HSPB1

Chr 7AD

heat shock protein family B (small) member 1

Also known as: CMT2F, HEL-S-102, HMN2B, HMND3, HS.76067, HSP27, HSP28, Hsp25

NCBI Gene: 3315 ENSG00000106211 UniProt: P04792 OMIM: 602195

The protein functions as a molecular chaperone that maintains denatured proteins in a folding-competent state and regulates neurofilament protein phosphorylation and axonal transport. Mutations cause autosomal dominant Charcot-Marie-Tooth disease type 2F and distal hereditary motor neuropathy, affecting peripheral nerves. The gene is highly tolerant to loss-of-function variants (pLI near zero, LOEUF 1.87), suggesting the pathogenic variants likely affect protein function through other mechanisms.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the small heat shock protein (HSP20) family of proteins. In response to environmental stress, the encoded protein translocates from the cytoplasm to the nucleus and functions as a molecular chaperone that promotes the correct folding of other proteins. This protein plays an important role in the differentiation of a wide variety of cell types. Expression of this gene is correlated with poor clinical outcome in multiple human cancers, and the encoded protein may promote cancer cell proliferation and metastasis, while protecting cancer cells from apoptosis. Mutations in this gene have been identified in human patients with Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. [provided by RefSeq, Aug 2017]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 1.872 OMIM phenotypes

Clinical Summary— HSPB1

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Gene-Disease Validity (ClinGen)

Charcot-Marie-Tooth disease axonal type 2F · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

44 unique Pathogenic / Likely Pathogenic· 221 VUS of 427 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — HSPB1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.87LOEUF

pLI 0.000

Z-score -0.63

OE 1.26 (0.74–1.87)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.51Z-score

OE missense 1.13 (0.98–1.30)

136 obs / 120.1 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.26 (0.74–1.87)

0≤0.351.4

Missense OE?1.13 (0.98–1.30)

0≤0.61.4

Synonymous OE?1.46

0≤1.21.6

LoF obs/exp: 9 / 7.2Missense obs/exp: 136 / 120.1Syn Z: -2.68

This gene — mechanism propensity

0.7034th %ile

GOF

0.5562th %ile

LOF

0.4529th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

LOF41% of P/LP variants are LoF

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.

Literature Evidence

DNWe demonstrate that the stable truncated HSPB1 binds wild type HSPB1, suggesting a dominant-negative effect, and strongly impairs the ability of the cells to cope with unfolded protein stress.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 26675522 ↗

ClinVar Variant Classifications

427 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17

Likely Pathogenic27

VUS221

Likely Benign115

Benign9

Conflicting31

Pathogenic

Likely Pathogenic

221

VUS

115

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	5	9	3	0	17
Likely Pathogenic	13	13	1	0	27
VUS	16	183	18	4	221
Likely Benign	0	3	43	69	115
Benign	0	0	8	1	9
Conflicting	—				31
Total	34	208	73	74	420

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

View in ClinVar →

25 pathogenic / likely-pathogenic (of 43) ClinVar copy-number / structural variants overlap HSPB1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →