TCOF1

Chr 5AD

treacle ribosome biogenesis factor 1

Also known as: MFD1, TCS, TCS1, treacle

NCBI Gene: 6949ENSG00000070814UniProt: Q13428

This gene encodes a nucleolar protein with a LIS1 homology domain. The protein is involved in ribosomal DNA gene transcription through its interaction with upstream binding factor (UBF). Mutations in this gene have been associated with Treacher Collins syndrome, a disorder which includes abnormal craniofacial development. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2008]

Primary Disease Associations & Inheritance

Treacher Collins syndrome 1MIM #154500
AD
668
ClinVar variants
121
Pathogenic / LP
0.95
pLI score· haploinsufficient
0
Active trials
Clinical Summary— TCOF1
🧬
Gene-Disease Validity (ClinGen)
Treacher-Collins syndrome · 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 0.95). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
121 Pathogenic / Likely Pathogenic· 344 VUS of 668 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.31LOEUF
pLI 0.954
Z-score 5.92
OE 0.19 (0.12–0.31)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

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.
0.34Z-score
OE missense 0.97 (0.91–1.02)
773 obs / 800.0 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.0.19 (0.12–0.31)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.97 (0.91–1.02)
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.1.09
0≤1.21.6
LoF obs/exp: 12 / 62.6Missense obs/exp: 773 / 800.0Syn Z: -1.24

ClinVar Variant Classifications

668 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic74
Likely Pathogenic47
VUS344
Likely Benign178
Benign7
Conflicting18
74
Pathogenic
47
Likely Pathogenic
344
VUS
178
Likely Benign
7
Benign
18
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
52
4
18
0
74
Likely Pathogenic
36
0
11
0
47
VUS
3
313
25
3
344
Likely Benign
0
26
49
103
178
Benign
0
0
5
2
7
Conflicting
—18
Total91343108108668

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

View in ClinVar →

Protein Context — Lollipop Plot

TCOF1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

TCOF1-related Treacher Collins syndrome

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. DisordersSkeletalEar
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Treacher Collins syndrome 1

MIM #154500

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — TCOF1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Treacher Collins Syndrome: Genetics, Clinical Features and Management.
Marszałek-Kruk BA et al.·Genes (Basel)
2021Review
NBS1 facilitates preribosomal RNA biogenesis.
Luo M et al.·Proc Natl Acad Sci U S A
2025
Treacher Collins syndrome.
Dixon J et al.·Orthod Craniofac Res
2007Review
FOSL1 is a key regulator of a super-enhancer driving TCOF1 expression in triple-negative breast cancer.
He Q et al.·Epigenetics Chromatin
2024
FuHsi maintains nucleolar integrity.
Yang X et al.·Biochem Biophys Res Commun
2025
High mutation detection rate in TCOF1 among Treacher Collins syndrome patients reveals clustering of mutations and 16 novel pathogenic changes.
Splendore A et al.·Hum Mutat
2000Review
nNOS-mediated S-nitrosylation of TCOF1 regulates KRAS proteostasis to suppress hepatoblastoma progression.
Wang M et al.·Redox Biol
2025
A novel intronic TCOF1 pathogenic variant in a Chinese family with Treacher Collins syndrome.
Sun H et al.·BMC Med Genomics
2024Case report
Identification of novel TCOF1 mutations in Treacher Collins syndrome and their functional characterization.
Chen Y et al.·Orphanet J Rare Dis
2025Functional
Genetic mutations in ribosomal biogenesis gene TCOF1 identified in human neural tube defects.
Wang F et al.·Mol Genet Genomic Med
2023
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