TBX19

Summary

TBX19 (T-box transcription factor 19, HGNC:11596) is a protein-coding gene on chromosome 1q24.2, encoding T-box transcription factor TBX19 (O60806). Transcriptional regulator involved in developmental processes.

This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. Mutations in this gene were found in patients with isolated deficiency of pituitary POMC-derived ACTH, suggesting an essential role for this gene in differentiation of the pituitary POMC lineage. ACTH deficiency is characterized by adrenal insufficiency symptoms such as weight loss, lack of appetite (anorexia), weakness, nausea, vomiting, and low blood pressure.

Source: NCBI Gene 9095 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital isolated adrenocorticotropic hormone deficiency (Definitive, GenCC)
• Clinical variants (ClinVar): 233 total — 15 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 18
• MANE Select transcript: NM_005149

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11596
Approved symbol	TBX19
Name	T-box transcription factor 19
Location	1q24.2
Locus type	gene with protein product
Status	Approved
Aliases	dj747L4.1, TPIT
Ensembl gene	ENSG00000143178
Ensembl biotype	protein_coding
OMIM	604614
Entrez	9095

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000367821, ENST00000431969, ENST00000441464, ENST00000465440

RefSeq mRNA: 1 — MANE Select: NM_005149 NM_005149

CCDS: CCDS1272

Canonical transcript exons

ENST00000367821 — 8 exons

Exon	Start	End
ENSE00000958507	168293144	168293278
ENSE00000958508	168297724	168297785
ENSE00000958509	168300422	168300483
ENSE00000958510	168305008	168305196
ENSE00000958511	168308742	168308877
ENSE00001844590	168312708	168314426
ENSE00002236854	168280877	168281293
ENSE00002260040	168291160	168291424

Expression profiles

Bgee: expression breadth ubiquitous, 167 present calls, max score 94.44.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0572 / max 56.2874, expressed in 5 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
6488	0.0385	5
6489	0.0124	3
6487	0.0063	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adenohypophysis	UBERON:0002196	94.44	gold quality
pituitary gland	UBERON:0000007	92.80	gold quality
lower esophagus mucosa	UBERON:0035834	84.02	gold quality
body of uterus	UBERON:0009853	80.67	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.18	gold quality
ascending aorta	UBERON:0001496	79.34	gold quality
thoracic aorta	UBERON:0001515	79.03	gold quality
granulocyte	CL:0000094	78.28	gold quality
descending thoracic aorta	UBERON:0002345	77.09	gold quality
aorta	UBERON:0000947	76.28	gold quality
right ovary	UBERON:0002118	76.13	gold quality
left ovary	UBERON:0002119	75.96	gold quality
right lung	UBERON:0002167	75.52	gold quality
popliteal artery	UBERON:0002250	74.50	gold quality
tibial artery	UBERON:0007610	74.50	gold quality
ectocervix	UBERON:0012249	74.30	gold quality
endocervix	UBERON:0000458	74.07	gold quality
skin of leg	UBERON:0001511	73.90	gold quality
right coronary artery	UBERON:0001625	73.79	gold quality
muscle layer of sigmoid colon	UBERON:0035805	73.59	gold quality
mucosa of stomach	UBERON:0001199	72.87	gold quality
monocyte	CL:0000576	72.86	gold quality
leukocyte	CL:0000738	72.78	gold quality
mononuclear cell	CL:0000842	72.59	gold quality
skin of abdomen	UBERON:0001416	72.47	gold quality
left coronary artery	UBERON:0001626	72.12	gold quality
spleen	UBERON:0002106	71.89	gold quality
tibial nerve	UBERON:0001323	71.79	gold quality
left uterine tube	UBERON:0001303	71.47	gold quality
vagina	UBERON:0000996	70.85	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.81

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

4 targets.

Target	Regulation
ADAM2
CEL
CRH
POMC	Unknown

JASPAR motifs

Motif	Name	Family
MA0804.1	TBX19	Brachyury-related factors
MA0804.2	TBX19	Brachyury-related factors

JASPAR matrix evidence (PMIDs): PMID:12093383

miRNA regulators (miRDB)

55 targeting TBX19, 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-5193	100.00	67.26	1744
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-580-3P	99.67	69.23	1841
HSA-MIR-519A-3P	99.67	71.67	1868
HSA-MIR-519B-3P	99.67	71.67	1868
HSA-MIR-519C-3P	99.67	71.67	1870
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-4756-3P	99.62	66.30	1319
HSA-MIR-4708-3P	99.51	67.99	870
HSA-MIR-4643	99.49	67.63	1791
HSA-MIR-582-5P	99.47	70.79	2635
HSA-MIR-330-3P	99.41	69.95	2521
HSA-MIR-6505-3P	99.34	67.39	1071
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-5582-5P	99.27	71.42	1879

Literature-anchored findings (GeneRIF, showing 20)

• Review. Association of 2 mutations with an ACTH deficiency is consistent with the role of tbx19 in differentiation of POMC cells. (PMID:11916612)
• TPIT has a role in expression of the pro-opiomelanocortin gene and terminal differentiation of the pituitary corticotroph lineage, and its mutation causes early onset pituitary ACTH deficiency (PMID:12651888)
• Tpit, along with NGFI-B and SRC-2, is part of a transcription regulatory complex assembled on the POMC promoter in response to hormonal stimulation. (PMID:12970370)
• mutations in the TPIT gene, a T-box factor selectively expressed in developing corticotroph cells, have been found in cases of early-onset isolated ACTH deficiency (PMID:15476446)
• TPIT gene mutations is the principal molecular cause of neonatal congenital isolated ACTH deficiency (PMID:15613420)
• We report largest series of congenital ACTH deficiency and demonstrate molecular mechanism involves Tpit in majority of cases. (PMID:15666849)
• a new mutation (IVS4+1G>A) that affects the first nucleotide of the splice site at the 5’ end of the fourth intron in isolated adrenocorticotropic hormone deviciency (PMID:16390921)
• Overtransmission of a haplotype GAC at the TBX19 locus was associated with increased angry/hostility scores among suicide attempters. (PMID:16899054)
• the M86R TPIT mutation is defining an important surface of the T domain for multiple protein interactions and for transcription (PMID:17652218)
• The coordinate expression of Etv1 with POMC cell differentiation and its interaction with the highly cell-restricted Tpit factor indicate that Etv1 participates in a combinatorial code for pituitary cell-specific gene expression. (PMID:21622576)
• Identification of nine new TPIT mutations in a large series of congenital isolated ACTH-deficiency patients. (PMID:22170728)
• TPIT is identified as a target autoantigen in 10.5% of patients with lymphocytic hypophysitis. (PMID:22193973)
• TBX19 mRNA expression was significantly increased in tumorous tissues compared to that in non-tumorous tissues, and increased TBX19 mRNA expression was associated with positive lymph node metastasis. (PMID:29199261)
• A new mutation in the TBX19 gene in a patient with isolated ACTH deficiency. While overgrowth is a known feature of some types of adrenal insufficiencies, including MC2R gene defects and POMC deficiency, it may be a novel feature for TPIT (T-box pituitary restricted transcription factor )deficiency, as in this patient. [review] (PMID:30747411)
• A Rare Cause of Adrenal Insufficiency - Isolated ACTH Deficiency Due to TBX19 Mutation. (PMID:32344415)
• [Analysis of TBX19 gene variant in a child with congenital isolated adrenocorticotropic hormone deficiency]. (PMID:33423260)
• T-box transcription factor 19 promotes hepatocellular carcinoma metastasis through upregulating EGFR and RAC1. (PMID:35217793)
• TRIM65 determines the fate of a novel subtype of pituitary neuroendocrine tumors via ubiquitination and degradation of TPIT. (PMID:35218667)
• A novel TBX19 gene mutation in patients with isolated ACTH deficiency from distinct families with a common geographical origin. (PMID:36890856)
• Heterogeneity of TPIT expression in ACTH-secreting extra-pituitary neuroendocrine tumors (NETs) supports the existence of different cellular programs in pancreatic and pulmonary NETs. (PMID:37726450)

Cross-species orthologs

14 orthologs

Organism	Symbol	Gene ID
danio_rerio	tbx19	ENSDARG00000079187
mus_musculus	Tbx19	ENSMUSG00000026572
rattus_norvegicus	Tbx19	ENSRNOG00000002979
drosophila_melanogaster	H15	FBGN0016660
drosophila_melanogaster	mid	FBGN0261963
drosophila_melanogaster	ocm	FBGN0266083
caenorhabditis_elegans		WBGENE00003106
caenorhabditis_elegans		WBGENE00004750
caenorhabditis_elegans		WBGENE00006545
caenorhabditis_elegans		WBGENE00006546
caenorhabditis_elegans		WBGENE00006556
caenorhabditis_elegans		WBGENE00006557
caenorhabditis_elegans		WBGENE00006559
caenorhabditis_elegans		WBGENE00044798

Paralogs (16): TBX21 (ENSG00000073861), TBX5 (ENSG00000089225), TBX15 (ENSG00000092607), TBX18 (ENSG00000112837), TBX2 (ENSG00000121068), TBX4 (ENSG00000121075), TBX22 (ENSG00000122145), TBX3 (ENSG00000135111), TBR1 (ENSG00000136535), TBX6 (ENSG00000149922), EOMES (ENSG00000163508), TBXT (ENSG00000164458), TBX20 (ENSG00000164532), TBX10 (ENSG00000167800), MGA (ENSG00000174197), TBX1 (ENSG00000184058)

Protein

Protein identifiers

T-box transcription factor TBX19 — O60806 (reviewed: O60806)

Alternative names: T-box factor, pituitary

All UniProt accessions (3): O60806, H0Y4B1, H0Y5A7

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional regulator involved in developmental processes. Can activate POMC gene expression and repress the alpha glycoprotein subunit and thyroid-stimulating hormone beta promoters.

Subcellular location. Nucleus.

Disease relevance. ACTH deficiency, isolated (IAD) [MIM:201400] An autosomal recessive disorder that is characterized by adrenal insufficiency symptoms, such as weight loss, lack of appetite (anorexia), weakness, nausea, vomiting and low blood pressure (hypotension). The pituitary hormone ACTH is decreased or absent, and other cortisol and other steroid hormone levels in the blood are abnormally low. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (1): NP_005140* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001699	TF_T-box	Family
IPR002070	TF_Brachyury	Family
IPR008967	p53-like_TF_DNA-bd_sf	Homologous_superfamily
IPR018186	TF_T-box_CS	Conserved_site
IPR036960	T-box_sf	Homologous_superfamily
IPR046360	T-box_DNA-bd	Domain

Pfam: PF00907

UniProt features (3 total): chain 1, DNA-binding region 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60806-F1	64.24	0.35

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 200 (showing top): MORF_FLT1, CCAWYNNGAAR_UNKNOWN, MORF_MSH3, GOBP_FORMATION_OF_PRIMARY_GERM_LAYER, NKX25_02, MODULE_45, MORF_BRCA1, GOBP_PITUITARY_GLAND_DEVELOPMENT, MORF_ESR1, LHX3_01, MORF_RAD51L3, GOBP_FOREBRAIN_DEVELOPMENT, GTGCCTT_MIR506, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, MORF_CTSB

GO Biological Process (12): mesoderm formation (GO:0001707), cell fate specification (GO:0001708), heart morphogenesis (GO:0003007), regulation of transcription by RNA polymerase II (GO:0006357), anatomical structure morphogenesis (GO:0009653), pituitary gland development (GO:0021983), regulation of cell population proliferation (GO:0042127), regulation of cell differentiation (GO:0045595), regulation of DNA-templated transcription (GO:0006355), cell fate commitment (GO:0045165), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944)

GO Molecular Function (8): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), sequence-specific double-stranded DNA binding (GO:1990837), cis-regulatory region sequence-specific DNA binding (GO:0000987), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
cellular developmental process	2
transcription by RNA polymerase II	2
regulation of cellular process	2
cell differentiation	2
DNA-templated transcription	2
regulation of transcription by RNA polymerase II	2
transcription cis-regulatory region binding	2
formation of primary germ layer	1
mesoderm morphogenesis	1
cell fate commitment	1
heart development	1
animal organ morphogenesis	1
developmental process	1
anatomical structure development	1
diencephalon development	1
endocrine system development	1
gland development	1
cell population proliferation	1
regulation of developmental process	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
positive regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
transcription regulator activity	1
binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

805 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TBX19	PITX1	P78337	870
TBX19	POMC	P01189	870
TBX19	POU1F1	P28069	727
TBX19	CRH	P06850	715
TBX19	PROP1	O75360	656
TBX19	NR5A1	Q13285	644
TBX19	HESX1	Q9UBX0	606
TBX19	LHX4	Q969G2	589
TBX19	LHX3	Q9UBR4	585
TBX19	PRL	P01236	583
TBX19	ESX1	Q8N693	554
TBX19	NEUROD1	Q13562	544
TBX19	FSHB	P01225	544
TBX19	GNAS	Q5JWF2	529
TBX19	TSHB	P01222	512

IntAct

46 interactions, top by confidence:

A	B	Type	Score
TBX19	TBX6	psi-mi:“MI:0915”(physical association)	0.560
TBX19	NEDD9	psi-mi:“MI:0915”(physical association)	0.560
TBX19	ZIC1	psi-mi:“MI:0915”(physical association)	0.560
TBX19	IRX6	psi-mi:“MI:0915”(physical association)	0.560
POGZ	TBX19	psi-mi:“MI:0915”(physical association)	0.560
HGS	TBX19	psi-mi:“MI:0915”(physical association)	0.560
TBX19	TFG	psi-mi:“MI:0915”(physical association)	0.560
TBX19	VENTX	psi-mi:“MI:0915”(physical association)	0.560
TBX19	PITX1	psi-mi:“MI:0915”(physical association)	0.560
TBX19	GCM2	psi-mi:“MI:0915”(physical association)	0.560
TBX19	RAB2B	psi-mi:“MI:0915”(physical association)	0.560
TBX19	HOXC8	psi-mi:“MI:0915”(physical association)	0.560
TBX19	PRR35	psi-mi:“MI:0915”(physical association)	0.560
TBX19	LONRF1	psi-mi:“MI:0915”(physical association)	0.560
IL37	TBX19	psi-mi:“MI:0915”(physical association)	0.370
XCL1	TBX19	psi-mi:“MI:0915”(physical association)	0.370
TBX19	CAD	psi-mi:“MI:0914”(association)	0.350
TBX6	TBX19	psi-mi:“MI:0915”(physical association)	0.000
NEDD9	TBX19	psi-mi:“MI:0915”(physical association)	0.000
ZIC1	TBX19	psi-mi:“MI:0915”(physical association)	0.000
PITX1	TBX19	psi-mi:“MI:0915”(physical association)	0.000
GCM2	TBX19	psi-mi:“MI:0915”(physical association)	0.000
IRX6	TBX19	psi-mi:“MI:0915”(physical association)	0.000
POGZ	TBX19	psi-mi:“MI:0915”(physical association)	0.000
PRR35	TBX19	psi-mi:“MI:0915”(physical association)	0.000
HGS	TBX19	psi-mi:“MI:0915”(physical association)	0.000
TFG	TBX19	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (18): TBX19 (Synthetic Lethality), TBX19 (Two-hybrid), TBX19 (Two-hybrid), TBX19 (Two-hybrid), TBX19 (Two-hybrid), TBX19 (Two-hybrid), TBX19 (Two-hybrid), POGZ (Two-hybrid), TBX6 (Two-hybrid), VENTX (Two-hybrid), ZIC1 (Two-hybrid), LONRF1 (Two-hybrid), IRX6 (Two-hybrid), PRR35 (Two-hybrid), HGS (Two-hybrid)

ESM2 similar proteins: O13161, O15178, O60806, O70306, O75333, O95935, P20293, P24781, P56158, P57082, P70325, P70326, P79742, P79777, P79778, P79779, P87377, Q07998, Q17134, Q28HY0, Q29131, Q32NH9, Q3SA46, Q3SA47, Q3UPF5, Q5DTV4, Q5I2P1, Q5WM45, Q5XNS0, Q66JL1, Q810F8, Q861Q9, Q8AV66, Q8AXX2, Q8AYI2, Q8K402, Q91989, Q96SF7, Q98UD2, Q99593

Diamond homologs: A1YF56, A2AWL7, D3ZJK7, E1BEA8, O01409, O13161, O15119, O15178, O17212, O43435, O54839, O60806, O70306, O73718, O75333, O95935, O95936, O95947, P20293, P24781, P55965, P56158, P57082, P70323, P70324, P70325, P70326, P70327, P79742, P79777, P79778, P79779, P79944, P80492, P87377, P90971, Q07998, Q13207, Q16650, Q17134

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	10
Uncertain significance	111
Likely benign	44
Benign	31

Top pathogenic / likely-pathogenic (25)

Variant ID	HGVS	Classification
1676659	NM_005149.3(TBX19):c.688G>T (p.Glu230Ter)	Pathogenic
1687306	NM_005149.3(TBX19):c.665+1G>T	Pathogenic
293458	NM_005149.3(TBX19):c.535C>T (p.Arg179Ter)	Pathogenic
4714001	NM_005149.3(TBX19):c.829_830del (p.His277fs)	Pathogenic
488619	NM_005149.3(TBX19):c.568C>T (p.Gln190Ter)	Pathogenic
495297	K146R	Pathogenic
520566	NM_005149.3(TBX19):c.75_78del (p.Glu26fs)	Pathogenic
5440	NM_005149.3(TBX19):c.856C>T (p.Arg286Ter)	Pathogenic
5441	NM_005149.3(TBX19):c.383C>T (p.Ser128Phe)	Pathogenic
5442	NM_005149.3(TBX19):c.257T>G (p.Met86Arg)	Pathogenic
5443	NM_005149.3(TBX19):c.782del (p.Asn261fs)	Pathogenic
560673	NM_005149.3(TBX19):c.265del (p.Leu89fs)	Pathogenic
560675	NM_005149.3(TBX19):c.665+1del	Pathogenic
561125	NM_005149.3(TBX19):c.627C>G (p.Tyr209Ter)	Pathogenic
828147	NM_005149.3(TBX19):c.377C>T (p.Pro126Leu)	Pathogenic
1283918	NM_005149.3(TBX19):c.206G>A (p.Arg69Gln)	Likely pathogenic
2500768	NM_005149.3(TBX19):c.666-2A>T	Likely pathogenic
3065395	NM_005149.3(TBX19):c.617A>G (p.Lys206Arg)	Likely pathogenic
3233371	NM_005149.3(TBX19):c.604-1G>C	Likely pathogenic
3692833	NM_005149.3(TBX19):c.666-1G>A	Likely pathogenic
4277977	NM_005149.3(TBX19):c.566C>T (p.Thr189Ile)	Likely pathogenic
4294492	NM_005149.3(TBX19):c.469-1G>A	Likely pathogenic
4848595	NM_005149.3(TBX19):c.288G>A (p.Thr96=)	Likely pathogenic
4848823	NM_005149.3(TBX19):c.299G>A (p.Arg100His)	Likely pathogenic
828166	NM_005149.3(TBX19):c.608C>T (p.Thr203Met)	Likely pathogenic

SpliceAI

1197 predictions. Top by Δscore:

Variant	Effect	Δscore
1:168281256:G:GT	donor_gain	1.0000
1:168281289:GGCAG:G	donor_gain	1.0000
1:168281290:GCAGG:G	donor_gain	1.0000
1:168281294:G:T	donor_loss	1.0000
1:168281295:T:G	donor_loss	1.0000
1:168291422:C:T	donor_gain	1.0000
1:168291422:CAGG:C	donor_loss	1.0000
1:168291423:AGGT:A	donor_loss	1.0000
1:168291424:GGTA:G	donor_loss	1.0000
1:168291426:T:A	donor_loss	1.0000
1:168297715:A:AG	acceptor_gain	1.0000
1:168297715:AAAT:A	acceptor_gain	1.0000
1:168297716:A:G	acceptor_gain	1.0000
1:168297718:T:TA	acceptor_gain	1.0000
1:168297721:A:AG	acceptor_gain	1.0000
1:168297722:A:G	acceptor_gain	1.0000
1:168281290:GCAG:G	donor_gain	0.9900
1:168281294:G:GG	donor_gain	0.9900
1:168291158:A:AG	acceptor_gain	0.9900
1:168291158:AGAC:A	acceptor_gain	0.9900
1:168291158:AGACG:A	acceptor_gain	0.9900
1:168291159:G:GA	acceptor_gain	0.9900
1:168291159:GAC:G	acceptor_gain	0.9900
1:168291159:GACG:G	acceptor_gain	0.9900
1:168291159:GACGG:G	acceptor_gain	0.9900
1:168297712:T:TA	acceptor_gain	0.9900
1:168305006:A:AG	acceptor_gain	0.9900
1:168305006:AGTG:A	acceptor_gain	0.9900
1:168305006:AGTGG:A	acceptor_gain	0.9900
1:168305007:G:GA	acceptor_gain	0.9900

AlphaMissense

2925 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:168281241:T:A	W51R	1.000
1:168281241:T:C	W51R	1.000
1:168281251:T:C	F54S	1.000
1:168281272:T:C	M61T	1.000
1:168281275:T:A	I62N	1.000
1:168281293:G:C	R68T	1.000
1:168291167:T:C	F71L	1.000
1:168291168:T:C	F71S	1.000
1:168291168:T:G	F71C	1.000
1:168291169:T:A	F71L	1.000
1:168291169:T:G	F71L	1.000
1:168291171:C:A	P72Q	1.000
1:168291278:T:A	W108R	1.000
1:168291278:T:C	W108R	1.000
1:168291280:G:C	W108C	1.000
1:168291280:G:T	W108C	1.000
1:168291350:G:T	G132W	1.000
1:168291351:G:A	G132E	1.000
1:168291359:T:A	W135R	1.000
1:168291359:T:C	W135R	1.000
1:168291396:T:C	L147P	1.000
1:168293246:T:C	F191L	1.000
1:168293247:T:C	F191S	1.000
1:168293248:C:A	F191L	1.000
1:168293248:C:G	F191L	1.000
1:168293253:C:A	A193D	1.000
1:168293262:C:A	A196D	1.000
1:168293264:T:C	Y197H	1.000
1:168293269:G:C	Q198H	1.000
1:168293269:G:T	Q198H	1.000

dbSNP variants (sampled 300 via entrez): RS1000066935 (1:168291911 A>G), RS1000262309 (1:168296512 G>A,T), RS1000384087 (1:168313145 A>G), RS1000407740 (1:168283645 T>G), RS1000435064 (1:168279514 C>A,T), RS1000454449 (1:168300309 G>C,T), RS1000533 (1:168313253 T>C,G), RS1000623680 (1:168284389 T>C), RS1000669102 (1:168290750 C>T), RS1000682616 (1:168281726 T>A), RS1000852498 (1:168303158 A>G), RS1000919186 (1:168288581 A>G), RS1001045833 (1:168294289 C>A,T), RS1001267860 (1:168288268 T>C), RS1001291019 (1:168313711 G>A)

Disease associations

OMIM: gene MIM:604614 | disease phenotypes: MIM:201400

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital isolated adrenocorticotropic hormone deficiency	Definitive	Autosomal recessive

Mondo (2): congenital isolated adrenocorticotropic hormone deficiency (MONDO:0008720), pituitary stalk interruption syndrome (MONDO:0019828)

Orphanet (2): Congenital isolated ACTH deficiency (Orphanet:199296), Pituitary stalk interruption syndrome (Orphanet:95496)

HPO phenotypes

18 total (18 of 18 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000835	Adrenal hypoplasia
HP:0000952	Jaundice
HP:0001250	Seizure
HP:0001396	Cholestasis
HP:0001998	Neonatal hypoglycemia
HP:0002153	Hyperkalemia
HP:0002173	Hypoglycemic seizures
HP:0002615	Hypotension
HP:0002902	Hyponatremia
HP:0003162	Fasting hypoglycemia
HP:0003593	Infantile onset
HP:0006579	Prolonged neonatal jaundice
HP:0008163	Decreased circulating cortisol level
HP:0011735	Adrenocorticotropin deficient adrenal insufficiency
HP:0011748	Adrenocorticotropic hormone deficiency
HP:0012115	Hepatitis
HP:0012378	Fatigue

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C535668	Adrenocorticotropic hormone deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases methylation	2
Cyclosporine	increases expression	2
aristolochic acid I	increases expression	1
bisphenol F	affects cotreatment, increases expression	1
terbufos	increases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
jinfukang	affects cotreatment, decreases expression	1
(+)-JQ1 compound	increases expression	1
Ethanol	affects response to substance	1
Cisplatin	affects cotreatment, decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Fonofos	increases methylation	1
Estriol	decreases abundance	1
Hydrocortisone	decreases abundance	1
Indomethacin	affects cotreatment, increases expression	1
Parathion	increases methylation	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06760546	PHASE3	RECRUITING	A Trial of Setmelanotide in Patients With Congenital Hypothalamic Obesity (Sub-study of NCT05774756)
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns