TBX19

Chr 1AR

T-box transcription factor 19

Also known as: TBS19, TPIT, dJ747L4.1

NCBI Gene: 9095 ENSG00000143178 UniProt: O60806 OMIM: 604614

TBX19 encodes a T-box transcription factor that activates POMC gene expression and is essential for differentiation of the pituitary POMC lineage. Biallelic mutations cause isolated adrenocorticotropic hormone (ACTH) deficiency, leading to adrenal insufficiency with symptoms including weight loss, anorexia, weakness, nausea, vomiting, and hypotension. The condition follows autosomal recessive inheritance.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.981 OMIM phenotype

Clinical Summary— TBX19

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

27 unique Pathogenic / Likely Pathogenic· 111 VUS of 232 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — TBX19

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.98LOEUF

pLI 0.000

Z-score 1.63

OE 0.59 (0.37–0.98)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.56Z-score

OE missense 0.90 (0.81–1.00)

228 obs / 253.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.59 (0.37–0.98)

0≤0.351.4

Missense OE?0.90 (0.81–1.00)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 11 / 18.6Missense obs/exp: 228 / 253.2Syn Z: -0.57

This gene — mechanism propensity

0.6840th %ile

GOF

0.5071th %ile

LOF

0.50top 25%

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

LOF63% of P/LP variants are LoF

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

232 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic15

Likely Pathogenic12

VUS111

Likely Benign44

Benign31

Conflicting7

Pathogenic

Likely Pathogenic

111

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	11	3	1	0	15
Likely Pathogenic	6	5	0	1	12
VUS	1	86	22	2	111
Likely Benign	0	3	16	25	44
Benign	0	1	24	6	31
Conflicting	—				7
Total	18	98	63	34	220

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

19 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap TBX19 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →