HSF1

Chr 8

heat shock transcription factor 1

Also known as: HSTF1

NCBI Gene: 3297 ENSG00000185122 UniProt: Q00613 OMIM: 140580

This transcription factor regulates the heat shock response by binding to heat shock elements and activating expression of molecular chaperones and heat shock proteins that protect cells from stress damage. Mutations cause autosomal dominant neurodevelopmental disorder with seizures, hypotonia, and developmental delay, with onset typically in infancy or early childhood. HSF1 is highly constrained against loss-of-function variants, suggesting an essential role in human development.

OMIM ResearchSummary from RefSeq, UniProt

The product of this gene is a transcription factor that is rapidly induced after temperature stress and binds heat shock promoter elements (HSE). This protein plays a role in the regulation of lifespan. Expression of this gene is repressed by phosphorylation, which promotes binding by heat shock protein 90. [provided by RefSeq, Jul 2017]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.41

Clinical Summary— HSF1

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.75) — some intolerance to loss-of-function variants.

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ClinVar Variants

67 VUS of 97 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.41LOEUF

pLI 0.748

Z-score 3.57

OE 0.18 (0.09–0.41)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.75Z-score

OE missense 0.88 (0.80–0.97)

293 obs / 331.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.18 (0.09–0.41)

0≤0.351.4

Missense OE?0.88 (0.80–0.97)

0≤0.61.4

Synonymous OE?1.21

0≤1.21.6

LoF obs/exp: 4 / 22.1Missense obs/exp: 293 / 331.6Syn Z: -2.04

This gene — mechanism propensity

0.5081th %ile

GOF

0.3689th %ile

LOF

0.67top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.41

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

97 submitted variants in ClinVar

ClinVar

Classification Summary

VUS67

Likely Benign6

Benign2

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	67	0	67
Likely Benign	3	3	6
Benign	0	2	2
Total	70	5	75

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

View in ClinVar →

57 pathogenic / likely-pathogenic (of 71) ClinVar copy-number / structural variants overlap HSF1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →