TRIP4

Chr 15AR

thyroid hormone receptor interactor 4

Also known as: ASC-1, ASC1, HsT17391, MDCDC, SMABF1, ZC2HC5

NCBI Gene: 9325ENSG00000103671UniProt: Q15650

This gene encodes a subunit of the tetrameric nuclear activating signal cointegrator 1 (ASC-1) complex, which associates with transcriptional coactivators, nuclear receptors and basal transcription factors to facilitate nuclear receptors-mediated transcription. This protein is localized in the nucleus and contains an E1A-type zinc finger domain, which mediates interaction with transcriptional coactivators and ligand-bound nuclear receptors, such as thyroid hormone receptor and retinoid X receptor alpha, but not glucocorticoid receptor. Mutations in this gene are associated with spinal muscular atrophy with congenital bone fractures-1 (SMABF1). [provided by RefSeq, Apr 2016]

Primary Disease Associations & Inheritance

?Muscular dystrophy, congenital, Davignon-Chauveau typeMIM #617066
AR
Spinal muscular atrophy with congenital bone fractures 1MIM #616866
AR
367
ClinVar variants
46
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— TRIP4
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
46 Pathogenic / Likely Pathogenic· 144 VUS of 367 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
0.67LOEUF
pLI 0.000
Z-score 3.18
OE 0.45 (0.30–0.67)
Tolerant

Typical tolerance to LoF variation

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.
0.57Z-score
OE missense 0.91 (0.82–1.00)
275 obs / 302.9 exp
Tolerant

Mild missense constraint

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.0.45 (0.30–0.67)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.91 (0.82–1.00)
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: 17 / 38.2Missense obs/exp: 275 / 302.9Syn Z: -0.37

ClinVar Variant Classifications

367 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic30
Likely Pathogenic16
VUS144
Likely Benign129
Benign31
Conflicting4
30
Pathogenic
16
Likely Pathogenic
144
VUS
129
Likely Benign
31
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
9
1
20
0
30
Likely Pathogenic
6
0
10
0
16
VUS
4
130
10
0
144
Likely Benign
0
5
68
56
129
Benign
0
0
25
6
31
Conflicting
—4
Total1913613362354

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

View in ClinVar →

Protein Context — Lollipop Plot

TRIP4 · protein map & ClinVar variants

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

Gene2Phenotype Curations

TRIP4-related prenatal spinal muscular atrophy and congenital bone fractures

strong
ARLoss 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

?Muscular dystrophy, congenital, Davignon-Chauveau type

MIM #617066

Molecular basis of disorder known

Autosomal recessive

Spinal muscular atrophy with congenital bone fractures 1

MIM #616866

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
ASC1 complex related conditions: Two novel paediatric patients with TRIP4 pathogenic variants and review of literature.
Dembour A et al.·Eur J Med Genet
2022Review
A review of core myopathy: central core disease, multiminicore disease, dusty core disease, and core-rod myopathy.
Ogasawara M et al.·Neuromuscul Disord
2021Review
Genetics of Alzheimer's disease.
Chouraki V et al.·Adv Genet
2014Review
'A novel TRIP4 Variant Associated with Peripheral Neuropathy: Expanding the Clinical and Genetic Spectrum of ASC1-Related Myopathy'.
Frongia I et al.·J Neuromuscul Dis
2024
GATA2 promotes cervical cancer progression under the transcriptional activation of TRIP4.
Wang R et al.·Cell Signal
2025
The Tumor-Promoting Role of TRIP4 in Melanoma Progression and its Involvement in Response to BRAF-Targeted Therapy.
Hao J et al.·J Invest Dermatol
2018
Exome reanalysis and proteomic profiling identified TRIP4 as a novel cause of cerebellar hypoplasia and spinal muscular atrophy (PCH1).
Töpf A et al.·Eur J Hum Genet
2021Case report
Inherited Defects of the ASC-1 Complex in Congenital Neuromuscular Diseases.
Meunier J et al.·Int J Mol Sci
2021Review
Clinical phenotype and next-generation sequencing as essential tools for the diagnosis of a rare form of congenital myopathy due to a TRIP4 intragenic deletion.
Decio A et al.·Neurol Sci
2024
Further clinical and genetic evidence of ASC-1 complex dysfunction in congenital neuromuscular disease.
Marais A et al.·Eur J Med Genet
2022
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools