HES6

Chr 2

hes family bHLH transcription factor 6

ENSG00000144485 UniProt: Q96HZ4 OMIM: 610331

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.

OMIM ResearchSummary from RefSeq, UniProt

Does not bind DNA itself but suppresses both HES1-mediated N box-dependent transcriptional repression and binding of HES1 to E box sequences. Also suppresses HES1-mediated inhibition of the heterodimer formed by ASCL1/MASH1 and TCF3/E47, allowing ASCL1 and TCF3 to up-regulate transcription in its presence. Promotes cell differentiation (By similarity)

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.38

LOEUF

Mechanism· predicted

Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

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 OE?0.45 (0.18–1.38)

0≤0.351.4

Missense OE?0.86 (0.73–1.02)

0≤0.61.4

Synonymous OE?0.72

0≤1.21.6

LoF obs/exp: 2 / 4.4Missense obs/exp: 95 / 110.3Syn Z: 1.60

Background carrier burden — how many people carry a rare variant somewhere in HES6?

gnomAD v4 · ~730k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 120

626 rare PASS variants

Rare truncating (LoF)

1 in 460

137 rare PASS variants

Rare synonymous (reference)

1 in 790

165 rare PASS variants

Rare missense and truncating variants are carried at similar rates in HES6; this gene does not show strong loss-of-function constraint by this measure. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 170	1 in 730
South Asian	~43k	1 in 79	1 in 930
Remaining (unassigned)	~30k	1 in 120	1 in 340
European (Finnish)	~26k	1 in 460	1 in 2,800
Admixed American	~22k	1 in 91	1 in 360
African / African American	~21k	1 in 110	1 in 390
East Asian	~20k	1 in 190	1 in 790
Ashkenazi Jewish	~13k	1 in 310	none seen
Middle Eastern	~2,884	1 in 120	≈ 1 in 1,200

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 1 of 4 coding exons well covered in gnomAD exomes; exons 1, 2, 3 marginal. Genomes: all 4.? see exons ↓