NAIP

Summary

NAIP (NLR family apoptosis inhibitory protein, HGNC:7634) is a protein-coding gene on chromosome 5q13.2, encoding Baculoviral IAP repeat-containing protein 1 (Q13075). Anti-apoptotic protein which acts by inhibiting the activities of CASP3, CASP7 and CASP9. It is a selective cancer dependency (DepMap: 42.9% of cell lines).

This gene is part of a 500 kb inverted duplication on chromosome 5q13. This duplicated region contains at least four genes and repetitive elements which make it prone to rearrangements and deletions. The repetitiveness and complexity of the sequence have also caused difficulty in determining the organization of this genomic region. This copy of the gene is full length; additional copies with truncations and internal deletions are also present in this region of chromosome 5q13. It is thought that this gene is a modifier of spinal muscular atrophy caused by mutations in a neighboring gene, SMN1. The protein encoded by this gene contains regions of homology to two baculovirus inhibitor of apoptosis proteins, and it is able to suppress apoptosis induced by various signals. Alternative splicing and the use of alternative promoters results in multiple transcript variants.

Source: NCBI Gene 4671 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 34 total
• Cancer dependency (DepMap): dependent in 42.9% of screened cell lines
• MANE Select transcript: NM_004536

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7634
Approved symbol	NAIP
Name	NLR family apoptosis inhibitory protein
Location	5q13.2
Locus type	gene with protein product
Status	Approved
Aliases	NLRB1
Ensembl gene	ENSG00000249437
Ensembl biotype	protein_coding
OMIM	600355
Entrez	4671

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 8 protein_coding, 2 retained_intron, 2 nonsense_mediated_decay

ENST00000194097, ENST00000315147, ENST00000447012, ENST00000503719, ENST00000508426, ENST00000508794, ENST00000514857, ENST00000517649, ENST00000519014, ENST00000523981, ENST00000943389, ENST00000943390

RefSeq mRNA: 3 — MANE Select: NM_004536 NM_001346870, NM_004536, NM_022892

CCDS: CCDS4009, CCDS43327

Canonical transcript exons

ENST00000517649 — 17 exons

Exon	Start	End
ENSE00000000313	70968166	70970468
ENSE00002132215	71024615	71025339
ENSE00002212623	70986745	70986802
ENSE00002214653	70983775	70985886
ENSE00002219419	70998724	70998823
ENSE00002284906	71012348	71012918
ENSE00002286626	70987793	70987874
ENSE00003488308	70976906	70977058
ENSE00003489009	71003776	71003857
ENSE00003504809	71001698	71001817
ENSE00003547420	71024318	71024406
ENSE00003550399	70976160	70976246
ENSE00003576621	71011275	71011374
ENSE00003590701	70979869	70980036
ENSE00003606270	70974129	70974293
ENSE00003668305	71020659	71020784
ENSE00003687350	71002092	71002143

Expression profiles

Bgee: expression breadth ubiquitous, 221 present calls, max score 97.44.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0857 / max 38.2607, expressed in 8 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
203580	0.0857	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	97.44	gold quality
leukocyte	CL:0000738	97.04	gold quality
spleen	UBERON:0002106	93.78	gold quality
granulocyte	CL:0000094	92.57	gold quality
vermiform appendix	UBERON:0001154	92.30	gold quality
bone marrow cell	CL:0002092	91.96	gold quality
right uterine tube	UBERON:0001302	91.76	gold quality
colonic epithelium	UBERON:0000397	91.19	gold quality
ganglionic eminence	UBERON:0004023	90.95	gold quality
embryo	UBERON:0000922	90.94	gold quality
right lung	UBERON:0002167	90.39	gold quality
blood	UBERON:0000178	89.52	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	89.03	gold quality
cortical plate	UBERON:0005343	88.79	gold quality
upper lobe of left lung	UBERON:0008952	88.35	gold quality
ventricular zone	UBERON:0003053	88.14	gold quality
left lobe of thyroid gland	UBERON:0001120	87.67	gold quality
buccal mucosa cell	CL:0002336	87.32	gold quality
cerebellar vermis	UBERON:0004720	87.14	gold quality
upper lobe of lung	UBERON:0008948	87.13	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.10	gold quality
right lobe of thyroid gland	UBERON:0001119	86.95	gold quality
right coronary artery	UBERON:0001625	86.82	gold quality
spinal cord	UBERON:0002240	86.65	gold quality
calcaneal tendon	UBERON:0003701	86.62	gold quality
thyroid gland	UBERON:0002046	86.17	gold quality
left testis	UBERON:0004533	86.01	gold quality
caecum	UBERON:0001153	85.76	gold quality
nerve	UBERON:0001021	85.74	gold quality
tibial nerve	UBERON:0001323	85.74	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-9801	yes	7.21
E-ANND-3	no	2.06

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNB1, PAX2, POU3F2, TCF7L2, TEAD1

miRNA regulators (miRDB)

96 targeting NAIP, 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-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-493-5P	99.96	72.47	2382
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-548O-5P	99.94	71.24	3488
HSA-MIR-548W	99.94	71.24	3488
HSA-MIR-548Y	99.94	71.28	3514
HSA-MIR-101-3P	99.94	75.03	2230

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 42.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• NAIP gene deletion was higher in type I spinal muscular atrophy than in type U or V. In type I patients lacking the NAIP gene, deterioration in their respiratory function is more rapid than in those type I patients retaining the NAIP gene. (PMID:11912351)
• NAIP-deltaEx10-11: a novel splice variant of the apoptosis inhibitor NAIP is differently expressed in drug-sensitive and multidrug-resistant HL60 leukemia cells. NAIP transcripts might be involved in tumor resistance to chemotherapeutic agents. (PMID:12127562)
• NAIP:Structural requirements for binding hippocalcin and effects on survival of sympathetic neurons. (PMID:12445469)
• NAIP does not interact with Smac and requires ATP to bind caspase-9 (PMID:15280366)
• Alterations in C/CAAT enhancer binding protein alpha and neuronal apoptosis inhibitory protein expression occurred in human adipose stromal-vascular cells after weight loss (PMID:15340105)
• Multiple, domesticated long terminal repeats (LTRs) of endogenous retroviral elements provide NAIP promoter function in human, mouse, and rat. (PMID:17222062)
• a role for NAIP in increasing the survival of cells undergoing terminal differentiation as well as the possibility that the protein serves as an intestinal pathogen recognition protein was suggested (PMID:17510375)
• 80% neuronal apoptosis inhibitory protein gene deletion in 5q-spinal muscular atrophy patients (91% spinal muscular atrophy-I, 50% spinal muscular atrophy-II and -III), and in 5% (two of forty) of spinal muscular atrophy parents, was found. (PMID:17903057)
• While there was no evidence of NAIP expression in the normal breast tissue, NAIP was expressed in all breast cancer samples. (PMID:17923748)
• May be a modifying factor for disease severity of spinal muscular atrophy. (PMID:17932457)
• The present study is the first one giving detailed information on SMN and NAIP deletion rates in Iranian SMA patients. (PMID:18071605)
• Data show elevated expression of NAIP in peripheral mononuclear cells from children with Fabry disease. (PMID:18339188)
• hNAIP and hIpaf mediate innate intracellular defense against flagellated Legionella in human cells. (PMID:18453601)
• The presence of one NAIP copy, that is, heterozygous NAIP deletion, was common in Vietnamese SMA, regardless of clinical phenotype. (PMID:18533950)
• HIAP-1 and HIAP-2 mRNA levels were elevated in resting T cells while NAIP mRNA was increased in whole blood in multiple sclerosis (PMID:18566024)
• in glioma & glioblastoma multiforme, selective upregulation of miRNA-221 & down-regulation of a miRNA-221 mRNA target encoding BIRC1 were observed; expression of BIRC5 & caspase-3 were found to be significantly up-regulated, particularly in stage IV GBM (PMID:18759060)
• Data show that NAIP deletion predicts disease severity in spinal muscular atrophy. (PMID:18842367)
• Among the SMA Type I patients, 43% showed deletions of SMN1 and NAIP. (PMID:18974562)
• findings of homozygous deletions of exon 7 and/or exon 8 of SMN1 gene confirmed the diagnosis of SMA, and suggested that the deletion of SMN1 exon 7 is a major cause of SMA in southern Chinese children. (PMID:19198020)
• higher number of SMN2 copies makes the clinical symptoms more benign, and the NAIP gene deletion is associated with a more severe phenotype (PMID:19287802)
• a novel NAIP isoform derives from intragenic Alu SINE promoters (PMID:19488400)
• Results provide the first structures of BIR domains from human NAIP and cIAP2. (PMID:19923725)
• Expression of NAIP may be associated with enhanced survival of prostate cancer in response to castration (PMID:20044205)
• an inhibitor of procaspase-9 preventing apoptosis at the initiation stage (PMID:20171302)
• NOD domain is essential for effective inhibition of procaspase-9 and procaspase-3 cleavage by the NAIP protein in apoptosis. (PMID:21371431)
• There is a close relationship between SMN2, NAIP and H4F5 gene copy number and spinal muscular atrophy disease severity (PMID:21821450)
• NAIPFull gene duplication might have been evolutionary maintained, or even selected for, because it may confer an advantage to the host against flagellated bacteria (PMID:22067212)
• the NAIP5-NLRC4 inflammasome is induced by direct interactions with conserved N- and C-terminal regions of flagellin (PMID:23012363)
• /NAIP1 and NAIP2/5 formed a large oligomeric complex with NLRC4 in the presence of corresponding bacterial ligands, and could support reconstitution of the NLRC4 inflammasome in a ligand-specific manner. (PMID:23940371)
• identified an intronic region of the NAIP gene responding to TEAD1/YAP activity, suggesting that regulation of NAIP by TEAD1/YAP is at the transcriptional level (PMID:23994529)
• Copy number variations of SMN2 and NAIP genes in patients are related to spinal muscular atrophy clinical types (P < 0.05). (PMID:24711022)
• Modulation of chemotherapeutic drug resistance in neuroblastoma SK-N-AS cells by the neural apoptosis inhibitory protein and miR-520f. (PMID:25137037)
• results revealed that SMN2 and NAIP copy numbers significantly influenced the age at onset, risk of death, and life expectancy in the spinal muscular atrophy patients and that the effect of SMN2 was more significant (PMID:25330799)
• The copy numbers and gene structures of NAIP genes were different in Chinese spinal muscular atrophy patients and healthy controls (PMID:25888055)
• human Naip functions to activate the inflammasome in response to flagellin, similar to murine Naip5/6. (PMID:26109648)
• Deletion in NAIP gene is associated with spinal muscular atrophy. (PMID:27754957)
• Data document a previously unknown localization of NAIP along the entire cytokinetic process whose dynamics exhibits a distinct behavior. (PMID:28059125)
• Our present report implies that NAIP will have broad implications for ALS symptoms as a risk factor and a promising prognostic biomarker. (PMID:29311650)
• NAIP expression is most abundant in M2 macrophages, while cIAP1 and cIAP2 show an inverse pattern of expression in polarized cells, cIAP2 is preferentially expressed in M1-macrophages and cIAP1 in M2-macrophages. IAP antagonist treatment of resting M0 macrophages preceding polarization stimulation, induced upregulation of NAIP in M2 and downregulation of cIAP1 in M1 and M2 but an induction of cIAP2 in M1 macrophages. (PMID:29518103)
• Results suggest that that the copy number variance of SMN2 and NAIP is correlated with the spinal muscular atrophy (SMA) phenotype in 40 patients. The copy number of SMN2 and NAIP gene had synergistic effect on SMA phenotype. Analysis of the copy number structure of the SMN1-SMN2-NAIP gene is helpful for SMA typing, disease prognosis prediction, and genetic counseling. (PMID:32011487)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
drosophila_melanogaster	Diap2	FBGN0015247
caenorhabditis_elegans		WBGENE00000250

Paralogs (7): BIRC3 (ENSG00000023445), BIRC5 (ENSG00000089685), NLRC4 (ENSG00000091106), BIRC7 (ENSG00000101197), XIAP (ENSG00000101966), BIRC2 (ENSG00000110330), BIRC6 (ENSG00000115760)

Protein

Protein identifiers

Baculoviral IAP repeat-containing protein 1 — Q13075 (reviewed: Q13075)

Alternative names: Neuronal apoptosis inhibitory protein

All UniProt accessions (4): Q13075, E5RJA3, E7EQW0, H0YAX2

UniProt curated annotations — full annotation on UniProt →

Function. Anti-apoptotic protein which acts by inhibiting the activities of CASP3, CASP7 and CASP9. Can inhibit the autocleavage of pro-CASP9 and cleavage of pro-CASP3 by CASP9. Capable of inhibiting CASP9 autoproteolysis at ‘Asp-315’ and decreasing the rate of auto proteolysis at ‘Asp-330’. Acts as a mediator of neuronal survival in pathological conditions. Prevents motor-neuron apoptosis induced by a variety of signals. Possible role in the prevention of spinal muscular atrophy that seems to be caused by inappropriate persistence of motor-neuron apoptosis: mutated or deleted forms of NAIP have been found in individuals with severe spinal muscular atrophy. Acts as a sensor component of the NLRC4 inflammasome that specifically recognizes and binds needle protein CprI from pathogenic bacteria C.violaceum. Association of pathogenic bacteria proteins drives in turn drive assembly and activation of the NLRC4 inflammasome, promoting caspase-1 activation, cytokine production and macrophage pyroptosis. The NLRC4 inflammasome is activated as part of the innate immune response to a range of intracellular bacteria such as C.violaceum and L.pneumophila.

