HSPA9

Chr 5ADAR

heat shock protein family A (Hsp70) member 9

Also known as: CRP40, CSA, EVPLS, GRP-75, GRP75, HEL-S-124m, HSPA9B, MOT

NCBI Gene: 3313 ENSG00000113013 UniProt: P38646 OMIM: 600548

The protein functions as a mitochondrial chaperone essential for protein import, folding and assembly, and plays a critical role in iron-sulfur cluster biogenesis and erythropoiesis. Mutations cause sideroblastic anemia 4 and Even-plus syndrome through both autosomal dominant and autosomal recessive inheritance patterns. The pathogenic mechanism involves disruption of mitochondrial protein quality control and iron-sulfur cluster assembly, leading to defective erythropoiesis and cellular dysfunction.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the heat shock protein 70 gene family. The encoded protein is primarily localized to the mitochondria but is also found in the endoplasmic reticulum, plasma membrane and cytoplasmic vesicles. This protein is a heat-shock cognate protein. This protein plays a role in cell proliferation, stress response and maintenance of the mitochondria. A pseudogene of this gene is found on chromosome 2.[provided by RefSeq, May 2010]

OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 0.322 OMIM phenotypes

Clinical Summary— HSPA9

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

6 unique Pathogenic / Likely Pathogenic· 75 VUS of 129 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 →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.32LOEUF

pLI 0.969

Z-score 4.74

OE 0.16 (0.09–0.32)

Highly constrained

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

Missense Constraint?

1.04Z-score

OE missense 0.85 (0.77–0.93)

312 obs / 368.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.16 (0.09–0.32)

0≤0.351.4

Missense OE?0.85 (0.77–0.93)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 6 / 37.2Missense obs/exp: 312 / 368.0Syn Z: -0.27

This gene — mechanism propensity

0.5771th %ile

GOF

0.5071th %ile

LOF

0.60top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOF1 literature citation · 50% of P/LP variants are LoF · LOEUF 0.32

Literature Evidence

LOFChen et al. (2011) concluded that haploinsufficiency for HSPA9 may contribute to abnormal hematopoiesis in myelodysplastic syndromes with deletions spanning chromosome 5q31.2.1

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 21123823 ↗

ClinVar Variant Classifications

129 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic2

VUS75

Likely Benign24

Benign5

Conflicting3

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	2	0	0	4
Likely Pathogenic	1	1	0	0	2
VUS	0	74	1	0	75
Likely Benign	0	3	4	17	24
Benign	1	1	2	1	5
Conflicting	—				3
Total	4	81	7	18	113

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

View in ClinVar →

12 pathogenic / likely-pathogenic (of 19) ClinVar copy-number / structural variants overlap HSPA9 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →