TRIP12

Chr 2AD

thyroid hormone receptor interactor 12

Also known as: MRD49, TRIP-12, TRIPC, ULF

NCBI Gene: 9320ENSG00000153827UniProt: Q14669

The protein encoded by this gene is an E3 ubiquitin-protein ligase involved in the degradation of the p19ARF/ARF isoform of CDKN2A, a tumor suppressor. The encoded protein also plays a role in the DNA damage response by regulating the stability of USP7, which regulates tumor suppressor p53. [provided by RefSeq, Jan 2017]

Primary Disease Associations & Inheritance

Intellectual developmental disorder, autosomal dominant 49MIM #617752
AD
UniProtClark-Baraitser syndrome
492
ClinVar variants
82
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— TRIP12
🧬
Gene-Disease Validity (ClinGen)
complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
82 Pathogenic / Likely Pathogenic· 322 VUS of 492 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.06LOEUF
pLI 1.000
Z-score 9.34
OE 0.02 (0.01–0.06)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
4.64Z-score
OE missense 0.60 (0.56–0.64)
639 obs / 1065.2 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.02 (0.01–0.06)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.60 (0.56–0.64)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.05
0≤1.21.6
LoF obs/exp: 2 / 105.5Missense obs/exp: 639 / 1065.2Syn Z: -0.76

ClinVar Variant Classifications

492 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic60
Likely Pathogenic22
VUS322
Likely Benign80
Benign3
Conflicting5
60
Pathogenic
22
Likely Pathogenic
322
VUS
80
Likely Benign
3
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
21
1
38
0
60
Likely Pathogenic
8
4
10
0
22
VUS
4
285
33
0
322
Likely Benign
0
32
11
37
80
Benign
0
0
0
3
3
Conflicting
—5
Total333229240492

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

View in ClinVar →

Protein Context — Lollipop Plot

TRIP12 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

TRIP12-related intellectual disability with or without autism spectrum disorder

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Intellectual developmental disorder, autosomal dominant 49

MIM #617752

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The neurodevelopmental and facial phenotype in individuals with a TRIP12 variant.
Aerden M et al.·Eur J Hum Genet
2023
The m(6)A methyltransferase METTL3 drives neuroinflammation and neurotoxicity through stabilizing BATF mRNA in microglia.
Wu X et al.·Cell Death Differ
2025
Targeting cTRIP12 counteracts ferroptosis resistance and augments sensitivity to immunotherapy in pancreatic cancer.
Lin H et al.·Drug Resist Updat
2025
LINC00921 reduces lung cancer radiosensitivity by destabilizing NUDT21 and driving aberrant MED23 alternative polyadenylation.
Zhang N et al.·Cell Rep
2023
Episignature Mapping of TRIP12 Provides Functional Insight into Clark-Baraitser Syndrome.
van der Laan L et al.·Int J Mol Sci
2022Functional
The Role of a Novel TRIP12 Mutation in Intellectual Disability: A Molecular and Clinical Investigation in Multiplex Family.
Nobakht R et al.·J Mol Neurosci
2025Case report
Unraveling the Molecular and Clinical Consequences of an Intragenic TRIP12 Duplication Using Genomic and RNA Analyses.
Du H et al.·Am J Med Genet A
2025Case report
Identification of new TRIP12 variants and detailed clinical evaluation of individuals with non-syndromic intellectual disability with or without autism.
Bramswig NC et al.·Hum Genet
2017
USP7 overexpression prevents the progression of clear cell renal cell carcinoma by enhancing pyroptosis via TRIP12 deubiquitination.
Li H et al.·Cancer Biol Ther
2025
Neurodevelopmental Phenotype Associated with TRIP12: Report of a Family Carrying the p.Asp1135Val Variant.
Margiotti K et al.·Genes (Basel)
2025Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10

External Resources

Links to major genomics databases and tools