SIX3

Chr 2AD

SIX homeobox 3

Also known as: HPE2

NCBI Gene: 6496 ENSG00000138083 UniProt: O95343 OMIM: 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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the sine oculis homeobox transcription factor family. The encoded protein plays a role in eye development. Mutations in this gene have been associated with holoprosencephaly type 2. [provided by RefSeq, Oct 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.322 OMIM phenotypes

Clinical Summary— SIX3

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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.

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ClinVar Variants

35 unique Pathogenic / Likely Pathogenic· 137 VUS of 267 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SIX3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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 OE?0.00 (0.00–0.32)

0≤0.351.4

Missense OE?0.59 (0.51–0.69)

0≤0.61.4

Synonymous OE?1.25

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

This gene — mechanism propensity

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 · 69% of P/LP variants are LoF · LOEUF 0.32 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFHaploinsufficiency of SIX3 Abolishes Male Reproductive Behavior Through Disrupted Olfactory Development, and Impairs Female Fertility Through Disrupted GnRH Neuron Migration.1

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

References

1.PMID 29589282 ↗

ClinVar Variant Classifications

267 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic22

Likely Pathogenic13

VUS137

Likely Benign72

Benign10

Conflicting12

Pathogenic

Likely Pathogenic

137

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	17	5	0	0	22
Likely Pathogenic	7	6	0	0	13
VUS	1	126	5	5	137
Likely Benign	0	2	5	65	72
Benign	0	2	5	3	10
Conflicting	—				12
Total	25	141	15	73	266

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

View in ClinVar →

14 pathogenic / likely-pathogenic (of 26) ClinVar copy-number / structural variants overlap SIX3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →