HSPD1

Chr 2ARAD

heat shock protein family D (Hsp60) member 1

Also known as: CPN60, GROEL, HLD4, HSP-60, HSP60, HSP65, HuCHA60, SPG13

NCBI Gene: 3329ENSG00000144381UniProt: P10809

This gene encodes a member of the chaperonin family. The encoded mitochondrial protein may function as a signaling molecule in the innate immune system. This protein is essential for the folding and assembly of newly imported proteins in the mitochondria. This gene is adjacent to a related family member and the region between the 2 genes functions as a bidirectional promoter. Several pseudogenes have been associated with this gene. Two transcript variants encoding the same protein have been identified for this gene. Mutations associated with this gene cause autosomal recessive spastic paraplegia 13. [provided by RefSeq, Jun 2010]

Primary Disease Associations & Inheritance

Leukodystrophy, hypomyelinating, 4MIM #612233
AR
Spastic paraplegia 13, autosomal dominantMIM #605280
AD
100
ClinVar variants
10
Pathogenic / LP
0.99
pLI score· haploinsufficient
0
Active trials
Clinical Summary— HSPD1
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
10 Pathogenic / Likely Pathogenic· 48 VUS of 100 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.27LOEUF
pLI 0.993
Z-score 4.11
OE 0.09 (0.03–0.27)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.26Z-score
OE missense 0.64 (0.57–0.72)
195 obs / 306.1 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.09 (0.03–0.27)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.64 (0.57–0.72)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.00
0≤1.21.6
LoF obs/exp: 2 / 23.5Missense obs/exp: 195 / 306.1Syn Z: -0.01

ClinVar Variant Classifications

100 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8
Likely Pathogenic2
VUS48
Likely Benign28
Benign12
Conflicting2
8
Pathogenic
2
Likely Pathogenic
48
VUS
28
Likely Benign
12
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
8
0
8
Likely Pathogenic
0
2
0
0
2
VUS
1
35
9
3
48
Likely Benign
0
1
16
11
28
Benign
0
0
12
0
12
Conflicting
—2
Total1384514100

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

View in ClinVar →

Protein Context — Lollipop Plot

HSPD1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

HSPD1-related leukodystrophy hypomyelinating

strong
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Leukodystrophy, hypomyelinating, 4

MIM #612233

Molecular basis of disorder known

Autosomal recessive

Spastic paraplegia 13, autosomal dominant

MIM #605280

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — HSPD1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Alternative mitochondrial quality control mediated by extracellular release.
Choong CJ et al.·Autophagy
2021
Mitophagy initiates retrograde mitochondrial-nuclear signaling to guide retinal pigment cell heterogeneity.
Datta S et al.·Autophagy
2023
LRRK2 mutations impair depolarization-induced mitophagy through inhibition of mitochondrial accumulation of RAB10.
Wauters F et al.·Autophagy
2020
A recurrent de novo HSPD1 variant is associated with hypomyelinating leukodystrophy.
Cömert C et al.·Cold Spring Harb Mol Case Stud
2020Review
Mitochondrial Protein Homeostasis and Cardiomyopathy.
Wachoski-Dark E et al.·Int J Mol Sci
2022Review
Heterozygous de novo variants in HSPD1 cause hypomyelinating leukodystrophy through impaired HSP60 oligomerisation.
Eskin-Schwartz M et al.·J Med Genet
2024Case report
Autoimmunity to stromal-derived autoantigens in rheumatoid ectopic germinal centers exacerbates arthritis and affects clinical response.
Corsiero E et al.·J Clin Invest
2024
A novel mitochondrial unfolded protein response-related risk signature to predict prognosis, immunotherapy and sorafenib sensitivity in hepatocellular carcinoma.
Zhang S et al.·Apoptosis
2024
Targeting the HSP60/p53 Axis with Extracellular Vesicle-Delivered siRNA Reprograms Glycolysis in Prostate Cancer.
Xu MY et al.·Int J Biol Sci
2026
Sequence variants in SPAST, SPG3A and HSPD1 in hereditary spastic paraplegia.
Svenstrup K et al.·J Neurol Sci
2009
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
LukS-PV targeting C5aR inhibits EMT in hepatocellular carcinoma via the BCL6/HDAC6/HSPD1 axis.
Ding P et al.·Commun Biol
2026🔓 Open Access
LINC00942 accelerates esophageal cancer progression via NAT10/HSPD1.
Wang L et al.·Cell Signal
2026
SIRT5 affects lipid accumulation in cells of a metabolic-associated fatty liver disease model by regulating the succinylation status of HSPD1.
Lu Y et al.·BMC Immunol
2025🔓 Open AccessFunctional
HSPD1 regulates angiotensin II‑induced atrial fibrillation via the PPAR signaling pathway.
Zhou Y et al.·Mol Med Rep
2025🔓 Open Access
Cuproptosis induced by curcumin interfering with proliferation and energy metabolism in colorectal cancer: 3D tumor model and computational simulations reveal curcumin inhibition of HSPD1 and CALCOCO2.
Cao JF et al.·Eur J Pharmacol
2025Functional
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools