SIX3

Chr 2AD

SIX homeobox 3

Also known as: HPE2

NCBI Gene: 6496ENSG00000138083UniProt: O95343OMIM: 603714

This gene encodes a homeobox transcription factor that regulates eye and forebrain development during embryogenesis. Loss-of-function mutations cause holoprosencephaly type 2 and schizencephaly through autosomal dominant inheritance. The protein is intolerant to loss-of-function variants, consistent with its critical role in early brain patterning.

OMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
LOFmechanismADLOEUF 0.322 OMIM phenotypes
Clinical Summary— SIX3
⚡
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
48 unique Pathogenic / Likely Pathogenic· 142 VUS of 292 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
0.32LOEUF
pLI 0.947
Z-score 2.82
OE 0.00 (0.00–0.32)
Highly constrained

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

Missense Constraint
2.07Z-score
OE missense 0.59 (0.51–0.69)
119 obs / 201.9 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.00 (0.00–0.32)
0≤0.351.4
Missense OE0.59 (0.51–0.69)
0≤0.61.4
Synonymous OE1.25
0≤1.21.6
LoF obs/exp: 0 / 9.3Missense obs/exp: 119 / 201.9Syn Z: -1.87
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveSIX3-related holoprosencephalyLOFAD
DN
0.3196th %ile
GOF
0.2796th %ile
LOF
0.83top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 48% of P/LP variants are LoF · LOEUF 0.32

Literature Evidence

LOFHaploinsufficiency of SIX3 Abolishes Male Reproductive Behavior Through Disrupted Olfactory Development, and Impairs Female Fertility Through Disrupted GnRH Neuron Migration.PMID:29589282

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

292 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic34
Likely Pathogenic14
VUS142
Likely Benign72
Benign17
Conflicting12
34
Pathogenic
14
Likely Pathogenic
142
VUS
72
Likely Benign
17
Benign
12
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
16
5
13
0
34
Likely Pathogenic
7
6
1
0
14
VUS
1
126
10
5
142
Likely Benign
0
2
5
65
72
Benign
0
2
12
3
17
Conflicting
—12
Total241414173291

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

View in ClinVar →

Protein Context — Lollipop Plot

SIX3 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients