HSPB8

Chr 12AD

heat shock protein family B (small) member 8

Also known as: CMT2L, DHMN2, E2IG1, H11, HMN2, HMN2A, HMND2, HSP22

NCBI Gene: 26353 ENSG00000152137 UniProt: Q9UJY1 OMIM: 608014

HSPB8 encodes a small heat shock protein that functions as a chaperone in chaperone-assisted selective autophagy (CASA), which is crucial for protein quality control in mechanically strained tissues like muscle. Mutations cause autosomal dominant Charcot-Marie-Tooth disease type 2L, distal hereditary motor neuronopathy type 2, and myofibrillar myopathy type 13 with rimmed vacuoles. The gene is not highly constrained against loss-of-function variants, and these neuromuscular conditions primarily affect the peripheral nervous system and skeletal muscle.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene belongs to the superfamily of small heat-shock proteins containing a conservative alpha-crystallin domain at the C-terminal part of the molecule. The expression of this gene in induced by estrogen in estrogen receptor-positive breast cancer cells, and this protein also functions as a chaperone in association with Bag3, a stimulator of macroautophagy. Thus, this gene appears to be involved in regulation of cell proliferation, apoptosis, and carcinogenesis, and mutations in this gene have been associated with different neuromuscular diseases, including Charcot-Marie-Tooth disease. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 1.143 OMIM phenotypes

Clinical Summary— HSPB8

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Gene-Disease Validity (ClinGen)

neuronopathy, distal hereditary motor, autosomal dominant · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.04) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

17 unique Pathogenic / Likely Pathogenic· 163 VUS of 282 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 →

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GeneReview available — HSPB8

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?

1.14LOEUF

pLI 0.043

Z-score 1.35

OE 0.44 (0.20–1.14)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.03Z-score

OE missense 0.99 (0.85–1.16)

110 obs / 110.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.44 (0.20–1.14)

0≤0.351.4

Missense OE?0.99 (0.85–1.16)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 3 / 6.8Missense obs/exp: 110 / 110.8Syn Z: -0.46

This gene — mechanism propensity

0.74top 25%

GOF

0.6638th %ile

LOF

0.3745th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function, loss-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports gain-of-function. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

LOF1 literature citation · 59% of P/LP variants are LoF

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.

Literature Evidence

GOFA knock-in/knock-out mouse model of HSPB8-associated distal hereditary motor neuropathy and myopathy reveals toxic gain-of-function of mutant Hspb8.1

LOFHSPB8 haploinsufficiency causes dominant adult-onset axial and distal myopathy.2

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

References

ClinVar Variant Classifications

282 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic10

Likely Pathogenic7

VUS163

Likely Benign69

Benign25

Conflicting6

Pathogenic

Likely Pathogenic

163

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	6	4	0	0	10
Likely Pathogenic	4	3	0	0	7
VUS	13	127	22	1	163
Likely Benign	0	4	21	44	69
Benign	0	1	20	4	25
Conflicting	—				6
Total	23	139	63	49	280

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

View in ClinVar →

14 pathogenic / likely-pathogenic (of 15) ClinVar copy-number / structural variants overlap HSPB8 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →