BHLHE40
Chr 3basic helix-loop-helix family member e40
Also known as: BHLHB2, Clast5, DEC1, HLHB2, SHARP-2, SHARP2, STRA13, Stra14
This gene encodes a transcriptional repressor that regulates circadian rhythm by negatively controlling clock genes and competing with CLOCK-BMAL1 complexes for E-box binding sites in target gene promoters. The gene is highly constrained against loss-of-function variants (pLI 0.99, LOEUF 0.19), but no specific Mendelian disorders have been definitively associated with BHLHE40 mutations in current medical literature. Given its role in circadian regulation and cardiovascular function, mutations would likely affect sleep-wake cycles and potentially blood pressure regulation, though the inheritance pattern and clinical phenotype remain to be established.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly LoF-intolerant (top ~10% of genes)
Mild missense constraint
The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).
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
155 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 0 | 72 | 0 | 72 |
Likely Pathogenic | 0 | 0 | 4 | 0 | 4 |
VUS | 0 | 53 | 15 | 0 | 68 |
Likely Benign | 0 | 2 | 2 | 1 | 5 |
Benign | 0 | 0 | 0 | 0 | 0 |
Conflicting | — | 1 | |||
| Total | 0 | 55 | 93 | 1 | 150 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
BHLHE40 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools