NNT

Summary

NNT (nicotinamide nucleotide transhydrogenase, HGNC:7863) is a protein-coding gene on chromosome 5p12, encoding NAD(P) transhydrogenase, mitochondrial (Q13423). The transhydrogenation between NADH and NADP is coupled to respiration and ATP hydrolysis and functions as a proton pump across the membrane.

This gene encodes an integral protein of the inner mitochondrial membrane. The enzyme couples hydride transfer between NAD(H) and NADP(+) to proton translocation across the inner mitochondrial membrane. Under most physiological conditions, the enzyme uses energy from the mitochondrial proton gradient to produce high concentrations of NADPH. The resulting NADPH is used for biosynthesis and in free radical detoxification.

Source: NCBI Gene 23530 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 11
• Clinical variants (ClinVar): 327 total — 21 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 42
• Druggable target: yes
• MANE Select transcript: NM_182977

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7863
Approved symbol	NNT
Name	nicotinamide nucleotide transhydrogenase
Location	5p12
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000112992
Ensembl biotype	protein_coding
OMIM	607878
Entrez	23530

Gene structure

Transcript identifiers

Ensembl transcripts: 44 — 35 protein_coding, 6 nonsense_mediated_decay, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000264663, ENST00000344920, ENST00000503059, ENST00000503651, ENST00000505678, ENST00000506893, ENST00000512422, ENST00000512996, ENST00000513390, ENST00000515208, ENST00000652986, ENST00000653251, ENST00000654405, ENST00000654931, ENST00000656666, ENST00000657172, ENST00000657973, ENST00000658729, ENST00000660676, ENST00000660752, ENST00000662525, ENST00000669601, ENST00000670904, ENST00000671668, ENST00000871260, ENST00000871261, ENST00000871262, ENST00000871263, ENST00000871264, ENST00000921858, ENST00000964737, ENST00000964738, ENST00000964739, ENST00000964740, ENST00000964741, ENST00000964742, ENST00000964743, ENST00000964744, ENST00000964745, ENST00000964746, ENST00000964747, ENST00000964748, ENST00000964749, ENST00000964750

RefSeq mRNA: 3 — MANE Select: NM_182977 NM_001331026, NM_012343, NM_182977

CCDS: CCDS3949, CCDS82994

Canonical transcript exons

ENST00000344920 — 22 exons

Exon	Start	End
ENSE00000742787	43619032	43619119
ENSE00000742788	43624032	43624120
ENSE00000742789	43628200	43628387
ENSE00000742790	43644192	43644325
ENSE00000742791	43644611	43644802
ENSE00000742792	43645357	43645510
ENSE00000742794	43649147	43649308
ENSE00000742796	43650477	43650587
ENSE00000742797	43651739	43651884
ENSE00000742798	43653018	43653213
ENSE00000742799	43655840	43656073
ENSE00000742800	43656653	43656813
ENSE00000742801	43659171	43659350
ENSE00000742804	43675511	43675670
ENSE00000742805	43677725	43677806
ENSE00000742806	43700119	43700237
ENSE00001148802	43609143	43609346
ENSE00001374370	43704255	43707396
ENSE00002080482	43603180	43603294
ENSE00003581945	43702621	43702736
ENSE00003671282	43615848	43616065
ENSE00003683434	43612908	43613137

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 98.35.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 35.5903 / max 639.5387, expressed in 1819 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
56339	26.7835	1814
56338	7.7102	1527
56340	0.8458	123
56342	0.2509	98

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
heart right ventricle	UBERON:0002080	98.35	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.17	gold quality
biceps brachii	UBERON:0001507	98.09	gold quality
diaphragm	UBERON:0001103	97.86	gold quality
heart left ventricle	UBERON:0002084	97.65	gold quality
cardiac ventricle	UBERON:0002082	97.64	gold quality
right atrium auricular region	UBERON:0006631	97.59	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.52	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.49	gold quality
gastrocnemius	UBERON:0001388	97.48	gold quality
vastus lateralis	UBERON:0001379	97.46	gold quality
muscle of leg	UBERON:0001383	97.31	gold quality
cardiac atrium	UBERON:0002081	97.21	gold quality
body of tongue	UBERON:0011876	97.01	gold quality
muscle organ	UBERON:0001630	97.00	gold quality
skeletal muscle organ	UBERON:0014892	97.00	gold quality
apex of heart	UBERON:0002098	96.86	gold quality
cortical plate	UBERON:0005343	96.84	gold quality
heart	UBERON:0000948	96.56	gold quality
triceps brachii	UBERON:0001509	96.39	gold quality
skeletal muscle tissue	UBERON:0001134	96.32	gold quality
right lobe of liver	UBERON:0001114	96.11	gold quality
quadriceps femoris	UBERON:0001377	95.92	gold quality
gluteal muscle	UBERON:0002000	95.69	gold quality
muscle tissue	UBERON:0002385	95.46	gold quality
adrenal tissue	UBERON:0018303	95.41	gold quality
ganglionic eminence	UBERON:0004023	95.31	gold quality
liver	UBERON:0002107	95.15	gold quality
ventricular zone	UBERON:0003053	94.88	gold quality
myocardium	UBERON:0002349	94.86	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.89
E-GEOD-81383	no	758.30
E-GEOD-137537	no	3.54

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

76 targeting NNT, 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-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-548A-3P	99.76	70.58	3524
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-3617-5P	99.75	69.41	1968
HSA-MIR-641	99.75	69.35	1975
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-519A-3P	99.67	71.67	1868
HSA-MIR-519B-3P	99.67	71.67	1868

Literature-anchored findings (GeneRIF, showing 24)

• the expression of the transhydrogenase gene in subsections of the human brain showed a distribution that apparently varied as a function of neuronal density (PMID:12223207)
• In the failing heart a partial loss of Nnt activity adversely impacts NADPH-dependent enzymes and the capacity to maintain membrane potential, thus contributing to a decline in bioenergetic capacity, redox regulation and antioxidant defense. (PMID:20388492)
• Results suggest that NNT may have a role in ROS detoxification in human adrenal glands. (PMID:22634753)
• NNT mRNA expression is significantly higher in visceral fat of obese patients and correlates with body weight, BMI, % body fat, visceral and sc fat area, waist and hip circumference, and fasting plasma insulin. (PMID:23592659)
• Data suggest mutations in nicotinamide nucleotide transhydrogenase (NNT) as contributory to left ventricular noncompaction (LVNC). (PMID:26025024)
• This report of a novel NNT mutation, p.G200S, expands the phenotype of NNT mutations to include mineralocorticoid deficiency. It provides the first evidence that NNT mutations can cause oxidative stress and mitochondrial defects. (PMID:26070314)
• identified a 6.67 Mb homozygous region harboring the NNT gene in a Dutch patient presenting with familial glucocorticoid deficiency (FGD); a novel homozygous mutation (NM_012343.3: c.1259dupG) in NNT was revealed; reviewed the literature for all the reported NNT mutations and their clinical presentation (PMID:26548497)
• NNT should be sequenced in all primary adrenal insufficiencies for which the most frequent etiologies have been ruled out. As NNT is involved in oxidative stress, careful follow-up is needed to evaluate mineralocorticoid biosynthesis extent, and gonadal, heart and thyroid function. (PMID:27129361)
• Study describes the fi rst structural model of the human NNT. The 3D model identifies functional and structural H-NNT key motifs and gain essential insight into the structural and functional effect of deleterious amino acid substitutions causing glucocorticoid de fi ciency and LVNC cardiomyopathy, as well as rare homozygote amino acid variations. (PMID:27459240)
• Findings suggest that NNT is essential to homeostasis of NADH and NADPH pools, anomalies of which affect HIF-1alpha- and HDAC1-dependent pathways, and hence retrograde response of mitochondria. (PMID:28478381)
• NNT knockdown in adrenocortical carcinoma increased intracellular levels of oxidative stress; this resulted in a pronounced suppression of cell proliferation and higher apoptotic rates, as well as sensitization of cells to chemically induced oxidative stress. (PMID:29850793)
• Overexpression of nicotinamide nucleotide transhydrogenase (NNT) was associated with shorter overall and disease free survival in gastric cancer. Knockdown of NNT caused significantly NADPH reduction, induced high levels of Reactive Oxygen Species and significant cell apoptosis under oxidative stress conditions such as glucose deprival and anoikis. (PMID:30059901)
• Low NNT expression is associated with gastric cancer. (PMID:31309731)
• Study looked at the expression of nicotinamide nucleotide transhydrogenase (NNT) and NNT-AS1 in the peripheral blood of multiple sclerosis patients to find their participation in the pathogenesis of this immune-related disorder. We detected up-regulation of NNT expression in male subjects aged over 50 compared with the corresponding control subjects. (PMID:31474168)
• LncRNA NNT-AS1 regulates the progression of lung cancer through the NNT-AS1/miR-3666/E2F2 axis. (PMID:31957837)
• Nicotinamide nucleotide transhydrogenase regulates mitochondrial metabolism in NSCLC through maintenance of Fe-S protein function. (PMID:32196080)
• Cellular Redox State Acts as Switch to Determine the Direction of NNT-Catalyzed Reaction in Cystic Fibrosis Cells. (PMID:33478087)
• NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism. (PMID:34233163)
• Nicotinamide nucleotide transhydrogenase mutation analysis in Chinese patients with thyroid dysgenesis. (PMID:34545694)
• Long-Term Follow-Up of Three Family Members with a Novel NNT Pathogenic Variant Causing Primary Adrenal Insufficiency. (PMID:35627102)
• Nicotinamide Nucleotide Transhydrogenase Is Essential for Adrenal Steroidogenesis: Clinical and In Vitro Lessons. (PMID:36478070)
• IL-1beta-associated NNT acetylation orchestrates iron-sulfur cluster maintenance and cancer immunotherapy resistance. (PMID:37244254)
• Coenzyme Q10 and nicotinamide nucleotide transhydrogenase: Sentinels for mitochondrial hydrogen peroxide signaling. (PMID:37573896)
• Lack of NAD(P)+ transhydrogenase activity in patients with primary adrenal insufficiency due to NNT variants. (PMID:38261461)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	nnt	ENSDARG00000023536
mus_musculus	Nnt	ENSMUSG00000025453
mus_musculus	Nnt	ENSMUSG00000116207
rattus_norvegicus	Nnt	ENSRNOG00000026842
caenorhabditis_elegans		WBGENE00003778

Protein

Protein identifiers

NAD(P) transhydrogenase, mitochondrial — Q13423 (reviewed: Q13423)

Alternative names: Nicotinamide nucleotide transhydrogenase, Pyridine nucleotide transhydrogenase

All UniProt accessions (14): Q13423, A0A590UJA4, A0A590UJI3, A0A590UJM2, A0A590UJM7, A0A590UJV8, A0A590UK15, A0A590UK29, A0A590UKC7, D6RAI5, D6RCR6, D6RHU2, E9PCX7, H0Y9R2

UniProt curated annotations — full annotation on UniProt →

Function. The transhydrogenation between NADH and NADP is coupled to respiration and ATP hydrolysis and functions as a proton pump across the membrane. May play a role in reactive oxygen species (ROS) detoxification in the adrenal gland.

Subunit / interactions. Homodimer.

Subcellular location. Mitochondrion inner membrane.

Tissue specificity. Widely expressed with expression most readily detectable in adrenal, heart, kidney, thyroid and adipose tissues.

Disease relevance. Glucocorticoid deficiency 4 with or without mineralocorticoid deficiency (GCCD4) [MIM:614736] A form of glucocorticoid deficiency, a rare autosomal recessive disorder characterized by resistance to ACTH action on the adrenal cortex, adrenal insufficiency and an inability of the adrenal cortex to produce cortisol. It usually presents in the neonatal period or in early childhood with episodes of hypoglycemia and other symptoms related to cortisol deficiency, including failure to thrive, recurrent illnesses or infections, convulsions, and shock. In a small number of patients hypoglycemia can be sufficiently severe and persistent that it leads to serious long-term neurological damage or death. The diagnosis is readily confirmed with a low plasma cortisol measurement in the presence of an elevated ACTH level, and normal aldosterone and plasma renin measurements. The disease is caused by variants affecting the gene represented in this entry.

Similarity. In the N-terminal section; belongs to the AlaDH/PNT family. In the C-terminal section; belongs to the PNT beta subunit family.

RefSeq proteins (3): NP_001317955, NP_036475, NP_892022* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007698	AlaDH/PNT_NAD(H)-bd	Domain
IPR007886	AlaDH/PNT_N	Domain
IPR008142	AlaDH/PNT_CS1	Conserved_site
IPR008143	Ala_DH/PNT_CS2	Conserved_site
IPR024605	NADP_transhyd_a_C	Domain
IPR026255	NADP_transhyd_a	Family
IPR029035	DHS-like_NAD/FAD-binding_dom	Homologous_superfamily
IPR034300	PNTB-like	Domain
IPR036291	NAD(P)-bd_dom_sf	Homologous_superfamily

Pfam: PF01262, PF02233, PF05222, PF12769

Enzyme classification (BRENDA):

• EC 1.6.1.2 — NAD(P)+ transhydrogenase (Re/Si-specific) (BRENDA: 0 organisms, 0 substrates, 0 inhibitors, 0 Km, 0 kcat entries)
• EC 7.1.1.1 — proton-translocating NAD(P)+ transhydrogenase (BRENDA: 25 organisms, 111 substrates, 114 inhibitors, 65 Km, 22 kcat entries)

Substrate kinetics (BRENDA)

10 substrates with measured Km, best-characterized 10. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
NADPH	0.0051–0.12	18
NADH	0.0017–0.066	15
THIO-NADP+	0.008–0.063	12
ACETYLPYRIDINE ADENINE DINUCLEOTIDE	0.028–0.166	4
NAD+	0.028–0.125	4
NADP+	0.0017–0.04	4
OXIDIZED 3-ACETYLPYRIDINE ADENINE DINUCLEOTIDE	0.06–0.8	4
NMNH	2.6–3.4	2
OXIDIZED ACETYLPYRIDINE ADENINE DINUCLEOTIDE	0.02–0.026	2
REDUCED ACETYLPYRIDINE ADENINE DINUCLEOTIDE	—	0

Catalyzed reactions (Rhea), 1 shown:

• NAD(+) + NADPH + H(+)(in) = NADH + NADP(+) + H(+)(out) (RHEA:47992)

UniProt features (81 total): transmembrane region 14, binding site 12, helix 12, sequence variant 11, sequence conflict 11, modified residue 7, strand 7, topological domain 4, transit peptide 1, chain 1, turn 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
1DJL	X-RAY DIFFRACTION	2
1U31	X-RAY DIFFRACTION	2.2
1PT9	X-RAY DIFFRACTION	2.42

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13423-F1	90.80	0.80

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 (12): 182–184; 237; 257–259; 287; 300; 319; 933; 965–970; 1007–1011; 1026–1027; 1042–1049; 1068–1069

Post-translational modifications (7): 70, 117, 224, 294, 331, 397, 1079

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-71403	Citric acid cycle (TCA cycle)

MSigDB gene sets: 341 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_DN, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, FREAC2_01, WANG_CLIM2_TARGETS_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, PAL_PRMT5_TARGETS_UP, GOBP_NADPPLUS_METABOLIC_PROCESS, GOZGIT_ESR1_TARGETS_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, MORF_HDAC2, FOXO1_01, MODULE_503, DOANE_BREAST_CANCER_CLASSES_DN, RODWELL_AGING_KIDNEY_NO_BLOOD_DN, GOBP_MONOATOMIC_CATION_TRANSPORT

GO Biological Process (11): tricarboxylic acid cycle (GO:0006099), NADPH regeneration (GO:0006740), positive regulation of mitochondrial membrane potential (GO:0010918), intracellular oxygen homeostasis (GO:0032364), response to vitamin (GO:0033273), negative regulation of apoptotic process (GO:0043066), cell redox homeostasis (GO:0045454), reactive oxygen species metabolic process (GO:0072593), cellular oxidant detoxification (GO:0098869), proton transmembrane transport (GO:1902600), positive regulation of hydrogen peroxide catabolic process (GO:1903285)

GO Molecular Function (6): NAD(P)+ transhydrogenase (Si-specific) activity (GO:0003957), proton-translocating NAD(P)+ transhydrogenase activity (GO:0008750), NADP binding (GO:0050661), NAD binding (GO:0051287), nucleotide binding (GO:0000166), oxidoreductase activity (GO:0016491)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), membrane (GO:0016020), respiratory chain complex (GO:0098803)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Aerobic respiration and respiratory electron transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
adenyl nucleotide binding	2
aerobic respiration	1
primary metabolic process	1
generation of precursor metabolites and energy	1
NADP+ metabolic process	1
positive regulation of membrane potential	1
regulation of mitochondrial membrane potential	1
intracellular chemical homeostasis	1
response to nutrient	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
cellular homeostasis	1
metabolic process	1
cellular detoxification	1
monoatomic cation transmembrane transport	1
positive regulation of catabolic process	1
hydrogen peroxide catabolic process	1
regulation of hydrogen peroxide catabolic process	1
positive regulation of reactive oxygen species metabolic process	1
oxidoreductase activity, acting on NAD(P)H as acceptor	1
proton transmembrane transporter activity	1
oxidoreduction-driven active transmembrane transporter activity	1
active monoatomic ion transmembrane transporter activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
cellular anatomical structure	1
protein-containing complex	1

Protein interactions and networks

STRING

1596 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NNT	IDH2	P48735	887
NNT	IDH3B	O43837	808
NNT	IDH3A	P50213	714
NNT	IDH3G	P51553	612
NNT	ACLY	P53396	574
NNT	GSR	P00390	554
NNT	TXNRD2	Q9NNW7	543
NNT	CYFIP2	Q96F07	520
NNT	IDH1	O75874	519
NNT	TXN	P10599	506
NNT	ME3	Q16798	489
NNT	NADK2	Q4G0N4	478
NNT	MC2R	Q01718	474
NNT	GLRX2	Q9NS18	469
NNT	PGD	P52209	439

IntAct

96 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
NDUFS7	NDUFS8	psi-mi:“MI:0914”(association)	0.640
EVA1B	NRP1	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
sseJ	AGPS	psi-mi:“MI:0914”(association)	0.460
CLDN7	NNT	psi-mi:“MI:0915”(physical association)	0.400
MVP	NNT	psi-mi:“MI:0915”(physical association)	0.370
Papss1	TCOF1	psi-mi:“MI:0914”(association)	0.350
Cdc26	PEX10	psi-mi:“MI:0914”(association)	0.350
Mkln1	NNT	psi-mi:“MI:0914”(association)	0.350
HUWE1	NCOA4	psi-mi:“MI:0914”(association)	0.350
SLAIN2	TARS3	psi-mi:“MI:0914”(association)	0.350
Wiz	CLNS1A	psi-mi:“MI:0914”(association)	0.350
Mis12	CTNNB1	psi-mi:“MI:0914”(association)	0.350
ATL2	ACRBP	psi-mi:“MI:0914”(association)	0.350
PAPD5	UNC119B	psi-mi:“MI:0914”(association)	0.350
NEIL3	SF3B2	psi-mi:“MI:0914”(association)	0.350
Junb	RGPD3	psi-mi:“MI:0914”(association)	0.350
MME		psi-mi:“MI:0914”(association)	0.350
Prdm16	ESYT2	psi-mi:“MI:0914”(association)	0.350
Mecom	ESYT2	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
ADGRE5	TMEM223	psi-mi:“MI:0914”(association)	0.350

BioGRID (233): NNT (Affinity Capture-MS), NNT (Affinity Capture-MS), NNT (Affinity Capture-MS), NNT (Affinity Capture-MS), NNT (Affinity Capture-MS), NNT (Affinity Capture-MS), NNT (Affinity Capture-MS), NNT (Affinity Capture-MS), NNT (Affinity Capture-MS), NNT (Proximity Label-MS), NNT (Proximity Label-MS), NNT (Proximity Label-MS), NNT (Proximity Label-MS), NNT (Proximity Label-MS), NNT (Proximity Label-MS)

ESM2 similar proteins: A0T0P0, A2ZBW5, C0HLB3, C0HLB4, C0HLB5, C0HLB6, O16110, O18882, O22552, O24011, P0DH92, P0DH93, P0DH94, P11024, P23380, P23956, P23957, P25515, P27449, P31403, P31413, P32842, P50515, P51246, P55277, P59228, P59229, P63081, P63082, P68161, P68162, Q00607, Q03105, Q0IUB5, Q13423, Q17046, Q21898, Q26250, Q40585, Q41773

Diamond homologs: A0QVQ8, E1V931, E5Y944, P07001, P0C186, P11024, P17556, P17557, P43842, P63478, P99151, P9WQB0, P9WQB1, Q08352, Q13423, Q2FG29, Q2FH00, Q2FXL7, Q2FYJ2, Q2RSB2, Q2YTD1, Q2YY66, Q49YD9, Q4L750, Q5HF65, Q5HFY4, Q5HNJ6, Q61941, Q6G8L8, Q6G9C3, Q6GFZ8, Q6GGW9, Q6LX40, Q8CNW8, Q8CX61, Q8NW54, Q8NWQ3, Q931P7, Q99TF4, Q9AIK2

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 114 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
Anchoring of the basal body to the plasma membrane	7	10.2×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	21
Likely pathogenic	8
Uncertain significance	150
Likely benign	99
Benign	25

Top pathogenic / likely-pathogenic (29)

Variant ID	HGVS	Classification
1119993	NM_182977.3(NNT):c.2274del (p.Ile758fs)	Pathogenic
1705295	NM_182977.3(NNT):c.1089del (p.Leu362_Tyr363insTer)	Pathogenic
1705519	NM_182977.3(NNT):c.2635-1G>T	Pathogenic
218365	NM_182977.3(NNT):c.1259dup (p.His421fs)	Pathogenic
265839	NM_182977.3(NNT):c.644T>C (p.Phe215Ser)	Pathogenic
265840	NM_182977.3(NNT):c.1163A>C (p.Tyr388Ser)	Pathogenic
265841	NM_012343.3(NNT):c.(-54+1_-53-1)_(381+1_382-1)del	Pathogenic
265843	NM_182977.3(NNT):c.385C>T (p.Arg129Ter)	Pathogenic
265844	NM_182977.3(NNT):c.211C>T (p.Arg71Ter)	Pathogenic
2686048	NM_182977.3(NNT):c.1025T>C (p.Val342Ala)	Pathogenic
35538	NM_182977.3(NNT):c.1598C>T (p.Ala533Val)	Pathogenic
35539	NM_182977.3(NNT):c.600-1del	Pathogenic
35540	NM_182977.3(NNT):c.2930T>C (p.Leu977Pro)	Pathogenic
35541	NM_182977.3(NNT):c.1107_1110del (p.Thr369_His370insTer)	Pathogenic
35542	NM_182977.3(NNT):c.3027T>G (p.Asn1009Lys)	Pathogenic
35543	NM_182977.3(NNT):c.3022G>C (p.Ala1008Pro)	Pathogenic
3880151	NM_182977.3(NNT):c.645del (p.Phe215fs)	Pathogenic
4082571	NM_182977.3(NNT):c.2635-1G>A	Pathogenic
4699098	NM_182977.3(NNT):c.2023C>T (p.Gln675Ter)	Pathogenic
4712698	NM_182977.3(NNT):c.1314del (p.Thr440fs)	Pathogenic
800942	NM_182977.3(NNT):c.98dup (p.Leu33fs)	Pathogenic
2027241	NM_182977.3(NNT):c.776+1G>A	Likely pathogenic
265842	NM_182977.3(NNT):c.598G>A (p.Gly200Ser)	Likely pathogenic
3649581	NM_182977.3(NNT):c.381+1del	Likely pathogenic
3767966	NM_182977.3(NNT):c.2519_2522dup (p.Tyr841Ter)	Likely pathogenic
4819794	NM_182977.3(NNT):c.1820dup (p.Gly608fs)	Likely pathogenic
4819930	NM_182977.3(NNT):c.1861C>T (p.Gln621Ter)	Likely pathogenic
930557	NM_182977.3(NNT):c.1575dup (p.Pro526fs)	Likely pathogenic
985183	NM_182977.3(NNT):c.2798A>G (p.Tyr933Cys)	Likely pathogenic

SpliceAI

3635 predictions. Top by Δscore:

Variant	Effect	Δscore
5:43613012:GGTTT:G	donor_gain	1.0000
5:43613108:G:GT	donor_gain	1.0000
5:43613108:G:T	donor_gain	1.0000
5:43613138:G:GG	donor_gain	1.0000
5:43616005:TTCC:T	donor_gain	1.0000
5:43616061:GCGGG:G	donor_gain	1.0000
5:43616063:GGG:G	donor_gain	1.0000
5:43616064:GG:G	donor_gain	1.0000
5:43616064:GGG:G	donor_gain	1.0000
5:43616065:GG:G	donor_gain	1.0000
5:43619029:A:G	acceptor_gain	1.0000
5:43619030:A:AG	acceptor_gain	1.0000
5:43619031:G:GG	acceptor_gain	1.0000
5:43628186:A:AG	acceptor_gain	1.0000
5:43628187:A:G	acceptor_gain	1.0000
5:43628189:A:AG	acceptor_gain	1.0000
5:43628190:A:G	acceptor_gain	1.0000
5:43628198:A:AG	acceptor_gain	1.0000
5:43628199:G:GG	acceptor_gain	1.0000
5:43628199:GA:G	acceptor_gain	1.0000
5:43628351:G:GT	donor_gain	1.0000
5:43628385:CAG:C	donor_loss	1.0000
5:43628386:AG:A	donor_loss	1.0000
5:43628387:GGT:G	donor_loss	1.0000
5:43644321:ATAAG:A	donor_loss	1.0000
5:43644322:TAAGG:T	donor_loss	1.0000
5:43644323:AAGGT:A	donor_loss	1.0000
5:43644324:AGG:A	donor_loss	1.0000
5:43644325:GGTAT:G	donor_loss	1.0000
5:43644326:GTAT:G	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000017005 (5:43665822 C>A,T), RS1000054570 (5:43664853 G>C), RS1000072182 (5:43620367 C>T), RS1000079362 (5:43618908 C>T), RS1000123780 (5:43703580 C>G,T), RS1000137227 (5:43635214 A>C), RS1000140021 (5:43707345 A>G), RS1000190425 (5:43638724 T>A), RS1000250985 (5:43689572 A>G), RS1000259768 (5:43659540 C>T), RS1000289381 (5:43671166 C>G,T), RS1000364337 (5:43632355 G>T), RS1000373525 (5:43676315 A>G), RS1000385144 (5:43633066 T>A), RS1000408672 (5:43620627 T>C)

Disease associations

OMIM: gene MIM:607878 | disease phenotypes: MIM:614736

GenCC curated gene-disease

Disease	Classification	Inheritance
glucocorticoid deficiency 4	Definitive	Autosomal recessive
familial glucocorticoid deficiency	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR

Mondo (2): glucocorticoid deficiency 4 (MONDO:0013874), familial glucocorticoid deficiency (MONDO:0008733)

Orphanet (1): Familial glucocorticoid deficiency (Orphanet:361)

HPO phenotypes

42 total (30 of 42 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000027	Azoospermia
HP:0000028	Cryptorchidism
HP:0000098	Tall stature
HP:0000127	Renal salt wasting
HP:0000826	Precocious puberty
HP:0000846	Adrenal insufficiency
HP:0000851	Congenital hypothyroidism
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001325	Hypoglycemic coma
HP:0001508	Failure to thrive
HP:0001639	Hypertrophic cardiomyopathy
HP:0001824	Weight loss
HP:0001943	Hypoglycemia
HP:0002013	Vomiting
HP:0002014	Diarrhea
HP:0002019	Constipation
HP:0002039	Anorexia
HP:0002153	Hyperkalemia
HP:0002173	Hypoglycemic seizures
HP:0002445	Tetraplegia
HP:0002574	Episodic abdominal pain
HP:0002615	Hypotension
HP:0002719	Recurrent infections
HP:0002902	Hyponatremia
HP:0002960	Autoimmunity
HP:0003154	Increased circulating ACTH level
HP:0004319	Decreased circulating aldosterone concentration

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST003265_365	Post bronchodilator FEV1/FVC ratio in COPD	1.000000e-06
GCST003265_366	Post bronchodilator FEV1/FVC ratio in COPD	1.000000e-06
GCST003265_367	Post bronchodilator FEV1/FVC ratio in COPD	1.000000e-06
GCST003265_368	Post bronchodilator FEV1/FVC ratio in COPD	1.000000e-06
GCST003265_392	Post bronchodilator FEV1/FVC ratio in COPD	2.000000e-06
GCST005091_2	Subcutaneous adipose tissue	3.000000e-07
GCST006629_96	Pulse pressure	4.000000e-11
GCST007429_34	Lung function (FVC)	3.000000e-12
GCST007430_32	Peak expiratory flow	7.000000e-10
GCST007432_65	FEV1	2.000000e-17
GCST010241_278	Apolipoprotein A1 levels	5.000000e-09

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004713	FEV/FVC ratio
EFO:0005763	pulse pressure measurement
EFO:0004312	vital capacity
EFO:0009718	peak expiratory flow
EFO:0004314	forced expiratory volume
EFO:0004614	apolipoprotein A 1 measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C565974	Familial Glucocorticoid Deficiency 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066471 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.25	Kd	5.676	nM	CHEMBL5653589
8.25	ED50	5.676	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 4 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148876: Binding affinity to human NNT incubated for 45 mins by Kinobead based pull down assay	kd	0.0057	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	5
bisphenol A	increases expression	3
Air Pollutants	decreases expression, affects expression, increases abundance	3
Cyclosporine	decreases expression	3
Benzo(a)pyrene	increases expression, decreases methylation	2
Hydrogen Peroxide	affects expression, affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	affects expression, affects cotreatment, increases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
triphenyl phosphate	affects expression	1
sodium arsenate	decreases expression	1
arsenite	increases methylation	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
tobacco tar	increases expression	1
ochratoxin A	increases expression	1
periodate-oxidized adenosine	affects expression	1
beta-methylcholine	affects expression	1
perfluoro-n-nonanoic acid	decreases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	increases expression, affects cotreatment	1
6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide	decreases response to substance, increases expression, decreases reaction	1
LDN 193189	affects cotreatment, increases expression	1
picoxystrobin	decreases expression	1
bisphenol AF	increases expression	1
Temozolomide	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651918	Binding	Binding affinity to human NNT incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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