:C:G	G1465R	1.000
7:45081129:A:C	F1464L	1.000
7:45081129:A:T	F1464L	1.000
7:45081131:A:G	F1464L	1.000
7:45081133:A:T	V1463D	1.000
7:45081159:C:A	K1454N	1.000
7:45081159:C:G	K1454N	1.000
7:45081166:A:T	V1452D	1.000
7:45081181:A:T	I1447N	1.000
7:45081186:A:C	F1445L	1.000
7:45081186:A:T	F1445L	1.000
7:45081187:A:G	F1445S	1.000
7:45081188:A:G	F1445L	1.000
7:45081211:A:T	I1437N	1.000
7:45081217:A:C	I1435S	1.000
7:45081217:A:T	I1435N	1.000
7:45081244:A:G	L1426S	1.000
7:45080519:A:G	L1560P	0.999
7:45080644:A:C	I1557S	0.999
7:45080644:A:G	I1557T	0.999
7:45080648:C:G	A1556P	0.999
7:45080677:A:G	L1546P	0.999
7:45080717:C:G	A1533P	0.999
7:45081121:G:T	A1467D	0.999
7:45081128:C:A	G1465C	0.999
7:45081130:A:C	F1464C	0.999

dbSNP variants (sampled 300 via entrez): RS1000210695 (7:45081429 A>C,G), RS1000339945 (7:45082299 C>T), RS1000397875 (7:45088520 T>A), RS1001304968 (7:45087665 G>T), RS1001377898 (7:45083216 T>C), RS1001952311 (7:45085928 C>A,T), RS1002409075 (7:45082675 C>G), RS1002690652 (7:45088926 C>A,T), RS1002714849 (7:45089213 G>A), RS1003127616 (7:45080413 C>T), RS1003381588 (7:45086322 G>A,C), RS1003594892 (7:45082050 AAGG>A), RS1003925909 (7:45080028 C>T), RS1004431445 (7:45090478 A>C), RS1004890969 (7:45086043 G>A)

Disease associations

OMIM: gene MIM:619419 | disease phenotypes: MIM:603284

GenCC curated gene-disease

Mondo (1): cerebral cavernous malformation 2 (MONDO:0011304)

Orphanet (1): Familial cerebral cavernous malformation (Orphanet:221061)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90002381_229	Eosinophil count	8.000000e-15

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004842	eosinophil count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C566394	Cerebral Cavernous Malformations 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, increases methylation	3
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
sodium arsenate	decreases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
Temozolomide	increases expression	1
Vorinostat	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Urethane	increases expression	1
Vitamin E	increases expression	1
Zinc	increases expression	1
Acrylamide	decreases expression	1
S-Nitrosoglutathione	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03652181	Not specified	COMPLETED	CASH (Cavernous Angiomas With Symptomatic Hemorrhage) Trial Readiness