HSPA4

Chr 5

heat shock protein family A (Hsp70) member 4

Also known as: APG-2, HEL-S-5a, HS24/P52, HSPH2, RY, hsp70, hsp70RY

NCBI Gene: 3308ENSG00000170606UniProt: P34932

Predicted to enable adenyl-nucleotide exchange factor activity. Involved in chaperone-mediated protein complex assembly and protein insertion into mitochondrial outer membrane. Located in cytosol and extracellular exosome. Implicated in Chagas disease. Biomarker of chronic obstructive pulmonary disease; rheumatoid arthritis; type 2 diabetes mellitus; and ulcerative colitis. [provided by Alliance of Genome Resources, Apr 2025]

106
ClinVar variants
14
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— HSPA4
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
14 Pathogenic / Likely Pathogenic· 79 VUS of 106 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Some data sources returned errors (1)

pubmed: Error: NCBI fetch failed: 502 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esummary.fcgi

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.
0.24LOEUF
pLI 1.000
Z-score 5.66
OE 0.12 (0.07–0.24)
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.
2.06Z-score
OE missense 0.72 (0.66–0.79)
311 obs / 431.2 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.0.12 (0.07–0.24)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.72 (0.66–0.79)
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.1.05
0≤1.21.6
LoF obs/exp: 6 / 48.5Missense obs/exp: 311 / 431.2Syn Z: -0.49

ClinVar Variant Classifications

106 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13
Likely Pathogenic1
VUS79
Likely Benign6
Benign7
13
Pathogenic
1
Likely Pathogenic
79
VUS
6
Likely Benign
7
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
13
0
13
Likely Pathogenic
0
0
1
0
1
VUS
0
76
3
0
79
Likely Benign
0
3
1
2
6
Benign
0
1
2
4
7
Total080206106

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

View in ClinVar →

Protein Context — Lollipop Plot

HSPA4 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
HSPA4 and SYVN1 positivity in osteoarthritis synovium as indicators of proteostasis dysfunction.
Roebuck MM et al.·Clin Exp Rheumatol
2026
HSPA4 restrains transferrin in dopaminergic neurons to attenuate ferroptosis in a Parkinson's disease model.
Gao T et al.·Commun Biol
2025🔓 Open AccessFunctional
Cerebrospinal fluid HSP90AA1, HSPA4, and STUB1/CHIP levels in Alzheimer's disease, mild cognitive impairment, and frontotemporal dementia.
Sordu P et al.·J Alzheimers Dis
2025
LINC01089 governs the miR-1287-5p/HSPA4 axis to negatively regulate osteogenic differentiation of mesenchymal stem cells.
Zou H et al.·Bone Joint Res
2024🔓 Open Access
HSPA4 Expression is Correlated with Melanoma Cell Proliferation, Prognosis, and Immune Regulation.
Wang X et al.·Clin Cosmet Investig Dermatol
2024🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Healthy Participants

Reality-monitoring & Stress

RECRUITING
NCT05595434Phase NAHôpital le VinatierStarted 2024-04-25
Acute Maastricht Stress Test (MAST), active condition.Acute Maastricht Stress Test (MAST), placebo condition

External Resources

Links to major genomics databases and tools