SIX1

Chr 14AD

SIX homeobox 1

Also known as: BOS3, DFNA23, TIP39

NCBI Gene: 6495ENSG00000126778UniProt: Q15475

The protein encoded by this gene is a homeobox protein that is similar to the Drosophila 'sine oculis' gene product. This gene is found in a cluster of related genes on chromosome 14 and is thought to be involved in limb development. Defects in this gene are a cause of autosomal dominant deafness type 23 (DFNA23) and branchiootic syndrome type 3 (BOS3). [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Branchiootic syndrome 3MIM #608389
AD
Deafness, autosomal dominant 23MIM #605192
AD
292
ClinVar variants
40
Pathogenic / LP
0.65
pLI score
0
Active trials
Clinical Summary— SIX1
🧬
Gene-Disease Validity (ClinGen)
branchio-oto-renal syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.65) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
40 Pathogenic / Likely Pathogenic· 161 VUS of 292 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.
0.52LOEUF
pLI 0.653
Z-score 2.69
OE 0.17 (0.07–0.52)
Moderately constrained

More LoF-intolerant than ~75% 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.
1.19Z-score
OE missense 0.74 (0.63–0.86)
119 obs / 161.6 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.0.17 (0.07–0.52)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.74 (0.63–0.86)
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.1.13
0≤1.21.6
LoF obs/exp: 2 / 12.1Missense obs/exp: 119 / 161.6Syn Z: -0.90

ClinVar Variant Classifications

292 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic21
Likely Pathogenic19
VUS161
Likely Benign63
Benign12
Conflicting16
21
Pathogenic
19
Likely Pathogenic
161
VUS
63
Likely Benign
12
Benign
16
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
7
13
0
21
Likely Pathogenic
2
9
8
0
19
VUS
8
114
36
3
161
Likely Benign
0
2
23
38
63
Benign
0
0
12
0
12
Conflicting
—16
Total111329241292

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

View in ClinVar →

Protein Context — Lollipop Plot

SIX1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

SIX1-related deafness

definitive
ADUndeterminedAltered Gene Product Structure
Ear
G2P ↗
missense variantinframe deletioninframe insertion

SIX1-related non-syndromic craniosynostosis

strong
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

SIX1-related branchiootic syndrome

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

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
SIX HOMEOBOX 1; SIX1
MIM #601205 · *

Branchiootic syndrome 3

MIM #608389

Molecular basis of disorder known

Autosomal dominant

Deafness, autosomal dominant 23

MIM #605192

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — SIX1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Branchio-oto-renal syndrome.
Kochhar A et al.·Am J Med Genet A
2007Review
Regulation of cancer stem cell properties by SIX1, a member of the PAX-SIX-EYA-DACH network.
Kingsbury TJ et al.·Adv Cancer Res
2019Review
Association of Polymorphisms at the SIX1-SIX6 Locus With Primary Open-Angle Glaucoma.
Lu SY et al.·Invest Ophthalmol Vis Sci
2019Meta-analysis
SIX1 enhances aerobic glycolysis and progression in cervical cancer through ENO1.
Liu X et al.·Hum Cell
2025
Unexpected role of SIX1 variants in craniosynostosis: expanding the phenotype of SIX1-related disorders.
Calpena E et al.·J Med Genet
2022Case report
Phenotype-genotype correlation in patients with typical and atypical branchio-oto-renal syndrome.
Masuda M et al.·Sci Rep
2022Cohort
Integrative Multiomics and Drug Sensitivity Profiling Reveal Potential Biomarkers and Therapeutic Strategies in Pediatric Solid Tumors.
ElHarouni D et al.·Cancer Res
2026
Phenotypic and molecular basis of SIX1 variants linked to non-syndromic deafness and atypical branchio-otic syndrome in South Korea.
Lee S et al.·Sci Rep
2023
Whole exome sequencing in 18 Brazilian families with vertical transmission of non-syndromic oral clefts.
Copelli MM et al.·J Craniomaxillofac Surg
2025
SIX1: A Prognostic Biomarker in Uterine Corpus Endometrial Carcinoma.
Zhao Q et al.·Comb Chem High Throughput Screen
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