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: 3308 ENSG00000170606 UniProt: P34932 OMIM: 601113

Predicted to enable adenyl-nucleotide exchange factor activity. Involved in chaperone-mediated protein complex assembly and protein import into mitochondrial matrix. 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, Jun 2026]

OMIM Research

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.24

LOEUF· LoF intol.

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

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?

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?

LoF OE?0.12 (0.07–0.24)

0≤0.351.4

Missense OE?0.72 (0.66–0.79)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 6 / 48.5Missense obs/exp: 311 / 431.2Syn Z: -0.49

Background carrier burden — how many people carry a rare variant somewhere in HSPA4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 100

912 rare PASS variants

Rare truncating (LoF)

1 in 5,400

61 rare PASS variants

Rare synonymous (reference)

1 in 130

357 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for HSPA4. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 110	1 in 7,000
South Asian	~43k	1 in 120	1 in 3,500
Remaining (unassigned)	~30k	1 in 99	1 in 5,900
European (Finnish)	~27k	1 in 300	≈ 1 in 27,000
Admixed American	~22k	1 in 110	≈ 1 in 6,400
African / African American	~21k	1 in 68	1 in 3,300
East Asian	~20k	1 in 120	1 in 790
Ashkenazi Jewish	~13k	1 in 250	1 in 2,200
Middle Eastern	~2,884	1 in 76	≈ 1 in 2,800

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 13 of 19 coding exons well covered in gnomAD exomes; exons 5, 6, 10, 13, 16, 17 marginal. Genomes: all 19.? see exons ↓