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

MultiplemechanismADLOEUF 1.143 OMIM phenotypes

Clinical Summary— HSPB8

🧬

Gene-Disease Validity (ClinGen)

neuronopathy, distal hereditary motor, autosomal dominant · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

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

📋

ClinVar Variants

30 unique Pathogenic / Likely Pathogenic· 164 VUS of 297 total submissions

💊

Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

📖

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 OE0.44 (0.20–1.14)

0≤0.351.4

Missense OE0.99 (0.85–1.16)

0≤0.61.4

Synonymous OE1.09

0≤1.21.6

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

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 · 33% 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.PMID:28780615

LOFHSPB8 haploinsufficiency causes dominant adult-onset axial and distal myopathy.PMID:28501893

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