HES2

Chr 1

hes family bHLH transcription factor 2

Also known as: bHLHb40

NCBI Gene: 54626 ENSG00000069812 UniProt: Q9Y543 OMIM: 609970

HES2 encodes a transcriptional repressor that inhibits genes requiring basic helix-loop-helix proteins for transcription and is predicted to regulate neurogenesis. The gene shows low constraint against loss-of-function variants (pLI 0.003, LOEUF 1.72), and no definitive disease associations have been established in the provided data.

OMIM ResearchSummary from RefSeq, UniProt

Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of neurogenesis. Predicted to be located in chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.72

Clinical Summary— HES2

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

27 VUS of 28 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?

1.72LOEUF

pLI 0.003

Z-score 0.33

OE 0.84 (0.41–1.72)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.84Z-score

OE missense 0.70 (0.55–0.90)

43 obs / 61.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.84 (0.41–1.72)

0≤0.351.4

Missense OE?0.70 (0.55–0.90)

0≤0.61.4

Synonymous OE?0.77

0≤1.21.6

LoF obs/exp: 4 / 4.8Missense obs/exp: 43 / 61.5Syn Z: 1.00

This gene — mechanism propensity

0.6938th %ile

GOF

0.5758th %ile

LOF

0.4332th %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

28 submitted variants in ClinVar

ClinVar

Classification Summary

VUS27

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	27	27
Likely Benign	0	0
Benign	0	0
Total	27	27

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

View in ClinVar →

58 pathogenic / likely-pathogenic (of 68) ClinVar copy-number / structural variants overlap HES2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →