HES6

Chr 2

hes family bHLH transcription factor 6

Also known as: C-HAIRY1, HES-6, bHLHb41, bHLHc23

NCBI Gene: 55502ENSG00000144485UniProt: Q96HZ4

The protein functions as a transcriptional cofactor that suppresses HES1-mediated repression and promotes cell differentiation by allowing transcription factors like ASCL1 to upregulate gene expression. Mutations cause autosomal recessive intellectual disability with seizures and microcephaly, typically presenting in early childhood. This gene shows tolerance to loss-of-function variants in the general population.

Summary from RefSeq, UniProt
Research Assistant →
0
Active trials
10
Pubs (1 yr)
84
P/LP submissions
0%
P/LP missense
1.38
LOEUF
DN
Mechanism· predicted
Clinical Summary— HES6
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.08) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
82 unique Pathogenic / Likely Pathogenic· 43 VUS of 127 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
1.38LOEUF
pLI 0.084
Z-score 1.07
OE 0.45 (0.18–1.38)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
0.52Z-score
OE missense 0.86 (0.73–1.02)
95 obs / 110.3 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.45 (0.18–1.38)
0≤0.351.4
Missense OE0.86 (0.73–1.02)
0≤0.61.4
Synonymous OE0.72
0≤1.21.6
LoF obs/exp: 2 / 4.4Missense obs/exp: 95 / 110.3Syn Z: 1.60
DN
0.6258th %ile
GOF
0.5465th %ile
LOF
0.3648th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

127 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic80
Likely Pathogenic2
VUS43
80
Pathogenic
2
Likely Pathogenic
43
VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
80
0
80
Likely Pathogenic
0
0
2
0
2
VUS
0
36
7
0
43
Likely Benign
0
0
0
0
0
Benign
0
0
0
0
0
Total036890125

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

View in ClinVar →

Protein Context — Lollipop Plot

HES6 · protein map & ClinVar variants

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

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
Pan-cancer analysis reveals dual roles of HES6 in cancer immunity and prognosis.
Sun Y et al.·Discov Oncol
2025Open Access
HES6knockdown in human hematopoietic precursor cells reduces their in vivo engraftment potential and their capacity to differentiate into erythroid cells, B cells, T cells and plasmacytoid dendritic cells.
De Vos T et al.·Haematologica
2024Open Access
HES6 Mediates Oxidative Phosphorylation Pathway to Promote Immune Infiltration of CD8 + T Cells in Lung Adenocarcinoma.
Chen Z et al.·J Immunother
2024
The novel GATA1-interacting protein HES6 is an essential transcriptional cofactor for human erythropoiesis.
Wang Z et al.·Nucleic Acids Res
2023Open Access
Exploring the effect of Weifuchun capsule on the toll-like receptor pathway mediated HES6 and immune regulation against chronic atrophic gastritis.
Wang B et al.·J Ethnopharmacol
2023
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