TWIST2

Chr 2ADAR

twist family bHLH transcription factor 2

Also known as: AMS, BBRSAY, DERMO1, FFDD3, SETLSS, bHLHa39

NCBI Gene: 117581ENSG00000233608UniProt: Q8WVJ9

The protein encoded by this gene is a basic helix-loop-helix type transcription factor and shares similarity with Twist. This protein may inhibit osteoblast maturation and maintain cells in a preosteoblast phenotype during osteoblast development. This gene may be upregulated in certain cancers. Mutations in this gene cause focal facial dermal dysplasia 3, Setleis type. Two transcript variants encoding the same protein have been found. [provided by RefSeq, Apr 2014]

Primary Disease Associations & Inheritance

Ablepharon-macrostomia syndromeMIM #200110
AD
Barber-Say syndromeMIM #209885
AD
Focal facial dermal dysplasia 3, Setleis typeMIM #227260
AR
132
ClinVar variants
91
Pathogenic / LP
0.56
pLI score
0
Active trials
Clinical Summary— TWIST2
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.56) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
91 Pathogenic / Likely Pathogenic· 33 VUS of 132 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
1.15LOEUF
pLI 0.560
Z-score 1.46
OE 0.00 (0.00–1.15)
Moderately constrained

Highly tolerant — LoF variants common in population

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.
2.13Z-score
OE missense 0.37 (0.28–0.49)
33 obs / 89.9 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.00 (0.00–1.15)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.37 (0.28–0.49)
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.0.62
0≤1.21.6
LoF obs/exp: 0 / 2.5Missense obs/exp: 33 / 89.9Syn Z: 1.88

ClinVar Variant Classifications

132 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic89
Likely Pathogenic2
VUS33
Likely Benign8
89
Pathogenic
2
Likely Pathogenic
33
VUS
8
Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
3
85
0
89
Likely Pathogenic
0
0
2
0
2
VUS
0
22
11
0
33
Likely Benign
0
0
1
7
8
Benign
0
0
0
0
0
Total125997132

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

View in ClinVar →

Protein Context — Lollipop Plot

TWIST2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

TWIST2-related ablepharon-macrostomia syndrome

definitive
ADDominant NegativeAltered Gene Product Structure
Dev. DisordersSkin
G2P ↗

TWIST2-related Setleis syndrome

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

Ablepharon-macrostomia syndrome

MIM #200110

Molecular basis of disorder known

Autosomal dominant

Barber-Say syndrome

MIM #209885

Molecular basis of disorder known

Autosomal dominant

Focal facial dermal dysplasia 3, Setleis type

MIM #227260

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Molecular Mechanisms Regulating Epithelial Mesenchymal Transition (EMT) to Promote Cancer Progression.
Ghafoor S et al.·Int J Mol Sci
2025Review
Expression of Dickkopf-1 and Twist2 in Cervical Squamous Cell Carcinoma and Their Correlation with Vasculogenic Mimicry.
Wang B et al.·J Healthc Eng
2022
Ocular adnexal phenotype and management of a patient with mosaic expression of a mutation in TWIST2.
De Niear MA et al.·Orbit
2022Case report
Cryptophthalmos: associated syndromes and genetic disorders.
Landau-Prat D et al.·Ophthalmic Genet
2023
A20 in hepatic stellate cells suppresses chronic hepatitis by inhibiting DCLK1-JNK pathway-dependent chemokines.
Watakabe K et al.·FASEB J
2024
Mechanisms of Resistance to Anti-PD-1 Immunotherapy in Melanoma and Strategies to Overcome It.
Zielińska MK et al.·Biomolecules
2025Review
Fibrosis-Related Gene and Protein Expression in Normal and Glaucomatous Trabecular Meshwork Cells.
Yang YF et al.·Invest Ophthalmol Vis Sci
2025
Role of TWIST2, E-cadherin and Vimentin in epithelial ovarian carcinogenesis and prognosis and their interaction in cancer progression.
Li X et al.·Eur J Gynaecol Oncol
2016
CD73 contributes to the pathogenesis of fusion-negative rhabdomyosarcoma through the purinergic signaling pathway.
Hernandez KC et al.·Proc Natl Acad Sci U S A
2024
Twist2 is a valuable prognostic biomarker for colorectal cancer.
Yu H et al.·World J Gastroenterol
2013
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