TRIB1

Chr 8

tribbles pseudokinase 1

Also known as: C8FW, GIG-2, GIG2, SKIP1, TRB-1, TRB1

NCBI Gene: 10221 ENSG00000173334 UniProt: Q96RU8 OMIM: 609461

The TRIB1 protein functions as an adapter that regulates protein degradation by directing COP1 ubiquitin ligase activity toward specific substrates like CEBPA, and controls myeloid cell differentiation including macrophages, eosinophils, and neutrophils. Mutations in TRIB1 cause autosomal dominant intellectual disability with macrocephaly, seizures, and behavioral abnormalities. This gene is highly constrained against loss-of-function variants, indicating that haploinsufficiency is likely not well-tolerated.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

Enables RNA polymerase II-specific DNA-binding transcription factor binding activity; mitogen-activated protein kinase kinase binding activity; and protein kinase inhibitor activity. Involved in several processes, including JNK cascade; negative regulation of lipopolysaccharide-mediated signaling pathway; and regulation of protein kinase activity. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2025]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.46

Clinical Summary— TRIB1

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.83) — some intolerance to loss-of-function variants.

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ClinVar Variants

48 VUS of 61 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — TRIB1

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.46LOEUF

pLI 0.833

Z-score 2.68

OE 0.10 (0.03–0.46)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.21Z-score

OE missense 0.73 (0.63–0.85)

119 obs / 162.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.10 (0.03–0.46)

0≤0.351.4

Missense OE?0.73 (0.63–0.85)

0≤0.61.4

Synonymous OE?1.16

0≤1.21.6

LoF obs/exp: 1 / 10.3Missense obs/exp: 119 / 162.4Syn Z: -1.05

This gene — mechanism propensity

0.3991th %ile

GOF

0.4677th %ile

LOF

0.68top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.46

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

61 submitted variants in ClinVar

ClinVar

Classification Summary

VUS48

Likely Benign2

Benign2

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	48	0	48
Likely Benign	0	2	2
Benign	1	1	2
Total	49	3	52

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

View in ClinVar →

53 pathogenic / likely-pathogenic (of 57) ClinVar copy-number / structural variants overlap TRIB1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →