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 several functions, including mitogen-activated protein kinase kinase binding activity; protein kinase inhibitor activity; and transcription regulator inhibitor activity. Involved in several processes, including negative regulation of signal transduction; negative regulation of smooth muscle cell proliferation; and regulation of MAP kinase activity. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Jun 2026]

GeneReviews OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.46

LOEUF

LOF

Mechanism· predicted

📖

GeneReview available — TRIB1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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

Background carrier burden — how many people carry a rare variant somewhere in TRIB1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 120

498 rare PASS variants

Rare truncating (LoF)

1 in 3,800

40 rare PASS variants

Rare synonymous (reference)

1 in 250

243 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TRIB1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 130	1 in 3,400
South Asian	~43k	1 in 150	1 in 2,200
Remaining (unassigned)	~30k	1 in 68	1 in 2,700
European (Finnish)	~27k	1 in 440	1 in 2,600
Admixed American	~22k	1 in 110	1 in 1,200
African / African American	~21k	1 in 140	1 in 3,800
East Asian	~20k	1 in 110	≈ 1 in 4,600
Ashkenazi Jewish	~13k	1 in 920	≈ 1 in 9,400
Middle Eastern	~2,884	1 in 230	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 2 of 3 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 3.? see exons ↓