MSX2

Chr 5AD

msh homeobox 2

Also known as: CRS2, FPP, HOX8, MSH, PFM, PFM1

NCBI Gene: 4488ENSG00000120149UniProt: P35548

This gene encodes a member of the muscle segment homeobox gene family. The encoded protein is a transcriptional repressor whose normal activity may establish a balance between survival and apoptosis of neural crest-derived cells required for proper craniofacial morphogenesis. The encoded protein may also have a role in promoting cell growth under certain conditions and may be an important target for the RAS signaling pathways. Mutations in this gene are associated with parietal foramina 1 and craniosynostosis type 2. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Craniosynostosis 2MIM #604757
AD
Parietal foramina 1MIM #168500
AD
Parietal foramina with cleidocranial dysplasiaMIM #168550
AD
291
ClinVar variants
32
Pathogenic / LP
0.26
pLI score
0
Active trials
Clinical Summary— MSX2
🧬
Gene-Disease Validity (ClinGen)
parietal foramina · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.
📋
ClinVar Variants
32 Pathogenic / Likely Pathogenic· 140 VUS of 291 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.
0.82LOEUF
pLI 0.262
Z-score 1.90
OE 0.26 (0.10–0.82)
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.
0.47Z-score
OE missense 0.89 (0.78–1.03)
141 obs / 157.6 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.0.26 (0.10–0.82)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.89 (0.78–1.03)
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.0.97
0≤1.21.6
LoF obs/exp: 2 / 7.7Missense obs/exp: 141 / 157.6Syn Z: 0.18

ClinVar Variant Classifications

291 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic28
Likely Pathogenic4
VUS140
Likely Benign63
Benign52
Conflicting4
28
Pathogenic
4
Likely Pathogenic
140
VUS
63
Likely Benign
52
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
3
3
22
0
28
Likely Pathogenic
2
1
1
0
4
VUS
1
99
39
1
140
Likely Benign
0
11
19
33
63
Benign
0
2
42
8
52
Conflicting
—4
Total611612342291

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

View in ClinVar →

Protein Context — Lollipop Plot

MSX2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

MSX2-related craniosynostosis

definitive
ADUndeterminedAltered Gene Product Structure
Dev. DisordersSkeletal
G2P ↗
missense variantinframe deletioninframe insertion

MSX2-related enlarged parietal foramina/cranium bifidum

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. DisordersSkeletal
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
MSH HOMEOBOX 2; MSX2
MIM #123101 · *

Craniosynostosis 2

MIM #604757

Molecular basis of disorder known

Autosomal dominant

Parietal foramina 1

MIM #168500

Molecular basis of disorder known

Autosomal dominant

Parietal foramina with cleidocranial dysplasia

MIM #168550

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — MSX2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Targeting Msx2 as a brake in the fusion fate of osteoclasts and an anabolic therapy in pre-clinical models of osteoporosis.
Ma Q et al.·Nat Commun
2025Functional
TRPV4 Promotes Vascular Calcification by Directly Associating With and Activating β-Catenin.
Yuan M et al.·Arterioscler Thromb Vasc Biol
2025
Management of craniosynostosis.
Panchal J et al.·Plast Reconstr Surg
2003Review
Craniosynostosis as a clinical and diagnostic problem: molecular pathology and genetic counseling.
Kutkowska-Kaźmierczak A et al.·J Appl Genet
2018Review
Craniosynostosis and related limb anomalies.
Wilkie AO et al.·Novartis Found Symp
2001Review
Cranial suture biology and dental development: genetic and clinical perspectives.
De Coster PJ et al.·J Oral Pathol Med
2007Review
The genetic basis of tooth impaction: a systematic review.
Papadopoulos S et al.·Clin Oral Investig
2025Review
Genetic basis of potential therapeutic strategies for craniosynostosis.
Melville H et al.·Am J Med Genet A
2010Review
Molecular genetics of craniosynostotic syndromes.
Müller U et al.·Graefes Arch Clin Exp Ophthalmol
1997Review
Prognostic Relevance and Function of MSX2 in Colorectal Cancer.
Liu J et al.·J Diabetes Res
2017
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