Subunit / interactions. Interacts (via NACHT domain) with APAF1 (via CARD and NACHT domains). Interacts with C.violaceum needle protein CprI.

Tissue specificity. Expressed in motor neurons, but not in sensory neurons. Found in liver and placenta, and to a lesser extent in spinal cord.

Domain organisation. Both the BIR and NACHT domains are essential for effective inhibition of pro-CASP9 cleavage. BIR3 domain binds to procaspase-9 and the NACHT domain interacts with the NACHT domain of APAF1 forming a bridge between pro-CASP9 and APAF1.

Isoforms (2)

UniProt ID	Names	Canonical?
Q13075-1	1	yes
Q13075-2	2

RefSeq proteins (3): NP_001333799, NP_004527, NP_075043 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001370	BIR_rpt	Repeat
IPR003593	AAA+_ATPase	Domain
IPR007111	NACHT_NTPase	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR028789	Naip	Family
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR040535	NLRC4_HD	Domain
IPR053882	Nlrc4-like_WHD	Domain

Pfam: PF00653, PF05729, PF17889, PF22524

UniProt features (29 total): helix 6, sequence conflict 5, binding site 5, repeat 3, strand 3, splice variant 2, chain 1, sequence variant 1, mutagenesis site 1, turn 1, domain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2VM5	X-RAY DIFFRACTION	1.8
8FVU	ELECTRON MICROSCOPY	3.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13075-F1	79.02	0.20

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (5): 315; 318; 335; 342; 473–478

Mutagenesis-validated functional residues (1):

Position	Phenotype
476	prevents the proper cleavage of pro-casp9, but does not inhibit the cleavage of pro-casp3 by casp9.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 177 (showing top): GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_NEGATIVE_REGULATION_OF_TUMOR_NECROSIS_FACTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_DETECTION_OF_OTHER_ORGANISM, GOBP_INTERLEUKIN_1_PRODUCTION, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GNF2_MCL1, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, FOSTER_TOLERANT_MACROPHAGE_DN

GO Biological Process (17): pattern recognition receptor signaling pathway (GO:0002221), apoptotic process (GO:0006915), nervous system development (GO:0007399), negative regulation of tumor necrosis factor-mediated signaling pathway (GO:0010804), detection of bacterium (GO:0016045), positive regulation of interleukin-1 beta production (GO:0032731), defense response to bacterium (GO:0042742), regulation of apoptotic process (GO:0042981), negative regulation of apoptotic process (GO:0043066), negative regulation of neuron apoptotic process (GO:0043524), innate immune response (GO:0045087), positive regulation of JNK cascade (GO:0046330), icosanoid biosynthetic process (GO:0046456), positive regulation of inflammatory response (GO:0050729), pyroptotic inflammatory response (GO:0070269), immune system process (GO:0002376), inflammatory response (GO:0006954)

GO Molecular Function (9): cysteine-type endopeptidase inhibitor activity (GO:0004869), ATP binding (GO:0005524), cysteine-type endopeptidase inhibitor activity involved in apoptotic process (GO:0043027), metal ion binding (GO:0046872), protein serine/threonine kinase binding (GO:0120283), nucleotide binding (GO:0000166), protein binding (GO:0005515), ATP hydrolysis activity (GO:0016887), peptidase inhibitor activity (GO:0030414)

GO Cellular Component (4): cytoplasm (GO:0005737), basolateral plasma membrane (GO:0016323), canonical inflammasome complex (GO:0061702), IPAF inflammasome complex (GO:0072557)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to bacterium	2
defense response	2
apoptotic process	2
inflammatory response	2
innate immune response-activating signaling pathway	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
system development	1
negative regulation of cytokine-mediated signaling pathway	1
regulation of tumor necrosis factor-mediated signaling pathway	1
tumor necrosis factor-mediated signaling pathway	1
detection of other organism	1
interleukin-1 beta production	1
regulation of interleukin-1 beta production	1
positive regulation of interleukin-1 production	1
regulation of programmed cell death	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
negative regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
immune response	1
defense response to symbiont	1
JNK cascade	1
positive regulation of MAPK cascade	1
regulation of JNK cascade	1
icosanoid metabolic process	1
carboxylic acid biosynthetic process	1
positive regulation of defense response	1
positive regulation of response to external stimulus	1
regulation of inflammatory response	1
biological_process	1
cysteine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
cysteine-type endopeptidase regulator activity involved in apoptotic process	1
cation binding	1
protein kinase binding	1

Protein interactions and networks

STRING

1592 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NAIP	AIM2	O14862	989
NAIP	NLRC4	Q9NPP4	988
NAIP	NLRP1	Q9C000	971
NAIP	NLRP3	Q96P20	965
NAIP	MEFV	O15553	954
NAIP	CASP1	P29466	946
NAIP	CIITA	P33076	928
NAIP	NLRP6	P59044	914
NAIP	PYCARD	Q9ULZ3	908
NAIP	SMN1	Q16637	875
NAIP	SERF1A	O75920	872
NAIP	NLRP7	Q8WX94	787
NAIP	NLRP12	P59046	741
NAIP	CASP5	P51878	731
NAIP	GTF2H2	Q13888	709

IntAct

6 interactions, top by confidence:

A	B	Type	Score
NAIP	prgI	psi-mi:“MI:0915”(physical association)	0.400
Prdm16	ESYT2	psi-mi:“MI:0914”(association)	0.350
Mecom	ESYT2	psi-mi:“MI:0914”(association)	0.350
MYC		psi-mi:“MI:0914”(association)	0.350
hslU	NAIP	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (12): NAIP (Affinity Capture-Western), NAIP (Affinity Capture-RNA), NAIP (Far Western), DIABLO (Affinity Capture-Western), NAIP (Affinity Capture-Western), NAIP (Reconstituted Complex), XAF1 (Affinity Capture-Western), NAIP (Protein-peptide), NAIP (Affinity Capture-Western), MAP3K7 (Affinity Capture-Western), NAIP (Affinity Capture-MS), MAP3K7 (Reconstituted Complex)

ESM2 similar proteins: A0A140LIF8, A0A2P1BRP3, A0A386CAB9, A0JN92, A1A4Y4, O14791, P27473, P59045, P86448, P86449, Q0GUM3, Q13075, Q3B7D9, Q3T9E4, Q3TL54, Q53G44, Q5NCI0, Q5RFJ8, Q60766, Q62293, Q66X01, Q66X03, Q66X05, Q66X22, Q6AYC2, Q6ZSC3, Q7Z745, Q84WJ0, Q86W28, Q8BV66, Q8BVM9, Q8C6J9, Q8CBA2, Q8CCN1, Q8TCB0, Q8TCY9, Q8TD90, Q90597, Q99388, Q99J64

Diamond homologs: A2AWP0, A5D8Q0, A9JTP3, A9ULZ2, D3ZDI6, O14064, O62640, O88738, P41437, Q05AK5, Q13075, Q24307, Q28H51, Q5BKL8, Q5E9J6, Q5NVC7, Q60989, Q68LP1, Q6AYH3, Q6GNY1, Q6R7D0, Q6R7I2, Q6TEM9, Q804S5, Q80SY4, Q86YT6, Q8JGN5, Q8JHV9, Q8R516, Q8WY64, Q969K3, Q96AX9, Q96CA5, Q96P09, Q99KR6, Q9JIB3, Q9JIB6, Q9LY87, Q9NR09, Q9QUK4

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
NAIP	down-regulates	CASP9	binding
NAIP	“form complex”	“NLRC4 inflammasome”	binding
DAMPS	“up-regulates activity”	NAIP
PAMPs	“up-regulates activity”	NAIP

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	25
Likely benign	4
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2361 predictions. Top by Δscore:

Variant	Effect	Δscore
5:70976155:CATA:C	donor_loss	1.0000
5:70976156:ATACC:A	donor_loss	1.0000
5:70976157:TA:T	donor_loss	1.0000
5:70976247:C:CC	acceptor_gain	1.0000
5:70976249:A:C	acceptor_gain	1.0000
5:70977054:TTTTA:T	acceptor_gain	1.0000
5:70977055:TTTA:T	acceptor_gain	1.0000
5:70977059:C:CC	acceptor_gain	1.0000
5:70979863:CCTTA:C	donor_loss	1.0000
5:70979866:TA:T	donor_loss	1.0000
5:70979867:A:AG	donor_loss	1.0000
5:70979868:C:CA	donor_loss	1.0000
5:70979892:G:C	donor_gain	1.0000
5:70980037:C:CC	acceptor_gain	1.0000
5:70998722:A:AC	donor_gain	1.0000
5:70998723:C:CC	donor_gain	1.0000
5:71001694:TCA:T	donor_loss	1.0000
5:71001695:CAC:C	donor_loss	1.0000
5:71001696:ACCTG:A	donor_loss	1.0000
5:71001819:T:C	acceptor_gain	1.0000
5:71003853:CACAT:C	acceptor_gain	1.0000
5:71003854:ACATC:A	acceptor_loss	1.0000
5:71003855:CAT:C	acceptor_gain	1.0000
5:71003856:ATC:A	acceptor_loss	1.0000
5:71003857:TCTGT:T	acceptor_loss	1.0000
5:71003858:C:CC	acceptor_gain	1.0000
5:71003858:CTGT:C	acceptor_loss	1.0000
5:71003859:T:G	acceptor_loss	1.0000
5:71011273:A:AC	donor_gain	1.0000
5:71011274:C:CC	donor_gain	1.0000

AlphaMissense

9291 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:71011285:A:G	W220R	0.987
5:71011285:A:T	W220R	0.987
5:71012359:A:G	F186S	0.987
5:71012622:G:C	F98L	0.986
5:71012622:G:T	F98L	0.986
5:71012624:A:G	F98L	0.986
5:71012727:C:A	R63S	0.986
5:71012727:C:G	R63S	0.986
5:71011322:C:A	W207C	0.985
5:71011322:C:G	W207C	0.985
5:71011280:G:C	F221L	0.984
5:71011280:G:T	F221L	0.984
5:71011282:A:G	F221L	0.984
5:71011324:A:G	W207R	0.983
5:71011324:A:T	W207R	0.983
5:71011354:A:G	C197R	0.981
5:71011291:C:G	A218P	0.980
5:71012358:A:C	F186L	0.979
5:71012358:A:T	F186L	0.979
5:71012360:A:G	F186L	0.979
5:71012538:G:C	F126L	0.979
5:71012538:G:T	F126L	0.979
5:71012540:A:G	F126L	0.979
5:71012658:A:C	F86L	0.979
5:71012658:A:T	F86L	0.979
5:71012659:A:G	F86S	0.979
5:71012660:A:G	F86L	0.979
5:71012728:C:G	R63T	0.978
5:71011290:G:T	A218D	0.975
5:71003848:A:C	F226L	0.974

dbSNP variants (sampled 300 via entrez): RS1000023510 (5:71106604 C>T), RS1000028176 (5:71010889 T>A), RS1000052755 (5:71106000 C>T), RS1000318405 (5:70997565 A>G), RS1000330265 (5:71063919 A>C), RS1000384897 (5:71017469 G>A,T), RS1000417888 (5:71016152 G>A), RS1000615393 (5:69598963 C>T), RS1000751547 (5:70989256 C>T), RS1000927154 (5:71056263 G>C,T), RS1000971094 (5:69601849 A>C), RS1001024742 (5:71099122 A>C), RS1001055756 (5:71097474 G>A), RS1001224638 (5:71026953 C>T), RS1001381046 (5:71070575 A>G)

Disease associations

OMIM: gene MIM:600355 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — Inhibitors of apoptosis (IAP) protein family

CTD chemical–gene interactions

64 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Curcumin	decreases expression, affects cotreatment, affects expression	4
Doxorubicin	affects cotreatment, affects expression, increases expression, decreases response to substance	4
Resveratrol	affects cotreatment, decreases expression	3
bisphenol A	decreases expression	2
entinostat	decreases expression, affects cotreatment	2
Arsenic	affects cotreatment, affects expression, decreases expression, increases abundance	2
Cisplatin	decreases expression, decreases response to substance	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Valproic Acid	decreases expression	2
Aflatoxin B1	decreases expression, decreases methylation	2
bisphenol F	increases expression	1
uranyl acetate	affects expression	1
VX-agent	decreases expression	1
decabromobiphenyl ether	decreases expression	1
trichostatin A	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
butyraldehyde	decreases expression	1
tetrabromobisphenol A	increases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
usnic acid	decreases expression	1
N(6)-(3-iodobenzyl)-5’-N-methylcarboxamidoadenosine	decreases expression, decreases response to substance	1
CGP 52608	affects binding, increases reaction	1
3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-1H-pyrrolo(2,3-b)pyridine	increases expression	1
pinostrobin	increases expression	1
EKB 569	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1

Clinical trials (associated diseases)

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